TW202416979A - Methods and compositions for treating acute stress disorder - Google Patents

Abstract

The present disclosure relates to the treatment of disorders associated with noradrenergic hyperarousal in a human subject. The present disclosure also provides a method of treating acute stress disorder (ASD) comprising administering a therapeutically effective amount of latrepirdine or dexmedetomidine or pharmaceutically acceptable salts thereof. The present disclosure also provides a method of treating autism spectrum disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrepirdine or dexmedetomidine alone or a combination thereof. The present disclosure provides oromucosal dosage forms comprising effective amounts of latrepirdine either alone or in combination with dexmedetomidine or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers and/excipients. Methods of their use are also provided. The present disclosure also provides a method of treating depression by administering oromucosally a therapeutically effective amount of dexmedetomidine alone or in combination with latrepirdine.

Description

Methods and compositions for treating acute stress

The present disclosure also relates to treating agitation in a subject in need thereof by administering an oromucosal dosage form comprising an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, alone or in combination with an effective amount of dexmedetomidine, and one or more pharmaceutically acceptable carriers and/or formulations. The present disclosure also provides a method of treating depression in a subject in need thereof, comprising oromucosally administering an effective amount of dexmedetomidine, alone or in combination with latrepirdine, for treating agitation.

Norepinephrine hyperarousal is a subclinical state in which there is excessive norepinephrine agonist signaling, resulting in hemodynamic and motor changes. Excessive norepinephrine agonist signaling is dependent on norepinephrine and can further lead to increased sympathetic tone and other stress-related psychiatric symptoms.

Acute stress disorder (ASD) is a mental health disorder that results from experiencing a traumatic event. According to DSM IV (Disease Category: Anxiety Disorders) and DSM 5 (Disease Category: Trauma- and Stress-Related Disorders), symptoms of ASD may include: a) increased anxiety; b) difficulty sleeping; c) excessive startle reactions; d) lack of motivation; e) irritability; and f) inability to stop moving or sitting still. Symptoms of ASD usually begin no less than 3 days after the traumatic event and no more than 4 weeks afterward. ASD may also be a precursor to the development of post-traumatic stress disorder (PTSD). ASD symptoms such as anxiety, irritability, and inability to stop moving are related to stress-mediated sympathetic overexcitation and should therefore be treatable with medications appropriate for treating agitation. Similarly, another symptom of ASD is lack of motivation or helplessness.

Therefore, there is a need to develop pharmacological treatments that have efficacy in both depression and agitation to effectively treat ASD. Although many existing pharmacological treatments such as selective serotonin reuptake inhibitors, tricyclic antidepressants or monoamine oxidase inhibitors are available and have demonstrated unclear response rates, these treatments require multiple doses or cause side effects such as memory impairment for traumatic events. Therefore, there is a major need to develop strategies that provide adequate solutions for patients with ASD.

Autism is a neurological and developmental disorder that affects how a person interacts with others, communicates, learns, and behaves. Although autism can be diagnosed at any age, it is called a "developmental disorder" because symptoms generally appear in the first 2 years of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) , a guide created by the American Psychiatric Association and used by health care providers to diagnose mental illnesses, people with autism often have difficulty communicating and interacting with others and have limited interests and repetitive behaviors that interfere with their ability to function in school, work, and other areas of life. Autism is referred to as a “pan” autistic disorder because the types and severity of symptoms experienced by people vary greatly. Currently, there are few treatment options for children and adults with autism, so more effective therapies are needed to treat people with autism.

ASD pathology is not well understood, but may be related to a genetic disorder that causes changes in the neural circuitry of newborns. Children with ASD have difficulty establishing and maintaining social relationships. For this reason, children with ASD often suffer from panic attacks and exhibit aggressive behavior. Children with ASD often experience overexcitation or increased norepinephrine excitatory signaling, which may cause panic and aggressive behavior (Patriquin MA, Hartwig EM, Friedman BH, Porges SW, Scarpa A. Autonomic response in autism spectrum disorder: Relationship to social and cognitive functioning. Biol Psychol. 2019 Jul;145:185-197).

Agitation is a complex biological phenomenon that represents a loss of behavioral control. No single drug is effective for all types of agitation. Many neural pathways and associated receptors mediate various aspects of agitation. These pathways include the amygdala, frontal cortex, nucleus acumbens, and locus coeruleus. Drugs that treat agitation in these brain regions and associated drug targets include antipsychotics and dopamine D2 receptors, benzodiazepines and GABA receptors, ketamine and glutamine receptors, and serotonin uptake inhibitors (Miller CW, Hodzic V, Weintraub E. Current Understanding of the Neurobiology of Agitation. Western Journal of Emergency Medicine. 2020 Jul;21(4):841). Depression is a mood disorder that causes persistent feelings of sadness and loss of interest that result from a complex interaction of social, psychological, and biological factors. During a depressive episode, an individual experiences depressed mood (e.g., feeling sad, irritable, or empty) or loss of pleasure or interest in activities that lasts for most of the day, nearly every day, for at least two weeks. Depressive episodes can be classified as mild, moderate, or severe, depending on the number and severity of symptoms and the effect on the individual's functioning. There is a large scientific and medical effort to develop drugs that target specific pathways and, therefore, treat specific aspects of depression.

Trauma induces changes in brain neurochemistry that initially cause ASD and eventually become PTSD. Fear memories intensify within 12 to 24 hours after experiencing a traumatic event. During this event, new connections are made between brain neurons associated with the traumatic memory and emotional responses.

Without being bound by theory, it is believed that the composition may be more effective when administered shortly after the traumatic event than when administered later. For example, the composition may be administered within about 30 minutes, 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 1 day, or about 2 days. In an embodiment, the composition is administered within about 1 hour to 1 day after the trauma. Long-term treatment is generally not required. Typically, one or more administrations may be given daily for a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, or up to 6 weeks.

The present disclosure provides an oromucosal dosage form comprising an effective amount of latromidine or a pharmaceutically acceptable salt thereof, alone or in combination with dexmedetomidine, and one or more pharmaceutically acceptable carriers and/or formulations. In an embodiment, the present disclosure provides a method of treating a stress-mediated neuropsychiatric disorder, such as ASD mediated by norepinephrine hyperstimulation, in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of dexmedetomidine, an α2 adrenergic receptor agonist; wherein the therapeutic intervention has a remedial effect on the stress-mediated neuropsychiatric disorder, such as ASD mediated by norepinephrine hyperstimulation.

The present disclosure provides methods for treating a disorder associated with norepinephrine-mediated hyperexcitation in a human subject, comprising administering to the human subject a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods for treating a disorder associated with norepinephrine-mediated hyperexcitation in a human subject, comprising orally administering to the human subject a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. The present disclosure provides methods for treating a disorder associated with norepinephrine-mediated hyperarousal in a human subject, comprising administering to the human subject via the oral mucosa a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

The present disclosure provides methods for treating acute stress disorder (ASD) in a subject in need thereof, comprising administering a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods for treating ASD in a subject in need thereof, comprising administering a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latrapyridine.

The present disclosure provides a method for preventing PTSD in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. The present disclosure further relates to a method for treating pan-autistic disorder in an individual in need thereof, comprising administering a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. The present disclosure further relates to a method for treating pan-autistic disorder in an individual in need thereof, comprising administering a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latrapyridine.

In embodiments, the disorder is acute stress.

In an embodiment, the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of anxiety, sleep disturbance, excessive startle reaction, irritability, inability to stop moving or sitting still, lack of motivation, and agitation.

In embodiments, the symptom is anxiety.

In embodiments, the symptom is sleep disturbance.

In embodiments, the symptom is an exaggerated fright reaction.

In embodiments, the symptom is irritability.

In embodiments, the symptom is an inability to stop moving or sitting still.

In embodiments, the symptom is lack of motivation. In embodiments, the symptom is agitation.

In an embodiment, the human individual suffers from a condition called pan-autistic disorder.

In embodiments, the method prevents the condition from developing into post-traumatic stress disorder. In embodiments, the condition is caused by a traumatic event experienced by a human individual.

In embodiments, latromidine is administered within 1 week, 2 weeks, or 4 weeks of the traumatic event.

In embodiments, latropyridine is administered within 3 days of the traumatic event. In embodiments, latropyridine is administered within 1 day of the traumatic event. In embodiments, latropyridine is administered within 4 hours of the traumatic event. In embodiments, latropyridine is administered within 6 hours of the traumatic event. In embodiments, latropyridine is administered within 12 hours of the traumatic event. In embodiments, latropyridine is administered once a day, twice a day, or three times a day.

In an embodiment, the present disclosure provides a method for treating a stress-mediated neuropsychiatric disorder mediated by norepinephrine induced hyperarousal in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating a stress-mediated neuropsychiatric disorder mediated by norepinephrine induced hyperarousal in a human subject in need thereof, the method comprising: orally administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In embodiments, the therapeutically effective amount of latromidine is in the range of about 5 mg to about 300 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 10 mg to about 200 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 10 mg to about 100 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 10 mg to about 80 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 15 mg to about 60 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 30 mg to about 45 mg per day.

In an embodiment, the therapeutically effective amount of latromidine is evenly distributed to be administered twice daily or three times daily.

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or intermittently.

In embodiments, the disclosure provides preclinical animal models established to correlate norepinephrine agonist signaling with psychiatric disorders such as acute stress, PTSD, depression, substance withdrawal, substance cravings, agitation, panic disorder, and anxiety.

In embodiments, preclinical animal models include a resident intruder assay, a forced swim test, a yohimbine-induced anxiety model, and a CCK-induced panic model.

In embodiments, preclinical animal models unexpectedly demonstrate that latrazopyridine unexpectedly reduces the severity of symptoms in stress-related psychiatric disorders including acute stress disorder, PTSD, depression, substance withdrawal, substance cravings, agitation, panic disorder, and anxiety.

In embodiments, the preclinical model relates norepinephrine agonist signaling to ADHD.

In embodiments, the methods of the present disclosure reduce the extent of symptoms experienced by patients and improve their clinical outcomes by enhancing compliance with basic therapeutic treatments, including adherence to medication regimens and participation in therapy.

In embodiments, improved clinical outcomes may result from patients with reduced symptoms interacting more effectively in social contexts, reducing aggression and panic symptoms that may result from a lack of social interaction, as seen in disorders such as autism.

In embodiments, the present disclosure provides effective symptom management to prevent disease progression, such as when acute stress disorder progresses to PTSD.

In embodiments, the present disclosure provides for the use of latrapyridine to treat and prevent the progression of symptoms such as acute stress and pan-autistic disorder over time.

In an embodiment, the present disclosure provides a method for treating norepinephrine-mediated hyperexcitation in an individual, comprising administering to the individual via the oral mucosa a dosage form comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof and (ii)  a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride).

In embodiments, oral mucosal administration includes sublingual, buccal, or gingival administration.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject as a single therapy a dosage formulation comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising orally administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof as a single treatment.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising orally administering to the subject a dosage form comprising about 10 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating ASD in a subject in need thereof, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg of latrepyridine or a pharmaceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 20 mg to about 40 mg of latrepyridine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating exacerbation of ASD following a traumatic event in a subject, comprising administering to the subject about 10 mg to about 100 mg of latrapyridine or a pharmaceutically acceptable salt thereof for a period of about 2 to about 4 weeks.

In an embodiment, the present disclosure provides a method of treating exacerbation of ASD following a traumatic event in a subject, comprising administering to the subject about 20 mg to about 40 mg of latrazopyridine or a pharmaceutically acceptable salt thereof for a period of about 2 to about 4 weeks.

In one embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets.

In an embodiment, the present disclosure provides a method of increasing protection against the development of PTSD following a traumatic event in a subject, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, a total daily dose of about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 40 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 60 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, the target plasma concentration of latrepyridine is about 1 to 5 ng/ml.

In embodiments, a dosage form comprising latrapyridine or a pharmaceutically acceptable salt thereof is administered immediately following the traumatic event. In embodiments, a dosage form comprising latrapyridine or a pharmaceutically acceptable salt thereof is administered between 1 minute and 48 hours (including all ranges and values in between) after the traumatic event. In embodiments, a dosage form comprising latrapyridine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the traumatic event. In embodiments, a dosage form comprising latrapyridine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event. In embodiments, a dosage form comprising latrapyridine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In embodiments, the traumatic event is directly and personally experienced by the individual. In embodiments, the traumatic event is witnessed by the individual. In embodiments, the dosage form comprising latromidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple units.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage formulation comprising about 10 mg to about 100 mg of latrazopyridine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event and continuing for a period of about 2 to about 4 weeks of the traumatic event.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage formulation comprising about 10 mg to about 100 mg of latrapyridine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event and up to 4 weeks of the traumatic event.

In an embodiment, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a dosage formulation comprising about 10 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered orally.

In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered sublingually. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered buccally. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried).

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered via the oral mucosa (sublingually or via the buccal or gingival) in the form of a wafer capsule, patch or film.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately following the traumatic event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered between 1 minute and 48 hours (including all ranges and values in between) after the traumatic event. In embodiments, a dosage form comprising latromidine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the event. In embodiments, a dosage form comprising latromidine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In an embodiment, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single unit or multiple units.

In embodiments, about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 micrograms, about 30 micrograms, about 40 micrograms, about 60 micrograms, about 80 micrograms, about 120 micrograms, about 150 micrograms, about 180 micrograms, or more. In embodiments, about 60 micrograms to about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, the target plasma concentration of dexmedetomidine is about 50 to 200 pg/ml.

In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered one or more times a day (e.g., once a day, twice a day, three times a day, or four times, five times, or six times a day), preferably once, twice, or three times a day.

In an embodiment, the present disclosure provides a method of treating ASD in an individual in need thereof, comprising administering to the individual oral mucosal (e.g., sublingually, intrabuccally, or intragingivally) a dosage form comprising about 20 μg to about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event to up to 4 weeks of the traumatic event.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject intraorally (e.g., sublingually, intrabuccally, or intragingivally) a dosage form comprising about 60 μg to about 80 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event to up to 4 weeks of the traumatic event.

In an embodiment, the present disclosure provides a method of treating ASD in an individual in need thereof, comprising administering to the individual oral mucosal (e.g., sublingually, intrabuccally, or intragingivally) a dosage form comprising about 20 μg to about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event to up to 4 weeks of the traumatic event.

In an embodiment, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a dosage form comprising 20 μg to about 180 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa (e.g., sublingually, buccally, or intragingivally).

In an embodiment, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a dosage form comprising 60 μg to about 80 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa (e.g., sublingually, buccally, or intragingivally).

In an embodiment, the present disclosure provides a method of increasing protection against the development of PTSD following a traumatic event in a subject, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In embodiments, the individual is experiencing aggressive, reckless or self-destructive behavior, sleep disturbances, hypervigilance, or related problems for more than one month.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or transgingivally in the form of a wafer, patch or film.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latrapyridine and dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, the present disclosure provides a therapeutically effective amount of about 20 mg to 40 mg of latrapyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of about 60 micrograms to about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine and dexmedetomidine or a pharmaceutically acceptable salt thereof.

In embodiments, the dosage form is administered immediately prior to an anticipated event that may lead to the development of PTSD. In embodiments, the dosage form is administered continuously during the PTSD-inducing event and/or for a period of time after the PTSD-inducing event.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating pan-autistic disorder in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in an individual, comprising administering to the individual a dosage form comprising about 10 mg to about 60 mg of latrapyridine or a pharmaceutically acceptable salt thereof, such as about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg, including all ranges and values therebetween.

In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In embodiments, a total daily dose of about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 40 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 60 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latropyridine.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latropyridine.

In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of tablets. In an embodiment, the tablets are lyophilized (or freeze-dried).

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered via the oral mucosa (sublingually or via the buccal or gingival) in the form of a wafer capsule, patch or film.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually/buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or transgingivally in the form of a wafer, patch or film.

In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple unit dose form.

In embodiments, latrolpyridine or a pharmaceutically acceptable salt thereof is administered in single or multiple unit dose forms.

In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered one or more times a day (e.g., once a day, twice a day, three times a day, or four times, five times, or six times a day), preferably once, twice, or three times a day.

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered one or more times a day (e.g., once a day, twice a day, three times a day, or four times, five times, or six times a day), preferably once, twice, or three times a day.

In embodiments, dexmedetomidine and latrepyridine are provided in two separate dosage forms for treating pan-autistic disorder in a subject, one dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other dosage form comprising a therapeutically effective amount of latrepyridine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepyridine or a pharmaceutically acceptable salt thereof are administered concurrently to a subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepyridine or a pharmaceutically acceptable salt thereof are administered sequentially to a subject in need thereof.

In an embodiment, dexmedetomidine and latromidine are provided in a single dosage form for treating pan-autistic disorder, wherein the dosage form comprises a therapeutically effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, the combination comprising latropyridine and dexmedetomidine or pharmaceutically acceptable salts thereof is administered for at least 7 days, at least 10 days, at least 30 days, at least 60 days, at least 180 days, at least 365 days, or longer.

In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale (CARS). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale 2-Standard Form (CARS2-ST). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale 2-High Functioning (CARS2-HF). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Aberrant Behavior Checklist (ABC). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Social Responsiveness Scale (SRS). In an embodiment, the severity of autism symptoms is assessed by the Vineland Adaptive Behavior Scale II (VABS-II).

In an embodiment, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale (CARS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on a Social Responsiveness Scale (SRS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on a social responsiveness scale (SRS) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on a Social Responsiveness Scale (SRS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, treatment results in a score reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the score before treatment, wherein the severity of pan-autistic symptoms is assessed based on the CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II scales. In embodiments, the score reduction is achieved after at least 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, or more of treatment.

In embodiments, treatment inhibits the progression of, or reduces the severity of, one or more symptoms of autism. In embodiments, treatment inhibits the progression of, or reduces the severity of, one or more symptoms of Asperger's. In embodiments, treatment inhibits the progression of, or reduces the severity of, one or more symptoms of childhood disintegrative disorder. In embodiments, treatment inhibits the progression of, or reduces the severity of, one or more symptoms of Rett's. In embodiments, treatment inhibits the progression of, or reduces the severity of, one or more symptoms of pervasive developmental disorder not otherwise specified (PDD-NOS).

The present disclosure provides methods for treating agitation in a subject, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods for treating agitation in an agitated individual, comprising administering to the individual a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods for treating acute agitation in an agitated individual, comprising administering to the individual a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods for treating acute agitation in an agitated individual, comprising administering to the individual a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. The present disclosure also provides methods for treating or preventing chronic agitation in an individual, comprising administering to the individual a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method for treating or preventing chronic agitation in an agitated individual, comprising administering to the individual a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a method for treating agitation in an agitated individual, the method comprising administering to the individual a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. In embodiments, agitation is caused by norepinephrine-induced overexcitation. In embodiments, the agitated individual also exhibits aggression. In embodiments, agitation is treated without causing significant sedation. The present disclosure also provides a method for treating acute agitation in an agitated individual, the method comprising administering to the individual a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating chronic agitation in a subject, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa (e.g., sublingually, buccally, or gingivally) a dosage form comprising a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa (e.g., sublingually, buccally, or gingivally) a dosage form comprising about 1 mg to about 100 mg of latrapyridine or a pharmaceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa (e.g., sublingually, buccally, or gingivally) a dosage form comprising about 10 mg to about 60 mg of latrepyridine or a pharmaceutically acceptable salt thereof, such as about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg mg or approximately 60 mg, including all ranges and values therebetween.

In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In embodiments, a total daily dose of about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 40 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 60 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, the present disclosure provides a method for treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa a dosage form comprising: (i) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual about 1 mg to about 500 mg of latrapyridine or a pharmaceutically acceptable salt thereof and about 5 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual oromucosally about 1 mg to about 100 mg of latrapyridine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa about 5 mg to about 100 mg of latrapyridine or a pharmaceutically acceptable salt thereof and about 20 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa about 5 mg to about 60 mg of latrapyridine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In one embodiment, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof,

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In one embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In one embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

In embodiments, the present disclosure provides a method of treatment comprising administering dexmedetomidine or a pharmaceutically acceptable salt to a subject in an oromucosal dosage form that provides rapid relief of agitation and then continuing treatment with latrapyridine or a pharmaceutically acceptable salt for an effective period of time. In embodiments, latrapyridine and dexmedetomidine or a pharmaceutically acceptable salt thereof are administered sublingually. In embodiments, latrapyridine and dexmedetomidine or a pharmaceutically acceptable salt thereof are administered buccally. In embodiments, latrapyridine and dexmedetomidine or a pharmaceutically acceptable salt thereof are administered sublingually or buccally in the form of tablets. In embodiments, the tablets are lyophilized. In an embodiment, latrolpyridine and dexmedetomidine or their pharmaceutically acceptable salts are administered sublingually or buccally or transgingivally in the form of a wafer. In an embodiment, latrolpyridine and dexmedetomidine or their pharmaceutically acceptable salts are administered sublingually or buccally or transgingivally in the form of a patch. In an embodiment, latrolpyridine and dexmedetomidine or their pharmaceutically acceptable salts are administered sublingually or buccally or transgingivally in the form of a film.

In an embodiment, the present disclosure provides a synergistic combination comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, and (ii)  a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for treating agitation in an individual in need thereof.

In embodiments, agitation is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy and other related neurodegenerative disorders. In embodiments, agitation is associated with Alzheimer's disease or the sunset syndrome in dementia. In embodiments, agitation is chronic and associated with dementia.

In embodiments, agitation is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, mania, bipolar mania, delirium, and depression. In embodiments, agitation is associated with alcohol and substance abuse withdrawal including opioid withdrawal. In embodiments, agitation is associated with an OPD/IPD procedure (e.g., MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedure).

In embodiments, agitation is caused by norepinephrine induced hyperexcitation.

In embodiments, agitation is treated without causing significant sedation.

In embodiments, agitation is a result of administration of an alpha-2 adrenergic receptor antagonist such as yohimbine. In embodiments, agitation is caused by administration of cocaine. In embodiments, agitation is caused by administration of lurasidone. In embodiments, agitation is caused by administration of mirtazapine. In embodiments, agitation is caused by administration of esmirtazapine. In embodiments, agitation is caused by administration of atipamezole. In embodiments, agitation is caused by administration of trazodone. In an embodiment, the present disclosure provides a method of treating agitation in a subject in need thereof, comprising oromucosally administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by the administration of yohimbine.

In embodiments, agitation may be acute or chronic. In embodiments, agitation may be severe or mild. In embodiments, agitation may be acute or chronic. In embodiments, agitation may be severe or mild.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, comprising administering to the subject via the oral mucosa a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

The present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject via the oral mucosa.

The present disclosure provides a method for treating depression in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. The present disclosure provides a method for treating depression in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof via the oral mucosa.

In embodiments, the present disclosure provides a method of treating depression in a subject in need thereof, the method comprising administering to the subject oromucosally from about 1 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof and from about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, an improvement in depressive symptoms is observed as measured by the HAM-D-17 depression subscale. In embodiments, the subject has a HAM-D-17 total score of ≥18 at the start of treatment.

In an embodiment, the present disclosure provides a method for reducing the score of a human subject suffering from depression on the HDRS scale, which comprises administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof through the oral mucosa. In an embodiment, the present disclosure provides a method for reducing the score of a human subject suffering from depression on the HDRS scale, which comprises administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa.

In an embodiment, the present disclosure provides a method for reducing the score of a human subject suffering from depression on the HDRS scale, comprising oromucosal administration of an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, the present disclosure provides a method for reducing the score of a human subject suffering from depression on the MADRS scale, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof through the oral mucosa. In embodiments, the present disclosure provides a method for reducing the score of a human subject suffering from depression on the MADRS scale, comprising administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof through the oral mucosa. In embodiments, the present disclosure provides a method for reducing the score of a human subject suffering from depression on the MADRS scale, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof through the oral mucosa.

In an embodiment, the depression is moderate or severe. In an embodiment, the depression is severe depression, bipolar disorder or mixed depression.

In an embodiment, the combination comprising latropyridine and dexmedetomidine or a salt thereof is administered once a day, twice a day, three times a day, or four, five, or six times a day, preferably once, twice, or three times a day.

In embodiments, the combination comprising latropyridine and dexmedetomidine or a salt thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

In an embodiment, the present disclosure provides a synergistic combination comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, and (ii)  a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for treating depression in a subject in need thereof.

In an embodiment, the present disclosure provides a method of treating a psychotic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating a psychotic disorder in a subject in need thereof, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating a psychotic disorder in a subject in need thereof, the method comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrazol or a pharmaceutically acceptable salt thereof.

In embodiments, treatment is effective without causing significant sedation.

In embodiments, treatment is effective without experiencing clinically significant cardiovascular effects. In embodiments, the severity of the individual's psychosis is assessed using the PANSS scale.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a sustained period of psychosis in a subject, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a sustained period of psychosis in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof to the subject.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a sustained period of psychosis in a subject, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrazolidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a sustained period of psychosis in an individual, comprising oromucosal administration to the individual of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, the PANSS score is reduced by at least about 20% to about 50% relative to the baseline score. In embodiments, the PANSS score is reduced by about 25% relative to the baseline score. In embodiments, the total PANSS score is reduced by about 30% relative to the baseline score. In embodiments, the total PANSS score is reduced by about 35% points relative to the baseline score. In embodiments, the total PANSS score is reduced by about 40% points relative to the baseline score. In embodiments, the total PANSS score is reduced by about 45% points relative to the baseline score. In embodiments, the total PANSS score is reduced by about 50% points relative to the baseline score.

In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the individual is agitated. In embodiments, the individual is not agitated.

In embodiments, the psychotic disorder is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia and mania or another related neuropsychiatric disorder. In embodiments, the psychotic disorder is associated with a neurodegenerative disorder.

In embodiments, the mental illness is associated with a condition such as a substance abuse disorder (e.g., alcohol, opioid and other substance withdrawal).

In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is a single episode. In embodiments, the psychosis is recurrent or includes recurrent episodes. In embodiments, the acute psychosis is associated with acute psychotic episodes and/or mixed episodes.

In embodiments, the dosage form disintegrates within about 1 second to about 10 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates within more than 1 minute after contact with the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 2 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 5 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa. In embodiments, the dosage form disintegrates in less than 60 seconds.

In an embodiment, the dosage form is an oral mucosal dosage form comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)  one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In an embodiment, the dosage form is an oral mucosal dosage form, which comprises: (i)      a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii)     one or more mucoadhesive agents; and (iii)    one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In an embodiment, the dosage form is an oral mucosal dosage form, which comprises: (i)    a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)   a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii)  one or more mucosal adhesives; and (iv)  one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In embodiments, the oral mucosal dosage form is a tablet, capsule, patch, film, sachet, rice paper capsule, powder, microtablet, pill, paste, gel, ointment, cream, drop, liquid (e.g., solution, suspension or emulsion), spray, microsphere or nanosphere, which can be formulated according to standard methods in the art.

In an embodiment, the dosage form is an oromucosal tablet for sublingual or buccal or gingival administration. In an embodiment, the dosage form is lyophilized (or freeze-dried).

In an embodiment, the dosage form is a lyophilized sublingual or buccal or gingival tablet, which comprises: (i)        a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)       sodium alginate; (iii)      sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv)      sucralose; (v)       magnesium stearate and/or silicon dioxide; (vi)      lactose or mannitol; and (vii)         other pharmaceutically acceptable excipients as appropriate; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In an embodiment, the dosage form is a lyophilized sublingual or buccal or gingival tablet, which comprises: (i)      a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii)     carbomer; (iii)    sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv)    sucralose; (v)     magnesium stearate and/or silicon dioxide; (vi)    lactose or mannitol; and (vii)    other pharmaceutically acceptable excipients as appropriate; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In an embodiment, the dosage form is a lyophilized sublingual or buccal or gingival tablet, which comprises: (i)      a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)     xanthan gum; (iii)    sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv)    sucralose; (v)     magnesium stearate and/or silicon dioxide; (vi)    lactose or mannitol; and (vii)    other pharmaceutically acceptable excipients as appropriate; wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In an embodiment, the dosage form is a lyophilized sublingual, buccal or intragingival tablet, which comprises: (i)      a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)     a therapeutically effective amount of dexmedetomidine or a salt thereof; (iii)    sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyethylene oxide; (iv)    sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (v)     sucralose; (vi)    magnesium stearate and/or silicon dioxide; (vii)   lactose or mannitol; and (viii) Other pharmaceutically acceptable dosage forms as appropriate; Wherein the dosage form disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In embodiments, dexmedetomidine and latrepyridine are provided in a single dosage form as an oromucosal tablet for treating agitation, the oromucosal tablet comprising a therapeutically effective amount of dexmedetomidine and latrepyridine or a pharmaceutically acceptable salt thereof. In embodiments, agitation is caused by norepinephrine-induced hyperexcitation. In embodiments, agitation is treated without additionally causing significant sedation.

In an embodiment, dexmedetomidine and latromidine are provided in a single dosage form as an oromucosal tablet for treating depression, wherein the oromucosal tablet comprises a therapeutically effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, dexmedetomidine and latrepyridine are provided as an oromucosal tablet for treating agitation in two separate dosage forms, one dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other dosage form comprising a therapeutically effective amount of latrepyridine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepyridine are administered concurrently to a subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepyridine are administered sequentially to a subject in need thereof. In embodiments, agitation is caused by norepinephrine induced hyperexcitation. In embodiments, agitation is treated without additionally causing significant sedation.

In embodiments, dexmedetomidine and latrepyridine are provided as two separate dosage forms as an oromucosal tablet for treating depression in a subject, one dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other dosage form comprising a therapeutically effective amount of latrepyridine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepyridine are administered concurrently to a subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepyridine are administered sequentially to a subject in need thereof.

In an embodiment, the active agents dexmedetomidine and latrazolidine or a pharmaceutically acceptable salt thereof are administered concurrently (e.g., in a single dosage form or in two separate dosage forms) to a subject for a specific period of time (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days In some embodiments, dexmedetomidine or a salt thereof is administered at least 1 hour before administration of latropyridine, so that symptoms are relieved as early as possible. In some embodiments, dexmedetomidine is administered at least 0.5 hours before administration of latropyridine, so that symptoms are relieved as early as possible. In an embodiment, dexmedetomidine is administered at least 0.25 hours prior to administration of latrepyridine, so that symptoms are relieved as early as possible. In an embodiment, dexmedetomidine is administered simultaneously with latrepyridine, so that symptoms are relieved as early as possible.

In an embodiment, the active agents dexmedetomidine and latrepiridine or a pharmaceutically acceptable salt thereof are administered to a subject intermittently (e.g., in a single dosage form or in two separate dosage forms) for a specific period of time (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 month, 2 months, 3 months, etc.), followed by a rest period (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 month, 2 months, 3 months, etc.). The dosage period may be about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, etc.) and followed by a dosing period (e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 1 month, 2 months, 3 months, etc.).

In an embodiment, the active agent is administered sequentially at appropriate intervals, such as about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes. , about 60 minutes (1 hour), about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours, including all ranges and values therebetween. In an embodiment, the active agents are administered simultaneously at the same time or in a short period of time, usually less than about 60 minutes (i.e., about 1 hour), preferably about 45 minutes, and more preferably about 15 minutes. In an embodiment, the active agents are administered simultaneously at the same time or within a short period of time, generally less than about 60 minutes (ie, about 1 hour), preferably about 45 minutes, more preferably about 15 minutes.

In an embodiment, the present disclosure provides a single unit oral mucosal lyophilized tablet dosage form provided in a kit, comprising: (i)      a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii)      a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; and (iii)    instructions for administering (i) and (ii) to a subject in need thereof.

In an embodiment, the present disclosure provides a dual unit dosage form provided in a kit, comprising: (i)    a first oromucosal lyophilized tablet dosage form comprising a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii)   a second oromucosal lyophilized tablet dosage form comprising a therapeutic amount of latromidine or a pharmaceutically acceptable salt thereof; and (iii) instructions for administering (i) and (ii) simultaneously, sequentially, or separately to a subject in need thereof.

Cross-references to related applications

This application claims priority to and the benefit of U.S. Provisional Application No. 63/402,855, filed on August 31, 2022, the contents of which are incorporated herein in their entirety as if set forth herein. Incorporated by Reference

The contents of PCT/US2022/017963, filed on February 25, 2022, and PCT/US2019/039268, filed on June 26, 2019, are incorporated herein in their entirety as if set forth herein.

Yohimbine is an alpha-2 adrenaline antagonist and can be used to test norepinephrine agonist-mediated hyperexcitation pathways. As described herein, yohimbine was used to induce sympathetic nerve hyperexcitation in rodents, and three different classes of drugs were tested to determine their ability to reduce hyperexcitation. Surprisingly, only latrapyridine (Dimebon), a drug with complex pharmacology, was able to reduce hyperexcitation. Latrapyridine is an orally active small molecule compound that works by multiple mechanisms of action and acts by complex mechanisms.

Administration of alpha-2 adrenergic receptor agonists or pharmaceutically acceptable salts thereof is a particularly effective and safe intervention for the treatment of agitation. Dexmedetomidine is an alpha-2 adrenergic agonist and has been reported to have anti-agitative effects when administered intravenously during surgery and in the intensive care unit (ICU) setting.

The inventors of the present application have discovered that administration of latromidine alone or in combination with dexmedetomidine provides significantly improved results in anti-agitation and other benefits over conventional treatments.

In the rodent forced swim model, it has been found that administration of a combination comprising latromidine and dexmedetomidine provides a significant increase in swimming behavior (associated with amotivational or helpless behavior, which is a symptom of depression and ASD) compared to dexmedetomidine and latromidine administered alone, as described below in Example 4.

The inventors of the present application have discovered that administration of latromidine and/or dexmedetomidine alone or in combination has a beneficial effect in reducing symptoms of stress-mediated sympathetic overexcitation, such as anxiety, agitation, and irritability, thereby treating symptoms associated with ASD and preventing the possible occurrence of PTSD.

These symptoms are present in psychiatric disorders including acute stress, PTSD, depression, withdrawal, substance cravings, agitation, panic, anxiety, ADHD and panic disorder. The inventors of the present application have discovered that the active agents (i.e., latrazopyridine and/or dexmedetomidine or a pharmaceutically acceptable salt thereof) reduce the level of symptoms in norepinephrine-dependent stress-induced psychiatric disorders. By treating these symptoms, patients are able to improve their clinical outcomes because (1) they are better able to comply with basic therapeutic treatments, including taking prescribed medications and participating in therapy; (2) they are better able to engage in social interaction, which reduces symptoms of aggression and panic caused by lack of social interaction, such as those seen in autism; and (3) patients are better able to manage their symptoms and prevent worsening, such as occurs when acute stress disorder develops into PTSD. Latrapyridine has also been found to not only treat the symptoms of conditions such as acute stress disorder or autism, but also prevent the symptoms from getting worse over time.

The inventors of the present application have also discovered that administration of latromidine and/or dexmedetomidine alone or in combination has a beneficial effect in the treatment of pan-autistic disorder. Abbreviations AD: Alzheimer's disease AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ANOVA: analysis of variance ASD: acute stress disorder CNS: central nervous system CT/CAT scan: computed tomography EPM: elevated plus maze FTD: frontotemporal dementia GABA: gamma-aminobutyric acid 5-HT: 5-hydroxytryptamine HDRS or (HAM-D): Hamilton Depression Rating Scale ICU: Intensive Care Unit IPD: Inpatient Department IM: Intramuscular IP: Intraperitoneal LC: Locus coeruleus MRI: Magnetic Resonance Imaging µg: microgram mg: milligram MADRS: Montgomery-Asberg Depression Rating Scale MW: molecular weight NE: norepinephrine NMDA: N -methyl-D-aspartate OPD: outpatient department PANSS: positive and negative syndrome scale PTSD: post-traumatic stress disorder wt%: weight percentage Definition

It should be understood that the terms used herein are for the purpose of describing the embodiments only and are not intended to be limiting. As used in this specification, the singular forms "a/an" and "the" include plural referents unless the context clearly dictates otherwise.

Unless otherwise indicated, any reference to a compound herein (e.g., latropyridine, dexmedetomidine) by structure, name, or any other means includes pharmaceutically acceptable salts; alternative solid forms, such as polymorphs, solvates, hydrates, and the like; tautomers; deuterium-modified compounds, such as deuterium-modified latropyridine or dexmedetomidine; or any chemical species that can be rapidly converted to a compound described herein under the conditions under which the compound is used as described herein.

As used herein, "about" or "approximately" when used in conjunction with a numerical variable generally refers to values of the variable and all values of the variable that are within the experimental error (e.g., within the 95% confidence interval of the mean) or within ±10% of the specified value, whichever is greater.

Throughout this specification, numerical ranges of certain quantities are provided. It should be understood that such ranges include all subranges therein. Thus, the range "50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). In addition, all values within a given range may be endpoints of the range thereby covered (e.g., the range 50-80 includes ranges having endpoints such as 55-80, 50-75, etc.).

The term "a" or "an" refers to one or more of the entity. Furthermore, reference to an "agent" by the indefinite article "a" or "an" does not necessarily exclude the possibility that more than one agent is present.

As used herein, the term "comprising" and its morphological variations as used in this specification and the scope of the patent application are used in their non-limiting sense, and are intended to include the items following the word, but not to exclude items not specifically mentioned. The present disclosure may appropriately "comprise", "consist of", or "consist essentially of" the steps, elements and/or reagents described in the scope of the patent application.

As used herein, the term "subject" preferably refers to a human patient. In embodiments, the subject can be any animal, including non-human mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates.

As used herein, unless otherwise indicated, the terms "dosage form," "pharmaceutical composition," "composition," "formulation," and "composition of the present disclosure" are used interchangeably. Unless otherwise stated, these terms are intended to encompass and are not limited to dosage forms containing the drug substance (i.e., dexmedetomidine or latromidine or both).

As used herein, the term "effective amount" is interchangeable with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce the desired effect. An effective amount is sufficient to improve a clinically significant condition in an individual. An effective amount can be administered in one or more administrations, applications, or dosages.

As used herein, "pharmaceutically acceptable salts" refer to salts that are known to be non-toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid, and the like. Salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. Preferred salts are hydrochlorides (or dihydrochlorides).

The term "treat" is used herein to mean relieving or alleviating at least one symptom of a disorder in an individual. For example, with respect to a behavioral disorder, the term "treat" may mean relieving or alleviating an agitated individual's agitation and any combination of its manifestations (e.g., pacing, rocking, gesturing, pointing fingers, restlessness, exhibiting repetitive behavior, yelling, talking in an excessively loud voice, using profane language, screaming, shouting, grasping, shoving, pushing, resisting, hitting others, kicking objects or people, grabbing, biting, throwing objects, hitting oneself, slamming doors, tearing things, destroying property, etc.). Treatment may be measured as a reduction in level of at least 10% or more, preferably 20% or more, more preferably 40% or more, even more preferably 60% or more, still more preferably 80% or more, and 90% or more, relative to a control. For example, in the case of agitation, the skilled artisan will appreciate that treatment may be measured according to well-known agitation scales, such as the PEC score, CGI-I, and ACES (each of which is described in detail in WO/2020/006119, which is incorporated by reference in its entirety for all purposes). As an example, when treating agitation in a patient, the patient may experience a decrease in the PEC total score of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or greater relative to baseline (e.g., measured 2 hours after dosing). Similarly, a treated patient may be measured on the CGI-I scale and may refer to a patient having a score of 1 or 2 (e.g., measured 1, 2, or 4 hours after dosing), or may be measured on the Agitation-Calmness Evaluation Scale (ACES) and may refer to a patient having a score of 3, 4, 5, 6, or 7.

The term "prevent" means to prevent a disease, illness or related symptoms from occurring or to prevent their recurrence, for example after a period of improvement.

The term "oromucosal delivery" or "oromucosal administration" and the like means administration into the oral mucosa. This includes delivery across any tissue of the oral cavity, pharynx, larynx, trachea, or upper gastrointestinal tract, particularly including sublingual, buccal, gingival, and palatal mucosal tissues.

The term "sublingual" means "under the tongue" and refers to a method of administering a substance via the oral cavity in a manner that allows the substance to be rapidly absorbed through the blood vessels under the tongue rather than through the digestive tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows the substance to enter the blood circulation directly, thereby providing direct systemic administration without gastrointestinal effects and avoiding undesirable first-pass hepatic metabolism. Therefore, by administering the dosage forms of the present disclosure sublingually, the total amount of latropyridine and/or dexmedetomidine can be reduced, thereby reducing the potential for harmful side effects and providing cost benefits to the manufacturer.

The term "transbuccal" means administration of the dosage form against the gums and inner lips or cheeks. Oral mucosal absorption occurs through the highly vascularized transmucosal mucosa, which allows substances to enter the blood circulation directly, thereby providing direct systemic administration independent of gastrointestinal effects and avoiding undesirable first-pass hepatic metabolism.

The term "disintegration" refers to the dissolution or loss of the structural cohesion of the constituent particles that make up a solid formulation. This can occur in a variety of different ways, including breaking into smaller pieces and eventually becoming fine and larger particles, or alternatively eroding from the outside in until the dosage form disappears.

The terms "oral dosage form," "oromucosal dosage form," and "oral transmucosal dosage form" are used interchangeably herein and refer to dosage forms used to practice the present disclosure, including the drug formulations as described herein. Oral dosage forms are typically sublingual or transbuccal, but other transoromucosal routes may be used in some cases. The present disclosure relies on such oral dosage forms to provide sustained delivery of the drug across the oral mucosa; by controlling the formulation design, immediate release, intermediate release, and sustained release of the drug can be achieved, as described below. The dosage forms comprise the active ingredients (dexmedetomidine and/or latromidine) and one or more mucoadhesive agents that provide adhesion to the oral mucosa of the patient, as well as other carriers and formulations as described in more detail herein.

The term "orally disintegrating tablet" (ODT) refers to an oral dosage form consisting of a tablet designed to disintegrate in the mouth without chewing or swallowing with liquid. An orally disintegrating tablet may have the characteristics described by the US Food & Drug Administration in Guidance for Industry: Orally Disintegrating Tablets (Dept. of Health and Human Services, US FDA Center for Drug Evaluation and Research, December 2008). The disintegration rate of the solid pharmaceutical composition of the present disclosure may be measured using various in vitro test methods, such as the USP <701> disintegration test. As explained in the aforementioned chapter of the United States Pharmacopeia, the USP disintegration test is conducted by placing the dosage form to be tested in a basket rack assembly, immersing the assembly in a specified fluid at a temperature between 35°C and 39°C for a given period of time, and raising and lowering the basket in the immersion fluid at a frequency of about 30 cycles per minute, traversing a distance of about 5.5 cm. The dosage form is visually inspected at the specified time for complete disintegration, which is defined in Chapter 701 of USP 24-NF 19 as a state where any residue of the dosage form remaining in the basket rack of the test apparatus is a "soft mass with no perceptible hard core". Therefore, it should be understood that the dosage form of the present invention is optimal for disintegration in the oral cavity without the need to drink additional water. Absorption occurs through the oral mucosa.

The term "film" herein includes films, sheets, and rice paper capsules in any shape, including rectangular, square, or other desired shapes. The film can have any desired thickness and size so that it can be conveniently placed under the tongue of the patient. For example, the film can be a relatively thin film with a thickness of about 20 microns to about 200 microns, or can be a slightly thicker film with a thickness of about 20 microns to about 1000 microns. In embodiments, the film may be even thicker, such as a thickness greater than about 30 mm.

The term "mucoadhesion" is used herein to refer to adhesion to a mucosal membrane, such as the mucosal membrane in the oral cavity. Mucoadhesion can be measured by "mucoadhesive strength" or "mucoadhesive peak force."

The term "mucoadhesive" refers to materials that adhere to the surface of mucosal tissue in vivo. This type of adhesion positions the dosage form adhesively to the mucosa, and requires the application of force to separate the mucoadhesive material from the mucosa.

As used herein, "therapeutic" may mean therapeutic and/or preventive, as the case may be.

The term "hyperarousal" is used herein to refer to a subclinical state in which there is excessive norepinephrine agonist signaling, resulting in hemodynamic and motor changes. Stress-related psychiatric symptoms may result from increased sympathetic tone (excessive norepinephrine agonist signaling).

The term "acute stress disorder" or "ASD" refers to a mental health disorder that is caused by experiencing a traumatic event. Symptoms of ASD usually begin no less than 3 days and no more than 4 weeks after the event.

The term "trauma" or "traumatic event" that may cause ASD includes, but is not limited to, spontaneous abortion, military combat, violent personal assault (sexual assault, physical assault, robbery, robbery), kidnapping, hostage-taking, terrorist attack, torture, imprisonment as a prisoner of war or in a concentration camp, natural or man-made disaster, automobile accident (including but not limited to severe automobile accident), or diagnosed with a life-threatening illness. For children, sexually traumatic events may include inappropriate sexual experiences without threat or actual violence or injury. Witness events include (but are not limited to) seeing another person seriously injured or unnaturally dead as a result of a violent attack, accident, war, or disaster, or unexpectedly witnessing a dead body or body parts. Other experiences learned of include (but are not limited to) a family member or close friend experiencing a violent personal attack, serious accident, or serious injury; learning of the sudden and unexpected death of a family member or close friend; or knowing that one's child has a life-threatening illness.

The term "post-traumatic stress disorder" is also known as PTSD. According to the DSM-5, the behavioral symptoms that accompany PTSD include four unique diagnostic clusters. They are called re-experiencing, avoidance, negative cognitions and emotions, and arousal. Re-experiencing involves spontaneous memories of the traumatic event, recurring dreams, flashbacks, or other intense or prolonged psychological disturbances associated with it. Avoidance refers to distress caused by memories, thoughts, feelings, or external cues about the event. Negative cognitions and emotions refer to a range of feelings, from persistent and distorted feelings of blaming oneself or others, to isolation from others or a marked decrease in interest in activities, to an inability to remember key aspects of the event. The agitation profile of PTSD is characterized by aggressive, reckless or self-destructive behavior, sleep disturbances, hyperarousal, or related problems. According to the DSM-5, PTSD is characterized by aggravation that persists for more than one month. (This eliminates the distinction between the acute and chronic stages of PTSD.) Regarding agitation and reactivity associated with PTSD, there must be significant changes in two (or more) of the following profiles: a) irritable behavior and rage (with little or no provocation), often manifesting as verbal or physical attacks on people or objects; b) reckless or self-destructive behavior; c) hyperarousal; d) exaggerated startle reactions; e) attention problems; f) sleep disturbances (such as difficulty falling or staying asleep or restless sleep).

The term "pan-autistic disorder" is used interchangeably with "autism" and refers to a complex developmental disorder involving persistent challenges with social communication, limited interests, and repetitive behaviors. The term "pan-autistic disorder" here refers to a variety of symptoms and severity. Symptoms may include behavioral symptoms, which include (i) insistence on sameness or opposition to change; (ii) difficulty expressing needs; (iii) repeating words or phrases instead of normal responsive language; (iv) laughing, shouting, and showing pain for reasons that are not obvious to others; (v) preferring to be alone or distant; (vi) anger; (vii) difficulty getting along with others; (viii) not wanting to be hugged or held (ix) little eye contact; (x) no response to normal teaching methods; (xi) continued abnormal behavior; (xii) marked over- or under-sensitivity to pain; (xiii) little fear of danger; (xiv) obvious physical hyperactivity or extreme hypoactivity; (xv) uneven gross motor/fine motor skills; and/or (xvi) no response to verbal cues. In embodiments, the behavioral symptoms are selected from the group consisting of: compulsive behavior, ritualized behavior, restricted behavior, stereotypy, identicalness, or self-injury. Pervasive autistic disorders include autism (classic autism), Asperger's syndrome, childhood disintegrative disorder (CDD), Rett syndrome (Rett syndrome), and pervasive developmental disorder not otherwise specified (often called PDD-NOS). The disorder begins in early childhood and eventually causes problems functioning in areas such as society - socially, in school, and at work. The term "Asperger's syndrome" refers to a type of pervasive autistic disorder that is milder than autism but shares some of its symptoms, such as language and communication, and repetitive or restricted patterns of thinking and behavior. Obsession with a particular subject is a major symptom of Asperger's syndrome. The term "pervasive developmental disorders" refers to a group of disorders characterized by delayed development of socialization and communication skills. Symptoms may include problems using and understanding language, difficulty relating to people or objects, difficulty changing routines or becoming familiar with one's surroundings, and repetitive body movements or behavior patterns. As used herein, the term "Rett syndrome" refers to a neurodevelopmental disorder classified as a pervasive autistic disorder by the DSM-IV. It most commonly affects girls and clinical features include a slowed head growth rate (including some microcephaly) and small hands and feet. Behavioral symptoms include stereotyped repetitive hand movements, such as biting or twisting.

As used herein, the term "agitation" means a condition characterized by symptoms of irritability, emotional outbursts, impaired thinking, or excessive motor and verbal activity, which symptoms may occur due to dysfunction of specific brain regions such as the prefrontal lobe or due to dysfunction of neurotransmitter systems such as the norepinephrine excitatory system. In embodiments, agitation may be caused by excessive excitation of norepinephrine excitatory system. In the present disclosure, an agitated individual may also exhibit aggression. Agitation may be acute or chronic. Agitation may be severe.

The term "acute agitation" means agitation that develops rapidly and is severe and sudden when it occurs. Acute agitation may be associated with, for example, neurodegenerative and neuropsychiatric disorders, but it may be particularly present in neuropsychiatric disorders. If left untreated, acute agitation may lead to chronic agitation.

The term "chronic agitation" means agitation that occurs over a long period of time and is less severe than acute agitation. Chronic agitation may be associated with, for example, neurodegenerative and neuropsychiatric disorders, but it may be particularly present in neurodegenerative disorders.

The term "no significant sedation" or "does not cause significant sedation" and similar terms mean that the patient experiences a level of sedation no greater than level 3 on the Ramsay Sedation Scale. Level 3 means sedated but responsive to commands. In embodiments, dexmedetomidine may be administered to achieve -1 ("mild sedation") on the Richmond Agitation Sedation Scale (RASS).

The term "neurodegenerative disorder" includes, but is not limited to, Alzheimer's disease, frontotemporal dementia (or Pick's disease), dementia (e.g., Lewy body dementia, vascular dementia), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy.

The term "neuropsychiatric disorder" includes but is not limited to schizophrenia, bipolar illness (mania, bipolar disorder), depression, and delirium.

The term "sundowning" refers to a late-day circadian syndrome of increased confusion, agitation, and/or restlessness, usually in patients with a form of dementia. Some individuals affected by sundowning may have more than one disease or condition. For example, a person with sundowning may have dementia, Alzheimer's disease, or both. Approximately 20% to 45% of patients with Alzheimer's disease experience some form of sundowning confusion. Sundowning also refers to worsening confusion and/or agitation in the evening, evening, or as the sun sets.

The term "behavioral and psychological symptoms" refers to agitation/aggression, delusions and/or hallucinations, unusual motor behavior, unusual vocalizations, anxiety, euphoria/elevated affect, irritability, depression/dysphoria, apathy, disinhibition, changes in sleep and nocturnal behavior, and changes in appetite and eating.

The term "freeze drying" or "freeze drying" refers to a process for producing a stable preparation of a substance by freezing a fluid formulation containing a substance and substantially removing the frozen liquid under vacuum. The term "freeze drying" refers to the art-recognized procedure for freeze drying a composition. "Freeze drying" and "freeze drying" are used synonymously herein.

The term "pharmaceutically acceptable carrier" refers to a pharmacologically inert substance used as a carrier. As used herein, the phrases "carrier" and "excipient" can be used interchangeably unless otherwise clearly intended to have different meanings.

The term "unit dosage form" as used herein refers to physically discrete units suitable for use as unit dosage, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

In the meaning of the present disclosure, the term "combined administration" or "simultaneous administration" is used to refer to the simultaneous administration of dexmedetomidine or its pharmaceutically acceptable salt and latrazolidine or its pharmaceutically acceptable salt in separate formulations or in a combined formulation, i.e., in a single dosage form.

The term "sequential administration" refers to the administration of latropyridine and dexmedetomidine in two or more separate dosage forms one after the other (i.e., not at the same time). If the disclosed drug substances are administered sequentially, administration of the last drug substance is usually initiated one hour or less (generally 30 minutes or less) after the start of administration of the first drug substance.

As used herein, "nanonization" means the process of reducing particles to a size within the range where the average particle size is less than 1000 nanometers, preferably less than 100 nanometers.

The phrase "spray drying" refers to the process involving breaking up a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the mixture in a spray drying apparatus, wherein there is a strong driving force for evaporating the solvent from the droplets. The phrase spray drying is known and widely used. Spray drying processes and spray drying apparatus are generally described in Perry, Robert H. and Don W. Green (Eds.), Perry's Chemical Engineers' Handbook , New York: McGraw-Hill, 2007 (8th edition).

The term "sublimation" refers to a physical phase change from a solid directly to a gas. More specifically, sublimation is the process by which a substance changes from a solid to a gas without passing through a liquid phase. Sublimation of a solution can be achieved by freeze drying.

As used herein, the term "granulation" refers to the process of agglomerating powder particles into larger agglomerates (i.e., granules) containing the active agent. The term "granulation" includes dry and wet granulation techniques. The term "wet granulation" refers to any process comprising the steps of adding water containing a liquid (preferably water) to a powder starting material, preferably kneading; and drying to obtain a solid dosage form. The term "dry granulation" refers to any process comprising compacting a powder, usually by weight or using a roller press, and preferably grinding the compacted powder to obtain granules. Dry granulation does not use a liquid. One or more compacted granules as disclosed herein are preferably prepared by dry granulation.

"Direct compression" refers to a process that involves blending the ingredients and then compressing them into tablets. I. Active Agent

Dexmedetomidine has the IUPAC name (+) 4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. As the monohydrochloride salt, it is primarily used as a drug for sedating patients during treatment in an intensive care setting or before and/or during surgery and other procedures. This drug is currently sold under the registered trade name "PRECEDEX ^® ".

The pharmaceutically acceptable salts of dexmedetomidine that can be used herein generally include any suitable salts that have been or may be approved for administration to humans by the US FDA or other appropriate foreign or domestic agencies. Non-limiting examples of suitable pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, hydrosulfuric acid and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, or combinations of these acid salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine appletate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate, or the like. In embodiments, deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.

Latrolpyridine (also known as dimeben) has the IUPAC name of 2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrido[4,3-b]indole and should be understood herein to include any pharmaceutically acceptable form. "Pharmaceutically acceptable form" means any pharmaceutically acceptable form, including solvates, hydrates, isomorphs, polymorphs, cocrystals, pseudomorphs, neutral forms, acid addition salt forms and prodrugs. It may exist in the form of a pharmaceutically acceptable acid salt and in the form of a quaternary ammonium derivative. Pharmaceutically acceptable base addition salts may be prepared from inorganic bases and/or organic bases.

Pharmaceutically acceptable acid addition salts of latropyridine are prepared in a known manner by treating a solution or suspension of the free base with, for example, one or two chemical equivalents of a pharmaceutically acceptable acid. Examples of suitable acids are acetic acid, lactic acid, succinic acid, citric acid, gluconic acid, ascorbic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, cinnamic acid, fumaric acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, dihydrochloric acid, hydrobromic acid, hydroiodic acid, aminosulfonic acid, sulfonic acids (such as methanesulfonic acid, benzenesulfonic acid) and related acids. In embodiments, latropyridine is present as a free base. In embodiments, latropyridine is present as latropyridine dihydrochloride. In the embodiment, the latropyridine is present in the form of latropyridine hydrochloride. Latropyridine is present in the form of latropyridine dihydrochloride dihydrate. In the embodiment, the latropyridine is present in the form of latropyridine dihydrochloride hydrate. II. Dosage

In an embodiment, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof administered is preferably in the range of about 0.5 μg to about 300 μg. Examples of suitable doses include: about 0.5 μg to about 280 μg, about 1 μg to about 270 μg, about 1 μg to about 260 μg, about 1 μg to about 250 μg, about 1 μg to about 240 μg, about 1 μg to about 230 μg, about 1 μg to about 220 μg, about 1 μg to about 210 μg, about 1 μg to about 200 μg, about 1 μg to about 190 μg, about 1 μg to about 180 μg, about 1 μg to about 170 μg, about 1 μg to about 160 μg, about 1 μg to about 150 μg, about 1 μg to about The dosage may be administered one or more times a day, for example, twice, three times, four times, five times, or six times a day.

In an embodiment, the amount per unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 55 μg, about 60 μg, about 65 μg, about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg, about 95 μg, about 100 μg, about 105 μg, about 110 μg, about 115 μg, about 120 μg, about 125 μg, about 130 μg, about 135 μg, about 140 μg, about 145 μg, about 150 μg, about 15 about 250 μg, about 255 μg, about 260 μg, about 265 μg, about 270 μg, about 275 μg, about 280 μg, about 285 μg, about 290 μg, about 295 μg, or about 300 μg, including all values and ranges therebetween.

Each unit can be administered to an individual one or more times per day, for example 1, 2, 3, 4, 5 or 6 times per day. In embodiments, each unit can be administered at appropriate dosing intervals (e.g., about 1 hour between each dose), or can be administered concurrently.

The effective total daily dose may, for example, include one or more unit doses up to a total daily dose of about 1 mg of dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 0.5 μg to about 500 μg, for example, the total daily dose is about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 55 μg, about 60 μg, about 65 μg, about 70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg, about 95 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, about 190 μg, about 200 μg. , about 210 μg, about 220 μg, about 230 μg, about 240 μg, about 250 μg, about 260 μg, about 270 μg, about 280 μg, about 290 μg, about 300 μg, about 310 μg, about 320 μg, about 330 μg, about 340 μg, about 350 μg, about 360 μg, about 370 μg, about 380 μg, about 390 μg, about 400 μg, about 410 μg, about 420 μg, about 430 μg, about 440 μg, about 450 μg, about 460 μg, about 470 μg, about 480 μg, about 490 μg or about 500 μg, including all ranges and values in between.

In an embodiment, the daily dose of latromidine or a pharmaceutically acceptable salt thereof administered is preferably in the range of about 0.5 mg to about 500 mg. Examples of suitable dosages include about 0.5 mg to about 450 mg, about 0.5 mg to about 400 mg, about 0.5 mg to about 350 mg, about 0.5 mg to about 300 mg, about 0.5 mg to about 250 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 150 mg, about 0.5 mg to about 100 mg, about 1 mg to about 500 mg, about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, about 2 mg to about 500 mg, about 2 mg to about 450 mg, about 2 mg to about 400 mg, about 2 mg to about 350 mg, about 2 mg to about 300 mg, about 2 mg to about 250 mg, about 2 From about 200 mg to about 150 mg, from about 2 mg to about 100 mg, from about 3 mg to about 500 mg, from about 3 mg to about 450 mg, from about 3 mg to about 400 mg, from about 3 mg to about 350 mg, from about 3 mg to about 300 mg, from about 3 mg to about 250 mg, from about 3 mg to about 200 mg, from about 3 mg to about 150 mg, from about 3 mg to about 100 mg, from about 4 mg to about 500 mg, from about 4 mg to about 450 mg, from about 4 mg to about 400 mg, from about 4 mg to about 350 mg, from about 4 mg to about 300 mg, from about 4 mg to about 250 mg, from about 4 mg to about 200 mg, from about 4 mg to about 150 mg, from about 4 mg to about 100 mg, from about 5 mg to about 500 mg, from about 5 mg to about 450 mg, from about 5 mg to about 400 mg, from about 5 mg to about 350 mg, mg to about 300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, or about 5 mg to about 10 mg. In embodiments, the daily dose of latrolpyridine or a pharmaceutically acceptable salt thereof administered is preferably in the range of about 10 mg to about 200 mg. In embodiments, the daily dose of latrolpyridine or a pharmaceutically acceptable salt thereof administered is preferably in the range of about 10 mg to about 100 mg. In embodiments, the daily dose of latrapyridine or a pharmaceutically acceptable salt thereof is preferably in the range of about 10 mg to about 80 mg. In embodiments, the daily dose of latrapyridine or a pharmaceutically acceptable salt thereof is preferably in the range of about 15 mg to about 6. In embodiments, the daily dose of latrapyridine or a pharmaceutically acceptable salt thereof is preferably in the range of about 15 mg to about 45 mg. In an embodiment, the daily dose of latrapyridine or a pharmaceutically acceptable salt thereof administered is preferably in the range of about 5 mg to about 60 mg, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg or about 60 mg, including all values and ranges therebetween.

In an embodiment, the amount per unit dose of latropyridine is about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg, about 0.5 mg or about 0.1 mg, including all ranges and values therebetween.

In an embodiment, the therapeutically effective amount of latromidine is evenly distributed to be administered twice daily or three times daily.

Exemplary dosages of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) and latrazopyridine or a pharmaceutically acceptable salt thereof (e.g., dihydrochloride) administered to a particular patient will depend on the type and extent of the disorder, the general health of the particular patient, the specific form of dexmedetomidine and latrazopyridine or a pharmaceutically acceptable salt thereof administered, and the specific formulation used to treat the patient. III. Dosage Forms

In an embodiment, the present disclosure provides an oromucosal dosage form comprising latromidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers.

In embodiments, the dosage forms described herein are effective within about 5 seconds to about 10 minutes after contact with the oral mucosa, such as about 5 seconds to about 10 minutes, about 5 seconds to about 5 minutes, about 5 seconds to about 1 minute, about 5 seconds to about 30 seconds, about 5 seconds to about 10 seconds, about 30 seconds to about 10 minutes, about 30 seconds to about 5 minutes, about 30 seconds to about 1 minute, about 1 minute to about 10 minutes after contact with the oral mucosa. In some embodiments, the dosage form disintegrates within about 1 minute, about 1 minute to about 5 minutes, about 1 minute to about 2 minutes, about 2 minutes to about 10 minutes, about 2 minutes to about 5 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 5 minutes, about 4 minutes to about 10 minutes, about 4 minutes to about 5 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 7 minutes, or about 7 minutes to about 10 minutes. In an embodiment, the dosage form disintegrates in less than about 1 minute, such as about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds (including all ranges and values therebetween) after contact with the oral mucosa. In embodiments, the dosage form does not disintegrate within 1 minute after contact with the oral mucosa. In embodiments, the dosage form disintegrates within more than 1 minute, such as about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes after contact with the oral mucosa. Thus, when tested by the <701> disintegration test method (see Industry Guide, which is incorporated herein by reference), the dosage form produced according to one embodiment of the present disclosure meets the disintegration time standard of disintegrating within about 5 seconds to about 10 minutes.

In embodiments, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the drug in a dosage form comprising a formulation of the disclosure is absorbed through the oral mucosa.

In embodiments, the dosage forms of the present disclosure have sufficient mechanical strength to resist abrasion/fracture during packaging in blisters and bottles, storage, and transportation for commercial distribution and end use.

In embodiments, the dosage forms described herein are effective in treating conditions associated with norepinephrine induced overexcitation. In embodiments, the dosage forms described herein are effective in reducing norepinephrine induced overexcitation. In embodiments, the dosage forms described herein are effective in treating acute stress disorder (ASD). In embodiments, the dosage forms described herein are effective in preventing post-traumatic stress disorder (PTSD). In embodiments, the dosage forms described herein are effective in treating pan-autistic disorder.

In embodiments, the dosage forms described herein are effective in treating agitation in an agitated individual. For example, as measured by PEC, CGI-I and/or ACES, the dosage forms described herein are effective in treating agitation in an individual. In embodiments, the dosage forms are effective in treating agitation in an individual without otherwise causing significant sedation. In embodiments, the individual is treated without experiencing clinically significant cardiovascular effects. In embodiments, agitation is caused by norepinephrine induced overexcitation.

In embodiments, the dosage forms described herein are effective in treating depression in a subject. For example, as measured by the HAM-D scale or the MADRS scale, the dosage forms described herein are effective in treating depression in a subject. In embodiments, the disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride), one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers to treat agitation. In embodiments, the dosage form disintegrates in less than about 1 minute after contact with the oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds (including all ranges and values therebetween). In an embodiment, the dosage form disintegrates in more than about 1 minute when in contact with the oral mucosa. In an embodiment, the dosage form disintegrates in no less than about 1 minute, such as about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes after contact with the oral mucosa. In an embodiment, the dosage form effectively treats agitation in an individual. In an embodiment, the dosage form effectively treats agitation in an individual without causing significant sedation in addition. In embodiments, agitation is caused by norepinephrine induced hyperexcitation. In embodiments, the dosage forms described herein are effective for treating depression in an individual.

In embodiments, the present disclosure provides dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrapyridine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers for treating a condition associated with norepinephrine-induced overexcitation. In embodiments, latrapyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or intermittently.

In embodiments, the present disclosure provides an oromucosal dosage form comprising latromidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers for treating ASD in an individual. In embodiments, the present disclosure provides an oromucosal dosage form comprising latromidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers for preventing PTSD in an individual.

In embodiments, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers for treating autistic disorder in a subject. In embodiments, the present disclosure provides an oromucosal dosage form comprising latromidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers for treating autistic disorder in a subject.

In an embodiment, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers for treating ASD in an individual. In an embodiment, the present disclosure provides an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers for preventing PTSD in an individual. In embodiments, the present disclosure provides an oral mucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latromidine or a pharmaceutically acceptable salt thereof, one or more mucoadhesive agents, and one or more pharmaceutically acceptable excipients or carriers to treat agitation. In embodiments, the dosage form disintegrates in less than about 1 minute after contact with the oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds after contact with the oral mucosa. In embodiments, the dosage form disintegrates in no less than about 1 minute after contact with the oral mucosa. For example, the dosage form may disintegrate in about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. In embodiments, the dosage form is effective to treat agitation in an individual. In embodiments, the dosage form is effective to treat agitation in an individual without otherwise causing significant sedation. In embodiments, agitation is caused by norepinephrine induced overexcitation. In embodiments, the dosage forms described herein are effective to treat depression in an individual.

In an embodiment, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and a second oromucosal dosage form comprising latromidine or a pharmaceutically acceptable salt thereof for concurrent or sequential co-administration to treat agitation.

In embodiments, the dosage form is administered to treat agitation associated with neurodegenerative disorders, neuropsychiatric disorders, and alcohol withdrawal or substance abuse withdrawal (including opioid withdrawal). In embodiments, the dosage form is administered to treat agitation associated with OPD/IPD procedures (e.g., MRI, CT or CAT scans, lumbar punctures, bone marrow aspirations/biopsies, tooth extractions or other dental procedures).

In an embodiment, the present disclosure provides a first oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and a second oromucosal dosage form comprising latromidine or a pharmaceutically acceptable salt thereof for concurrent or sequential co-administration to treat depression in a subject.

In embodiments, the dosage form disintegrates in less than about 1 minute after contact with the oral mucosa. For example, the dosage form may disintegrate in about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds after contact with the oral mucosa. In embodiments, the dosage form disintegrates in no less than about 1 minute after contact with the oral mucosa. For example, the dosage form may disintegrate in about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes.

In embodiments, the oral mucosal (e.g., sublingual or buccal) dosage forms of the present disclosure are tablets, capsules, discs, patches or films, sachets, wafers, powders, microtablets, pills, pastes, gels, ointments, creams, drops, liquids (solutions, suspensions or emulsions), sprays, microspheres or nanospheres that can be formulated according to standard methods in the art.

In an embodiment, the dosage form is an oromucosal wafer. In an embodiment, the wafer is lyophilized. In an embodiment, the wafer disintegrates in less than about 1 minute after contact with the oral mucosa. In an embodiment, the wafer disintegrates in more than about 1 minute after contact with the oral mucosa. In an embodiment, the wafer comprises a molding agent such as hydroxypropyl cellulose, lactose, mannitol, glycine and the like.

In an embodiment, the dosage form is an oral mucosal microtablet. In an embodiment, the microtablet disintegrates in less than about 1 minute after contact with the oral mucosa. In an embodiment, the microtablet disintegrates in more than about 1 minute after contact with the oral mucosa. In an embodiment, the microtablet comprises a co-processed mannitol-based excipient. In an embodiment, the microtablet contains a directly compressible excipient. In an embodiment, the compressible excipient is in the form of a hydrate and can be selected from organic compounds such as dextrose monohydrate, maltodextrin, lactose monohydrate and dextrin; and inorganic compounds including calcium hydrogen phosphate dihydrate, sodium hydrogen phosphate dihydrate, sodium hydrogen phosphate heptahydrate, sodium hydrogen phosphate dodecahydrate, sodium hydrogen phosphate monohydrate and sodium hydrogen phosphate dihydrate. In an embodiment, the rapidly disintegrating tablet portion comprises a compressible excipient selected from the group consisting of isomalt, dextrose monohydrate, a hydrogenated starch hydrolysate base, maltodextrin, lactose monohydrate, dextrin, mannitol, lactitol, sorbitol, xylitol, erythritol, sucrose and lactose.

In embodiments, the oromucosal dosage form is in the form of a tablet or disc or a filled powder.

In embodiments, the dosage form is a hard or compressed powdered sublingual or buccal tablet having a low coarse particle component for a sensory pleasant mouthfeel. In embodiments, the tablet (or particles thereof containing the active agent, which particles may be compressed to form a tablet) comprises a protective outer coating, such as any polymer known to form microparticles and microcapsules. In embodiments, the dosage form is a sublingual (or buccal) tablet containing an effervescent agent. Sublingual compositions containing effervescent agents are disclosed in U.S. Patent No. 6,200,604, which is incorporated herein by reference in its entirety for all purposes.

In embodiments, oral mucosal tablets preferably include active ingredients in a matrix. In embodiments, the matrix is composed of, for example, at least one filler and/or lubricant. Fillers include, for example, lactose or mannitol, and suitable lubricants include, but are not limited to, magnesium stearate, silicon dioxide, and talc. The matrix may also include one or more of the following: a binder (e.g., polyvidone, sugar, or carboxymethyl cellulose), a disintegrant (e.g., cross-linked sodium carboxymethyl cellulose, cross-linked polyvidone, or sodium starch glycolate), a sweetener (e.g., sucralose), and the like. Tablets preferably have a friability of about 2% or less and a hardness of about 15 to about 50 Newtons.

In an embodiment, the oral mucosal dosage form is in the form of a patch or a film (e.g., a thin film). The patch may have an adhesive quality to prevent the patch from moving or swallowing the patch. Suitable film compositions comprising dexmedetomidine are disclosed in U.S. Patent No. 10,792,246, which is incorporated herein by reference in its entirety for all purposes.

In an embodiment, the oral mucosal dosage form is in the form of a paste, gel or ointment. The viscosity of the paste, gel or ointment can be adjusted to allow retention under the tongue or near the gums or cheeks or upper lip.

In embodiments, the oral mucosal dosage form is in liquid form (e.g., as a solution, suspension, or emulsion) and can be presented, for example, as a spray or drops. In specific embodiments of the present disclosure, latromidine and/or dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in liquid form, for example, as a flavored or unflavored saline solution. The liquid dosage form is preferably administered as drops or as a spray under the tongue or near the gums or cheeks or upper lip. The solution comprises the active ingredient and a diluent, such as water, normal saline, sodium chloride solution, or any other suitable solvent (such as propylene glycol, glycerol, ethanol, etc.). The diluent of the solution can be, in particular, a saline solution or water.

The spray formulation of the present disclosure for oral mucosal administration may include one or more pharmaceutically acceptable liquids (e.g., present in an amount of about 30% to about 99.99% by weight of the composition). Such liquids may be solvents, co-solvents, or non-solvents for dexmedetomidine and latromidine or their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable liquids include water, ethanol, dimethyl sulfoxide, propylene glycol, polyethylene glycol, propylene carbonate, pharmaceutically acceptable oils (e.g., soybean, sunflower, peanut, peppermint, etc.) and the like. The pharmaceutically acceptable liquid is selected to dissolve the active drug ingredient, produce a stable and uniform suspension or solution thereof, or form any combination of suspensions or solutions. In addition to these ingredients, the spray formulation may include one or more excipients, such as viscosity adjusting materials (e.g., polymers, sugars, sugar alcohols, gums, clays, silica, etc.), such as polyvinylpyrrolidone (PVP); preservatives (e.g., ethanol, benzyl alcohol, propyl paraben and methyl paraben); flavorings (e.g., peppermint oil), sweeteners (e.g., sugars such as sucrose, glucose, dextrose); , maltose, fructose, etc.), artificial sweeteners (e.g., saccharin, aspartame, acesulfame potassium, sucralose) or sugar alcohols (e.g., mannitol, xylitol, lactitol, maltitol syrup); buffers and pH adjusters (e.g., sodium hydroxide, citrate and citric acid); colorants; fragrances, chelating agents (e.g., EDTA); UV absorbers and defoaming agents (e.g., low molecular weight alcohols, dimethicone). In addition to being suitable for sublingual or buccal administration of one or more of the aforementioned ingredients, the spray may also contain one or more excipients, such as viscosity adjusting materials (e.g., water-soluble or water-swellable polymers such as carbopol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose).

Sprays can be prepared by mixing appropriate amounts of the aforementioned ingredients according to standard good manufacturing practices. Such excipients may be included in the formulation to improve patient or individual acceptance or taste, increase bioavailability, increase shelf life, reduce manufacturing and packaging costs, comply with government regulatory agency requirements, and achieve other purposes. The relative amounts of the ingredients should not interfere with the desired pharmacological and pharmacokinetic properties of the resulting formulation.

In one embodiment, the patient can be treated by sublingual or buccal administration of 1 to 2 actuations from a spray pump. The advantage of spray delivery is the ability to easily titrate the patient to 1 or 2 doses required per single actuation.

Pump-action spraying is characterized by the need for external pressure to be applied for actuation, such as external manual, mechanical or electrically induced pressure. This is in contrast to pressurized systems, such as propeller-driven aerosol spraying, in which actuation is usually achieved by controlled release of pressure, such as by controlled opening of a valve.

The non-solid dosage forms of the present disclosure may be suitably administered by spraying, instilling, smearing or spraying the composition under the tongue or near the gums or cheeks or upper lip.

In an embodiment, an oromucosal tablet dosage form is prepared by lyophilization (or freeze drying). A suspension containing the active agent can be prepared with an appropriate excipient, and the active agent (latrepyridine/dexmedetomidine) suspension can be dispensed into blister packs and freeze dried. An exemplary freeze dried formulation platform that can be used for latrepyridine and/or dexmedetomidine oral disintegrating tablets (ODT) is ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, the excipient is blended and the active agent is milled to a certain size separately and then mixed with the excipient. The solution/suspension is then freeze dried by flash freezing and freeze drying. This aqueous solution/suspension must be chemically and morphologically stable throughout the administration process. Gelatin may be used to give the dosage form sufficient strength to prevent breakage during removal from the package, but once placed in the mouth, gelatin allows the dosage form to disintegrate immediately. Other alternatives may be used, such as fish gelatin and modified starch. During handling, the administered solution/suspension is preferably frozen by passing through a gaseous medium. This serves to quickly fix the solution/suspension, thereby increasing manufacturing efficiency. Examples of oral mucosal dosage forms include orally disintegrating tablets disclosed in U.S. Patent No. 6,509,040, U.S. Patent No. 7,972,621, U.S. Patent No. 1,054,8839, U.S. Patent No. 9,775,819, U.S. Patent No. 5,188,825, U.S. Patent No. 5,631,023, U.S. Patent No. 6,297,240, U.S. Patent No. 6,413,549, U.S. Patent No. 5,976,577, U.S. Patent No. 6,156,339, U.S. Patent No. 5,827,541, U.S. Patent No. 5,729,958 ...6,976,577, U.S. Patent No. 6,156,339, U.S. Patent No. 6,976,577, U.S. Patent No. 6,976,577, U.S. Patent No. 6,976,577, U.S. Patent No. 6,976,577, U.S. Patent No. 6,976,577, U.S. Patent No. 6,726,928, U.S. Patent No. 9,192,580, U.S. Patent No. 6,709,669, U.S. Application Publication No. 20200138721, U.S. Application Publication No. 20190276707, U.S. Application Publication No. 20190314274, U.S. Application Publication No. 20040156894, PCT Publication No. 1999038496, PCT Publication No. 2000044351 and U.S. Application Publication No. 20090226522 and related patents/patent publications are incorporated herein by reference in their entirety for all purposes.

Other methods for preparing oral mucosal dosage forms such as ODT may be used without limitation, and detailed descriptions of general methods thereof are disclosed, for example, in the following: U.S. Patent No. 5,837,287; U.S. Patent No. 6,149,938; U.S. Patent No. 6,212,791; U.S. Patent No. 6,284,270; U.S. Patent No. 6,316,029; U.S. Patent No. 6,465,010; U.S. Patent No. 6,471,992; U.S. Patent No. 6,471,992; U.S. Patent No. 6,814,978; U.S. Patent No. 6,908,626; U.S. Patent No. 6,908,626; U.S. Patent No. 6,982,251; U.S. Patent No. 7,282,217; U.S. Patent No. U.S. Patent No. 7,425,341; U.S. Patent No. 7,939,105; U.S. Patent No. 7,993.674; U.S. Patent No. 8,048,449; U.S. Patent No. 8,127,516; U.S. Patent No. 8,158,152; U.S. Patent No. 8,221,480; U.S. Patent No. 8,256,233; U.S. Patent No. 8,313,768; U.S. Patent No. 5,039,540; U.S. Patent No. 5,120,549; U.S. Patent No. 5,330,763; U.S. Patent No. 4,760,093; U.S. Patent No. 4,760,094; and U.S. Patent No. 4,767,789, which are incorporated herein by reference in their entirety for all purposes.

Different technologies that can be used to prepare the oral mucosal dosage forms of the present disclosure include, but are not limited to, Flash Dose, Orasolv, durasolv, wowtab technology, Flash Tab technology, Oraquick technology, Quick-Dis technology, Nanocrystal technology, Shearform technology, Ceform technology, Pharmaburst technology, Frosta technology, Ziplet technology, humidity treatment, sintering, Lyoc technology, Quicksolv technology, Nanocrystal technology, Pharmafreeze, AdvaTab technology, cotton-candy technology, etc.

In embodiments, the oral mucosal dosage forms (e.g., sublingual or buccal or gingival tablets) of the present disclosure may be prepared by sublimation, nano-ization, spray drying, granulation (including wet granulation, dry granulation) or direct compression and the like. U.S. Patent Nos. 5,178,878, 6,269,615 and 6,221,392 disclose the manufacture of friable orally disintegrating tablets by direct compression and packaging in specially designed dome blister packages using a robotically controlled integrated tablet-packaging system; the patents are incorporated herein by reference in their entirety for all purposes.

In an embodiment, the oral mucosal tablet dosage form as used herein can be prepared by direct compression including mixing the active agent (latrepyridine and/or dexmedetomidine) with one or more pharmaceutically acceptable excipients, lubricating the blend, and directly compressing into tablets.

In an embodiment, a method for preparing an oral mucosal tablet dosage form by dry granulation is provided, which comprises the following steps: (i)   preparing a mixture containing an active agent (latropyridine and/or dexmedetomidine) and one or more pharmaceutically acceptable excipients; (ii)  compacting the mixture obtained in step (i) to form granules; (iii) optionally mixing the granules obtained in step (ii) with the remaining excipients; and (iv) subjecting the granules to compression to obtain a tablet.

In an embodiment, the compaction in step (ii) is performed by roller pressing or weight pressing technique.

In an embodiment, a method for preparing an oral mucosal tablet dosage form by wet granulation is provided, which comprises the following steps: (i)   preparing a mixture containing an active agent (latropyridine and/or dexmedetomidine) and one or more pharmaceutically acceptable excipients; (ii)   granulating the mixture obtained in step (i) with a suitable granulating liquid to form wet granules, (iii)   drying the wet granules obtained in step (ii); (iv)   mixing the dried granules obtained in step (iii) with one or more excipients as appropriate; and (v)  The granules obtained in step (iii) or the mixture obtained in step (iv) are subjected to compression to obtain tablets.

In embodiments, the mixture of step (i) is granulated with any suitable solvent including but not limited to water, alcohols such as ethanol or isopropanol, or mixtures thereof.

The dosage forms of the present disclosure can be administered to mammals, including humans, as well as non-mammalian animals in need thereof (eg, rats, cats, and dogs).

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are formulated as a sublingual tablet or a buccal tablet.

In embodiments, the dosage form comprises a mucoadhesive agent to adhere one or more active agents to the oral mucosa. The mucoadhesive agent may have the property of swelling and expanding upon contact with water, thereby causing the tablet to disintegrate upon wetting with saliva. In embodiments, the dosage form comprises one or more mucoadhesive agents in an amount of about 0.5% to about 30% w/w. For example, the one or more mucoadhesive agents are present in an amount ranging from about 0.5% w/w to about 30% w/w, about 0.5% w/w to about 25% w/w, about 0.5% w/w to about 20% w/w, about 0.5% w/w to about 10% w/w, about 0.5% w/w to about 5% w/w, about 1% w/w to about 30% w/w, about 1% w/w to about 20% w/w, about 1% w/w to about 10% w/w, about 1% w/w to about 5% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, about 3% w/w to about 30% w/w, about 3% w/w to about 20% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 5% w/w, about 5% w/w to about w/w to about 30% w/w, about 5% w/w to about 20% w/w, about 5% w/w to about 10% w/w, about 10% w/w to about 30% w/w, about 10% w/w to about 20% w/w, about 10% w/w to about 15% w/w, about 15% w/w to about 30% w/w, about 15% w/w to about 20% w/w, about 20% w/w to about 30% w/w, about 20% w/w to about 25% w/w, or about 25% w/w to about 30% w/w. In embodiments, the mucoadhesive is present in an amount from about 1% w/w to about 5% w/w. In embodiments, the mucoadhesive agent is present at about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, about 20% w/w, about 21% w/w, about 22% w/w, about 23% w/w, about 24% w/w, about 25% w/w, about w/w, about 26% w/w, about 27% w/w, about 28% w/w, about 29% w/w or about 30% w/w, including all ranges and values therebetween.

In embodiments, the mucoadhesive dosage form has a mucoadhesive strength of at least about 50 dynes/cm2, such as about 50 dynes/cm2, about 75 dynes/cm2, about 100 dynes/cm2, about 150 dynes/cm2, about 200 dynes/cm2, about 250 dynes/cm2, about 300 dynes/cm2, about 350 dynes/cm2, about 400 dynes/cm2, about 450 dynes/cm2, or about 500 dynes/cm2. dynes/cm2, about 500 dynes/cm2, about 550 dynes/cm2, about 600 dynes/cm2, about 650 dynes/cm2, about 700 dynes/cm2, about 750 dynes/cm2, about 800 dynes/cm2, about 850 dynes/cm2, about 900 dynes/cm2, about 950 dynes/cm2 or about 1000 dynes/cm2 (including all ranges and values therebetween). In embodiments, the mucoadhesive formulation has a mucoadhesive strength greater than about 1000 dynes/cm2. In embodiments, the dosage form has a mucoadhesion peak force of greater than about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g, or about 1500 g. In embodiments, the dosage form has a mucoadhesion peak force of about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g, or about 1500 g (including all ranges and values therebetween).

In embodiments, suitable mucoadhesive agents for use in the present disclosure include, but are not limited to, polyacrylic acid polymers (such as carbomer (e.g., with low viscosity), polycarbophil, etc.), methacrylic acid polymers, cellulose derivatives such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC-such as MW ＜150K Dalton (lower viscosity grade), ethyl hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC-such as grades with lower viscosity, such as K100L or 4000cps or less), methyl cellulose, sodium carboxymethyl cellulose, thiolated carboxymethyl cellulose; polysaccharides (such as chitosan, pectin, etc.); xanthan gum, karaya gum ( gum), astragalus gum; propylene glycol, propylene glycol alginate, sodium alginate, polyethylene oxide (PEO), microcrystalline cellulose (Avicel), cross-linked carboxymethyl cellulose, poloxamer (i.e., a non-ionic triblock copolymer consisting of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene; for example, poloxamer 407), and mixtures thereof.

In an embodiment, the excipient or carrier included in the oral mucosal dosage form is selected from the group consisting of: disintegrants, fillers/diluents (matrix formers), binders, glidants, lubricants, plasticizers, pH adjusters, colorants, flavoring agents, taste masking agents, viscosity enhancers, sweeteners, and combinations thereof. Carriers that dissolve easily in saliva are preferred.

In the embodiments, examples of suitable disintegrants used in the present disclosure include but are not limited to cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch, natural starch, carboxymethyl starch, sodium hydroxyacetic acid starch, pregelatinized starch, dextrin and other modified starches (starch in which the hydroxyl groups have been esterified), hydroxypropyl di-starch phosphate), enzyme-modified starch, pregelatinized distarch phosphate, hydroxyethyl starch, hydroxypropyl starch, pregelatinized acetylated distarch phosphate and pregelatinized purified starch); calcium carboxymethyl cellulose, sodium carboxymethyl cellulose (or cross-linked sodium carboxymethyl cellulose), microcrystalline cellulose, cellulose gel and mixtures thereof. In embodiments, the amount of disintegrant present in the dosage form may range from about 1% w/w to about 5% w/w. For example, the amount of disintegrant present in the dosage form can range from about 1% w/w to about 5% w/w, about 1% w/w to about 4% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, about 2% w/w to about 5% w/w, about 2% w/w to about 4% w/w, about 2% w/w to about 3% w/w, about 3% w/w to about 5% w/w, about 3% w/w to about 4% w/w, or about 4% w/w to about 5% w/w. In embodiments, the disintegrant is present in an amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, or about 5% w/w. In embodiments, the disintegrant is present in an amount of about 1% w/w. In an embodiment, the disintegrant is present in an amount of about 2% w/w. In an embodiment, the disintegrant is present in an amount of about 3% w/w. In an embodiment, the disintegrant is present in an amount of about 4% w/w. In an embodiment, the disintegrant is present in an amount of about 5% w/w.

In embodiments, examples of suitable diluents/fillers (also referred to as matrix formers) include, but are not limited to, materials derived from animal or plant proteins, such as mammalian gelatin, non-mammalian gelatin, fish gelatin (e.g., high molecular weight gelatin with more than 50%, more than 60%, or more than 70% of the molecular weight distribution of gelatin greater than 30,000 Daltons); standard molecular weight gelatin, wherein more than substantially 50%, preferably more than 60%, and most preferably more than 70% of the molecular weight distribution of gelatin is less than 30,000 Daltons and may form a combination in which the ratio of high molecular weight gelatin to standard molecular weight gelatin (HMW:SMW) ranges from substantially 1:1 to 1:9), dextrin and soy, wheat and aliphatic. psyllium protein; gums such as gum arabic, guar gum, agar, and xanthan gum; polysaccharides; alginates; carboxymethylcellulose; carrageenan; polydextrose; pectin; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-arabic gum complex, starch, mannitol, dicalcium phosphate, potassium sulfate, microcrystalline fiber The invention relates to a pharmaceutical composition comprising a diluent/filler (or matrix former) and a composition comprising a diluent/filler. The composition comprises a diluent/filler (or matrix former) and a composition comprising a diluent/filler (or matrix former) and a composition comprising a diluent/filler (or matrix former). The diluent/filler (or matrix former) comprises a diluent/filler (or matrix former) and a composition comprising ... For example, the amount of diluent/filler present in the dosage form can range from about 1% w/w to about 50% w/w, about 1% w/w to about 20% w/w, about 1% w/w to about 10% w/w, about 1% w/w to about 5% w/w, about 5% w/w to about 50% w/w, about 5% w/w to about 25% w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w/w, about 10% w/w to about 50% w/w, about 10% w/w to about 40% w/w, about 10% w/w to about 30% w/w, about 10% w/w to about 20% w/w, about 10% w/w to about 15% w/w, about 20% w/w to about 50% w/w, about 20% w/w to about w/w to about 40% w/w, about 20% w/w to about 30% w/w, about 20% w/w to about 25% w/w, about 30% w/w to about 50% w/w, about 30% w/w to about 40% w/w, about 30% w/w to about 35% w/w, about 40% w/w to about 50% w/w, or about 40% w/w to about 45% w/w. In embodiments, the diluent/filler is present in an amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, or about 50% w/w, including all ranges and values therebetween.

In embodiments, examples of suitable binders include, but are not limited to, starch, pregelatinized starch, PVP (polyvinyl pyrrolidone), polyethylene oxide, polyethylene glycol, gum arabic, alginic acid, tragacanth, sucrose, guar gum, bentonite, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts; and mixtures thereof. In embodiments, the binder is present in the range of about 0% to about 20% w/w of the dosage form. For example, the amount of binder present in the dosage form can range from about 1% w/w to about 20% w/w, about 1% w/w to about 10% w/w, about 1% w/w to about 5% w/w, about 5% w/w to about 20% w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w/w, about 10% w/w to about 20% w/w, or about 10% w/w to about 15% w/w. In embodiments, the binder is present in an amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w, or about 20% w/w, including all ranges and values therebetween.

In embodiments, examples of suitable flow aids are selected from the group consisting of calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, talc, colloidal silica, silica gel, precipitated silica, and mixtures thereof. In embodiments, the flow aid is present in the range of about 0% to about 5% w/w of the dosage form. For example, the amount of glidant present in the dosage form can range from about 0.1% w/w to about 5% w/w, about 0.1% w/w to about 3% w/w, about 0.1% w/w to about 1% w/w, about 0.5% w/w to about 5% w/w, about 0.5% w/w to about 3% w/w, about 0.5% w/w to about 1% w/w, about 1% w/w to about 5% w/w, about 1% w/w to about 4% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, about 2% w/w to about 5% w/w, about 2% w/w to about 4% w/w, about 2% w/w to about 3% w/w, about 3% w/w to about 5% w/w, about 3% w/w to about 4% w/w, or about 4% w/w. In embodiments, the glidant is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, or about 5% w/w, including all ranges and values therebetween.

In the embodiment, examples of suitable lubricants include but are not limited to magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearate, sucrose fatty acid esters, aluminum stearate, potassium sodium tartrate, light silicic anhydride, carnauba wax, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydrated silica, hydrogenated oil, hydrogenated rapeseed oil, and mixtures thereof. In the embodiment, the lubricant is present in the range of about 0% to about 3% w/w of the dosage form. For example, the amount of lubricant present in the dosage form can range from about 0.1% w/w to about 3% w/w, about 0.1% w/w to about 2% w/w, about 0.1% w/w to about 1% w/w, about 0.5% w/w to about 3% w/w, about 0.5% w/w to about 2% w/w, about 0.5% w/w to about 1% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, or about 2% w/w to about 3% w/w. In embodiments, the lubricant is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, or about 3% w/w, including all ranges and values therebetween.

In the embodiment, examples of suitable plasticizers include but are not limited to polyethylene glycol, triethyl citrate, acetylated monoglycerides, glycerol, monoacetate, diacetate, triacetin, phthalate derivatives (such as dimethyl phthalate, diethyl phthalate and dibutyl phthalate), polysorbate 80 and propylene glycol, 1,2,3-propanediol triacetate, hydrogenated starch hydrolysate, corn syrup, distilled acetylated monoglycerides, castor oil or its derivatives, sucrose acetate isobutyrate and mixtures thereof. In the embodiment, the plasticizer is present in the range of about 0% to about 10% w/w of the dosage form. For example, the amount of plasticizer present in the dosage form can range from about 0.1% w/w to about 10% w/w, about 0.1% w/w to about 5% w/w, about 0.1% w/w to about 3% w/w, about 0.1% w/w to about 1% w/w, about 0.5% w/w to about 10% w/w, about 0.5% w/w to about 5% w/w, about 0.5% w/w to about 3% w/w, about 0.5% w/w to about 1% w/w, about 1% w/w to about 10% w/w, about 1% w/w to about 5% w/w, about 1% w/w to about 4% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 5% w/w, w/w, about 2% w/w to about 4% w/w, about 2% w/w to about 3% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 5% w/w, about 3% w/w to about 4% w/w, about 4% w/w to about 10% w/w, about 4% w/w to about 5% w/w, or about 5% w/w to about 10% w/w. In embodiments, the plasticizer is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about 10% w/w, including all ranges and values therebetween.

In embodiments, examples of suitable pH adjusters include, but are not limited to, inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid), inorganic bases (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide), organic acids (e.g., citric acid, acetic acid, tartaric acid, succinic acid, boric acid, edetic acid, glucuronic acid, glutaric acid, malic acid, formic acid, gluconic acid, ascorbic acid or fatty acids) and/or organic bases (e.g., ethanolamine, triethanolamine) or mixtures thereof. In embodiments, the pH adjuster is present in the range of about 0% to about 2% w/w of the dosage form. For example, the amount of pH adjuster present in the dosage form can range from about 0.1% w/w to about 2% w/w, about 0.1% w/w to about 1% w/w, about 0.5% w/w to about 2% w/w, about 0.5% w/w to about 1% w/w, or about 1% w/w to about 2% w/w. In embodiments, the pH adjuster is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, or about 2% w/w, including all ranges and values therebetween.

In embodiments, examples of suitable coloring agents include, but are not limited to, food, drug and cosmetic (FD&C) dyes (FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lake), Ponceau, indigo drug and cosmetic (D&C) blue, indigo carmine; iron oxides (e.g., red iron oxide, yellow, black), quinoline yellow, flame red, brilliant red (carmine), carmoisine, sunset yellow, and mixtures thereof. In embodiments, the amount of coloring agent used ranges from about 0% to about 3% w/w of the dosage form. For example, the amount of colorant present in the dosage form can range from about 0.1% w/w to about 3% w/w, about 0.1% w/w to about 2% w/w, about 0.1% w/w to about 1% w/w, about 0.5% w/w to about 3% w/w, about 0.5% w/w to about 2% w/w, about 0.5% w/w to about 1% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, or about 2% w/w to about 3% w/w. In embodiments, the colorant is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, or about 3% w/w, including all ranges and values therebetween.

In embodiments, examples of suitable flavoring agents include, but are not limited to, strawberry, apple, pear, peach, plum, orange, pineapple, apricot, lemon, mint, black currant, banana, raspberry, raspberry flavor, wild berry, caramel, mint, licorice, grapefruit, caramel, vanilla, cherry and grape flavors; flavoring oils such as cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil and cassia oil, and mixtures thereof. In embodiments, the amount of flavoring agent used ranges from about 0% to about 3% w/w of the dosage form. For example, the amount of flavoring agent present in the dosage form can range from about 0.1% w/w to about 3% w/w, about 0.1% w/w to about 2% w/w, about 0.1% w/w to about 1% w/w, about 0.5% w/w to about 3% w/w, about 0.5% w/w to about 2% w/w, about 0.5% w/w to about 1% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, or about 2% w/w to about 3% w/w. In embodiments, the flavoring agent is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, or about 3% w/w, including all ranges and values therebetween.

In embodiments, suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated active substances. In embodiments, the amount of taste masking agent used ranges from about 0% to about 10% w/w of the dosage form. For example, the amount of taste masking agent present in the dosage form can range from about 0.1% w/w to about 10% w/w, about 0.1% w/w to about 5% w/w, about 0.1% w/w to about 3% w/w, about 0.1% w/w to about 1% w/w, about 0.5% w/w to about 10% w/w, about 0.5% w/w to about 5% w/w, about 0.5% w/w to about 3% w/w, about 0.5% w/w to about 1% w/w, about 1% w/w to about 10% w/w, about 1% w/w to about 5% w/w, about 1% w/w to about 4% w/w, about 1% w/w to about 3% w/w, about 1% w/w to about 2% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 5% w/w, w/w, about 2% w/w to about 4% w/w, about 2% w/w to about 3% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 5% w/w, about 3% w/w to about 4% w/w, about 4% w/w to about 10% w/w, about 4% w/w to about 5% w/w, or about 5% w/w to about 10% w/w. In embodiments, the taste masking agent is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about 10% w/w, including all ranges and values therebetween.

In embodiments, suitable viscosity enhancers include, but are not limited to, polymers, sugars, sugar alcohols, gums, clays, silica, and the like. In embodiments, the amount of viscosity enhancer used ranges from about 0% to about 65% w/w of the dosage form. For example, the amount of viscosity enhancing agent present in the dosage form can range from about 0.1% w/w to about 65% w/w, about 0.1% w/w to about 50% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 10% w/w, about 0.1% w/w to about 5% w/w, about 5% w/w to about 65% w/w, about 5% w/w to about 50% w/w, about 5% w/w to about 25% w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w/w, about 10% w/w to about 65% w/w, about 10% w/w to about 50% w/w, about 10% w/w to about 40% w/w, about 10% w/w to about 30% w/w, about 10% w/w to about w/w to about 20% w/w, about 10% w/w to about 15% w/w, about 20% w/w to about 65% w/w, about 20% w/w to about 50% w/w, about 20% w/w to about 40% w/w, about 20% w/w to about 30% w/w, about 20% w/w to about 25% w/w, about 30% w/w to about 65% w/w, about 30% w/w to about 50% w/w, about 30% w/w to about 40% w/w, about 30% w/w to about 35% w/w, about 40% w/w to about 65% w/w, about 40% w/w to about 50% w/w, about 40% w/w to about 45% w/w, about 50% w/w to about 65% w/w, about 50% w/w to about 60% w/w w/w or about 50% w/w to about 55% w/w. In embodiments, the viscosity enhancing agent is present in an amount of about 0% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about % w/w or about 65% w/w, including all ranges and values therebetween.

In the embodiment, examples of suitable sweeteners include, but are not limited to, fructose, sucrose, glucose, maltose, sorbitol, erythritol, xylitol, aspartame, stevia extract, licorice, ruhan fruit glycosides, sodium cyclohexylamine sulfonate, saccharin, sodium saccharin, acesulfame potassium, dextrose, sucralose, monosodium glycyrrhizinate, monoammonium glycyrrhizinate, isomalt, glycerol, dipotassium glycyrrhizinate, thaumatin, and mixtures thereof. In the embodiment, the amount of the sweetener ranges from about 0.5% to about 2% w/w of the dosage form. For example, the amount of sweetener present in the dosage form can range from about 0.5% w/w to about 2% w/w, about 0.5% w/w to about 1% w/w, or about 1% w/w to about 2% w/w. In embodiments, the sweetener is present in an amount of about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, or about 2% w/w, including all ranges and values therebetween.

In embodiments, the present disclosure provides an oral mucosal dosage form comprising: (i)      a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)     one or more mucoadhesive agents; and (iii)    one or more pharmaceutically acceptable formulators or carriers; wherein the dosage form disintegrates within not less than about 1 minute after contact with the oral mucosa. In embodiments, the dosage form is lyophilized (freeze-dried).

In an embodiment, the mucoadhesive agent is sodium alginate. In an embodiment, the mucoadhesive agent is carbomer.

In an embodiment, a lyophilized tablet for oral mucosa (e.g., sublingual or buccal or gingival) is provided, which comprises: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) sodium alginate; (iii) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate; (vi) lactose monohydrate; and (vii) other pharmaceutically acceptable excipients as appropriate. In an embodiment, the tablet disintegrates within more than about 1 minute after contact with the oral mucosa.

In an embodiment, a lyophilized tablet for oral mucosa (e.g., sublingual or buccal or gingival) is provided, which comprises: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) sodium alginate; (iii) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv) sucralose; (v) silicon dioxide; (vi) mannitol; and (vii) other pharmaceutically acceptable excipients as appropriate. In an embodiment, the tablet disintegrates within more than about 1 minute after contact with the oral mucosa.

In an embodiment, a lyophilized tablet for oral mucosa (e.g., sublingual or buccal or gingival) is provided, which comprises: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) carbomer; (iii) sodium cross-linked carboxymethylcellulose or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate; (vi) mannitol; and (vii) other pharmaceutically acceptable excipients as appropriate. In an embodiment, the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

In an embodiment, an oral mucosal (e.g., sublingual or buccal) lyophilized tablet is provided, comprising: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) carbomer; (iii) sodium cross-linked carboxymethylcellulose or sodium starch glycolate; (iv) sucralose; (v) silicon dioxide; (vi) lactose monohydrate; and (vii) other pharmaceutically acceptable excipients as appropriate. In an embodiment, the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

In an embodiment, the mucoadhesive agent is xanthan gum.

In an embodiment, an oral mucosal (e.g., sublingual or buccal) lyophilized tablet is provided, comprising: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) xanthan gum; (iii) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate; (vi) lactose monohydrate; and (vii) other pharmaceutically acceptable excipients as appropriate. In an embodiment, the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

In an embodiment, an oral mucosal (e.g., sublingual or buccal) lyophilized tablet is provided, comprising: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) xanthan gum; (iii) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv) sucralose; (v) silicon dioxide; (vi) mannitol; and (vii) other pharmaceutically acceptable excipients as appropriate. In an embodiment, the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

In an embodiment, the dosage form is a sublingual tablet and is oval or ovoid. In an embodiment, the dosage form is a transbuccal tablet and is ovoid in shape. In an embodiment, the dosage form is for treating agitation. In an embodiment, the dosage form is for reducing norepinephrine-induced hyperexcitation. In an embodiment, the dosage form is for treating depression.

In an embodiment, the present disclosure provides an oral mucosal tablet dosage form comprising: (i)      a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii)     one or more mucoadhesive agents; and (iii)    one or more pharmaceutically acceptable excipients or carriers.

In an embodiment, the tablet disintegrates in not less than about 1 minute after contact with the oral mucosa.

In an embodiment, the present disclosure provides an oral mucosal tablet dosage form comprising: (i)      a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)     one or more mucosal adhesives; and (iii)    one or more pharmaceutically acceptable excipients or carriers.

In an embodiment, the tablet disintegrates in not less than about 1 minute after contact with the oral mucosa.

In an embodiment, the present disclosure provides an oral mucosal dosage form comprising: (i)     a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)    a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii)   one or more mucosal adhesives; and (iv)   one or more pharmaceutically acceptable excipients or carriers.

In an embodiment, the tablet disintegrates within about 5 seconds to about 10 minutes after contact with the oral mucosa.

In embodiments, the dosage form is lyophilized (freeze-dried).

In embodiments, the dosage form is used to treat a condition associated with norepinephrine induced hyperarousal. In embodiments, the dosage form is used to treat ASD. In embodiments, the dosage form is used to prevent PTSD. In embodiments, the dosage form is used to treat pan-autistic disorder. In embodiments, the dosage form is used to treat agitation caused by norepinephrine induced hyperarousal. In embodiments, the agitation of an individual is treated without causing significant sedation. In embodiments, the dosage form is used to treat depression in an individual.

In an embodiment, the present disclosure provides an oral mucosal (sublingual or buccal) lyophilized tablet comprising: (i) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or polyethylene oxide; (iv) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (v) sucralose; (vi) magnesium stearate and/or silicon dioxide; (vii) lactose or mannitol; and (viii) other pharmaceutically acceptable excipients as appropriate. In an embodiment, the tablet disintegrates in not less than about 1 minute after contact with the oral mucosa.

In an embodiment, the oromucosal tablet comprises from about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof and from about 0.1 mg to about 100 mg of latromidine per unit. In an embodiment, the oromucosal tablet comprises about 10 μg to 240 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., about 30 μg, about 60 μg, about 90 μg, about 120 μg, 180 μg, about 210 μg, or about 240 μg, including all ranges and values therebetween) and about 1 mg to about 50 mg of latrazopyridine or a pharmaceutically acceptable salt thereof (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg, including all ranges and values therebetween) per unit.

In embodiments, the tablet is administered sublingually, buccally, or transgingivally. In embodiments, the dosage form is administered via a single dosage form or via multiple dosage forms. IV. Methods and Administration

In an embodiment, the present disclosure provides a method of reducing norepinephrine-induced hyperexcitation in a human subject, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing norepinephrine-induced hyperexcitation in a human subject, comprising orally administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating a disorder associated with norepinephrine-induced overexcitation in a human subject, comprising administering to the human subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In embodiments, the disorder is acute stress.

In embodiments, the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of anxiety, sleep disturbance, excessive startle reaction, irritability, inability to stop moving or sitting still, lack of motivation, or agitation.

In embodiments, the symptom is anxiety.

In embodiments, the symptom is sleep disturbance.

In embodiments, the symptom is an exaggerated fright reaction.

In embodiments, the symptom is irritability.

In embodiments, the symptom is an inability to stop moving or sitting still.

In embodiments, the symptom is lack of motivation.

In embodiments, the symptom is agitation.

In an embodiment, the human individual suffers from autism.

In embodiments, the methods prevent the condition from developing into post-traumatic stress disorder.

In embodiments, the disorder results from a traumatic event experienced by a human individual.

In embodiments, latromidine is administered within 1 week, 2 weeks, or 4 weeks of the traumatic event.

In an embodiment, latropyridine is administered within 3 days of the traumatic event. In an embodiment, latropyridine is administered within 1 day of the traumatic event. In an embodiment, latropyridine is administered within 4 hours of the traumatic event. In an embodiment, latropyridine is administered within 6 hours of the traumatic event. In an embodiment, latropyridine is administered within 12 hours of the traumatic event.

In embodiments, latromidine is administered once a day, twice a day, or three times a day.

In embodiments, the therapeutically effective amount of latromidine is in the range of about 5 mg to about 300 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 10 mg to about 200 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 10 mg to about 100 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 10 mg to about 80 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 15 mg to about 60 mg per day. In embodiments, the therapeutically effective amount of latromidine is in the range of about 30 mg to about 45 mg per day.

In an embodiment, the therapeutically effective amount of latromidine is evenly distributed to be administered twice daily or three times daily.

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or intermittently.

In embodiments, the disclosure provides preclinical animal models established to correlate norepinephrine agonist signaling with psychiatric disorders such as acute stress, PTSD, depression, substance withdrawal, substance cravings, agitation, panic disorder, and anxiety.

In embodiments, preclinical animal models include the resident intruder assay, the forced swim test, the yohimbine-induced anxiety model, and the CCK-induced panic model.

In an embodiment, the preclinical animal model is a home intruder assay and latromidine treatment reduces aggression in response to social exclusion.

In embodiments, the preclinical animal model is a CCK-induced panic model, where when rodents are administered CCK, they become panicky or anxious and will avoid leaving the closed arms of the maze. In embodiments, when latropyridine is administered, rodents leave the closed arms and explore the open arms, indicating that they are less anxious. In embodiments, CCK also induces panic in healthy human volunteers, indicating that this is a translatable model.

In embodiments, preclinical animal models unexpectedly demonstrate that latromidine unexpectedly reduces the severity of symptoms in stress-related psychiatric disorders including acute stress disorder, PTSD, depression, substance withdrawal, substance cravings, agitation, panic disorder, and anxiety.

In embodiments, preclinical models relate norepinephrine agonist signaling to ADHD.

In embodiments, the methods described herein reduce the extent of symptoms experienced by patients and improve their clinical outcomes due to enhanced compliance with basic therapeutic treatments, including adherence to medication regimens and participation in therapy.

In embodiments, the improved clinical outcome results from patients with reduced symptoms interacting more effectively in social contexts, reducing aggression and panic symptoms that may result from a lack of social interaction, as seen in disorders such as autism.

In embodiments, the methods described herein provide effective symptom management to prevent disease progression, such as occurs when acute stress disorder progresses to PTSD.

In embodiments, the present disclosure provides for the use of latrapyridine to treat and prevent the progression of symptoms such as acute stress and pan-autistic disorder over time.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject as a single therapy a dosage formulation comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising orally administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof as a single treatment.

In an embodiment, the present disclosure provides a method for preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD following a traumatic event in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating ASD in a subject in need thereof, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of increasing the defense against the development of PTSD after a traumatic event in an individual, comprising administering to the individual via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of latrazolidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage form comprising about 10 mg to about 100 mg (including all ranges or values therebetween) of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, about 10 mg to about 40 mg of latrolpyridine or a pharmaceutically acceptable salt thereof is administered once, twice, or three times a day. In an embodiment, about 20 mg to about 80 mg of latrolpyridine or a pharmaceutically acceptable salt thereof is administered once, twice, or three times a day.

In embodiments, a total daily dose of about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 40 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 60 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject.

In embodiments, a dosage form comprising latrompyridine or a pharmaceutically acceptable salt thereof is administered immediately following the traumatic event. In embodiments, a dosage form comprising latrompyridine or a pharmaceutically acceptable salt thereof is administered between 1 minute and 48 hours (including all ranges and values in between) after the traumatic event. In embodiments, a dosage form comprising latrompyridine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event. In embodiments, a dosage form comprising latrompyridine or a pharmaceutically acceptable salt thereof is administered within 48 hours of the traumatic event. In embodiments, a dosage form comprising latrompyridine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In embodiments, administration of latrolpyridine continues for up to 4 weeks. In embodiments, the dosage form comprising latrolpyridine or a pharmaceutically acceptable salt thereof is administered in a single or multiple units.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of preventing PTSD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating ASD following a traumatic event in a subject in need thereof, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of increasing protection against the development of PTSD following a traumatic event in a subject, comprising administering to the subject via the oral mucosa (e.g., sublingually, buccally, or intragingivally) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately following the traumatic event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours (including all ranges and values in between) after the traumatic event. In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 1 hour of the traumatic event (or prior to the onset of ASD). In embodiments, a dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event (or prior to the onset of ASD). In embodiments, administration of dexmedetomidine continues for up to 4 weeks. In an embodiment, the dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single unit or multiple units.

In embodiments, about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a subject, including all ranges or values therebetween. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 micrograms, about 30 micrograms, about 40 micrograms, about 60 micrograms, about 80 micrograms, about 120 micrograms, about 150 micrograms, about 180 micrograms, or more.

In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or more times a day (e.g., once a day, twice a day, three times a day, or four times, five times, or six times a day), preferably once, twice, or three times a day.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or transgingivally in the form of a wafer, patch or film.

In an embodiment, the present disclosure provides a method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine and dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event and for a period of up to 4 weeks.

In an embodiment, the present disclosure provides a method of preventing PTSD in an individual in need thereof, comprising administering a therapeutically effective amount of latromidine and dexmedetomidine or a pharmaceutically acceptable salt thereof within 24 hours of the traumatic event and continuing for a period of up to 4 weeks.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof as a single therapy.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising orally administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof as a single treatment.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject comprising administering to the subject a dosage form comprising about 1 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the dosage form comprises about 10 mg to about 60 mg of latrepyridine or a pharmaceutically acceptable salt thereof, for example, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg, including all ranges and values therebetween.

In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In an embodiment, about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In an embodiment, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered once a day. In an embodiment, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered twice a day. In embodiments, about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered three times a day. In embodiments, a total daily dose of about 10 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 20 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 30 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 40 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject. In embodiments, a total daily dose of about 60 mg of latrepyridine or a pharmaceutically acceptable salt thereof is administered to a subject.

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally. In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried).

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered via the oral mucosa (sublingually or via the buccal or gingival) in the form of a wafer capsule, patch or film.

In embodiments, latrolpyridine or a pharmaceutically acceptable salt thereof is administered in single or multiple unit dose forms.

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered once or more times a day (e.g., once a day, twice a day, three times a day, or four times, five times, or six times a day), preferably once, twice, or three times a day.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latropyridine.

In an embodiment, the present disclosure provides a method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latropyridine.

In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually/buccally. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet. In embodiments, the tablet is lyophilized (or freeze-dried). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally or transgingivally in the form of a wafer, patch or film.

In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple unit dose form.

In an embodiment, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once or more times a day (e.g., once a day, twice a day, three times a day, or four times, five times, or six times a day), preferably once, twice, or three times a day.

In an embodiment, the unit dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latromidine is administered simultaneously at the same time or within a short period of time, usually less than 1 hour, preferably 0.5 hour, and more preferably 0.25 hour.

In an embodiment, the unit dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latrapyridine is administered sequentially at any time period within about 24 hours from each other, such as about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour.

In embodiments, dexmedetomidine and latrepyridine are provided in two separate dosage forms for treating pan-autistic disorder in a subject, one dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, and the other dosage form comprising a therapeutically effective amount of latrepyridine or a pharmaceutically acceptable salt thereof. In embodiments, the active agents dexmedetomidine and latrepyridine are administered concurrently to a subject in need thereof. In embodiments, the active agents dexmedetomidine and latrepyridine are administered sequentially to a subject in need thereof.

In an embodiment, dexmedetomidine and latromidine are provided in a single dosage form for treating pan-autistic disorder, wherein the dosage form comprises a therapeutically effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, the combination comprising latropyridine and dexmedetomidine or a salt thereof is administered for at least 7 days, at least 10 days, at least 30 days, at least 60 days, at least 180 days, at least 365 days, or longer.

In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale (CARS). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale 2-Standard Form (CARS2-ST). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale 2-High Functioning (CARS2-HF). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Aberrant Behavior Checklist (ABC). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Social Responsiveness Scale (SRS). In an embodiment, the severity of autism symptoms is assessed by the Vineland Adaptive Behavior Scale-II (VABS-II).

In embodiments, the improvement in scores is measured after at least 8, 16, 24, 32, 40, 50, 60, or 80 weeks of treatment and compared to the scores before treatment.

In embodiments, improvement in symptoms is measured after at least 2, 4, 6, 8, 10 or more weeks of discontinuation of treatment and compared to measurements prior to treatment.

In an embodiment, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on a Social Responsiveness Scale (SRS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on a social responsiveness scale (SRS) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on a Social Responsiveness Scale (SRS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, treatment results in a score reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the score before treatment, wherein the severity of pan-autistic symptoms is assessed based on the CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II scales. In embodiments, the score reduction is achieved after at least 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, or more of treatment.

In embodiments, treatment achieves a reduction in autism symptom severity of between 10% and 20%, between 10% and 30%, between 10% and 40%, between 10% and 50%, between 10% and 60%, between 10% and 70%, between 10% and 80%, between 10% and 90%, between 20% and 30%, between 20% and 40%, between 20% and 50%, between 20% and 60%, between 20% and 70%, between 20% and 80%, between 20% and 90%, between 30% and 40%, between 30% and 50%, between 30% and 50%, between 30% and 60%, between 30% and 70%, between 30% and 5 ... between 0%, between 30% and 60%, between 30% and 70%, between 30% and 80%, between 30% and 90%, between 40% and 50%, between 40% and 60%, between 40% and 70%, between 40% and 80%, between 40% and 90%, between 50% and 60%, between 50% and 70%, between 50% and 80%, or between 50% and 90%, wherein autism symptom severity is assessed by a method selected from the group consisting of: CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, treatment achieves a reduction in autism symptom severity of between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% after 8 or more weeks of treatment compared to before the start of treatment, wherein autism symptom severity is assessed by a method selected from the group consisting of: CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, treatment achieves a reduction in autism symptom severity of between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% after 12 or more weeks of treatment compared to before the start of treatment, wherein autism symptom severity is assessed by a method selected from the group consisting of: CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, treatment achieves a reduction in ASD symptom severity of between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% after 18 weeks or more of treatment compared to before the start of treatment, wherein autism symptom severity is assessed by a method selected from the group consisting of: CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II. In embodiments, treatment achieves a reduction in autism symptom severity of between 10% and 90%, between 20% and 80%, between 30% and 70%, or between 40% and 60% after 24 weeks or more of treatment compared to before the start of treatment, wherein autism symptom severity is assessed by a method selected from the group consisting of: CARS, CARS2-ST, CARS2-HF, ABC, SRS, and VABS-II.

In embodiments, the subject is a toddler, a teenager, a pediatric patient, or a geriatric patient. In embodiments, the subject is a child less than about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In embodiments, the subject is an adult patient. In embodiments, the subject is a geriatric patient. In embodiments, the subject is over about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old.

In embodiments, the treatment inhibits the progression of autism or reduces the severity of one or more symptoms thereof. In embodiments, the treatment inhibits the progression of Asperger's syndrome or reduces the severity of one or more symptoms thereof. In embodiments, the treatment inhibits the progression of childhood disintegrative disorder or reduces the severity of one or more symptoms thereof. In embodiments, the treatment inhibits the progression of Rett's syndrome or reduces the severity of one or more symptoms thereof.

In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale (CARS). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale 2-Standard Form (CARS2-ST). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Child Autism Rating Scale 2-High Functioning (CARS2-HF). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Aberrant Behavior Checklist (ABC). In an embodiment, the severity of pan-autistic disorder symptoms is assessed by the Social Responsiveness Scale (SRS). In an embodiment, the severity of autism symptoms is assessed by the Vineland Adaptive Behavior Scale-II (VABS-II).

The Childhood Autism Rating Scale (CARS) is a 15-item scale: relating to people; imitation; emotional responses; use of body; use of objects; adaptation to change; visual responses; auditory responses; taste, smell, and touch responses and use; fears; verbal communication; nonverbal communication; activities; level and consistency of intellectual responses; and global impression. It can be used to diagnose both autism and ASD and to assess the overall severity of symptoms. The CARS assessment is performed after the ADIR assessment by the same assessor.

The second version of the CARS, called the Childhood Autism Rating Scale-2 or CARS2, was developed by Schopler et al. (Childhood Autism Rating Scale—Second edition (CARS2): Manual. Los Angeles: Western Psychological Services, 2010). The original CARS was developed primarily for individuals with comorbid intellectual functioning and has been criticized for not accurately identifying higher functioning individuals with ASD. The CARS-2 retains the original CARS form for younger or lower functioning individuals (now renamed the "Standard Form" from the CARS2-ST) and also includes an additional rating scale for higher functioning individuals (the "High Functioning" scale is named CARS2-HF) and an unscored information collection scale (the "Parent or Caregiver Questionnaire" or CARS2-QPC) for use in the CARS2ST and CARS2-HF assessments.

The Aberrant Behavior Checklist (ABC) is a symptom-rating checklist used to assess and categorize problematic behaviors in children and adults in a variety of settings. The ABC consists of 58 items organized into five subscales: (1) irritability/agitation; (2) lethargy/social withdrawal; (3) stereotyped behavior; (4) hyperactivity/noncompliance; and (5) inappropriate speech.

The Social Responsiveness Scale (SRS) is a 65-item scale that assesses social impairment, a core problem in autism, including social cognition, social information processing, mutual social communication skills, social anxiety/avoidance, and autistic prejudices and traits. See Constantino et al., Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord. 2003 Aug;33(4):427-33.

The Repetitive Behavior Scale-Revised (RBS-R) (Bodfish et al., The Repetitive Behavior Scale: A test manual (1998)) is an empirically derived clinical rating scale used to measure the presence and severity of various forms of restricted repetitive behaviors that characterize individuals with autism. The RBS-R consists of six subscales: stereotyped behaviors, self-injurious behaviors, compulsive behaviors, routine behaviors, identity behaviors, and restricted behaviors. The scale provides an overall raw score for the severity of the repetitive behaviors and another measure of each subtype of repetitive behaviors. High scores indicate more severe behavioral symptoms.

The Vineland Adaptive Behavior Scale II (VABS-II) is a measure of functional level in four different domains: communication, daily living skills, socialization, and motor skills, and 11 subdomains. Raw scores are converted to age-equivalent scores. It complements the ABCs of problem behavior assessment. See Sara et al., Vineland Adaptive Behavior Scales, Second Edition (Vineland™-II), Pearson Publishing, 2005.

Other scales that can be used to assess improvement in general autism include the Clinical Global Impression Scale (CGI), the Pervasive Developmental Disorder Behavior Inventory (PDDBI), the Expressive Word Picture Vocabulary Test-4 (EOWPVT-4), the Behavioral Assessment of Social Skills for Children subscale, the Sensory Experience Questionnaire, an intelligence scale (Mullen Scales of Early Learning or Stanford-Binet), the Language Environment Analysis, the Preschool Psychiatric Assessment, the Prelingual Autism Diagnostic Observation Scale (PL-ADOS), the Autism Diagnostic Interview-Revised (ADI-R), the ATN GI Symptom Inventory, and the Parenting Stress Index.

In embodiments, the present disclosure provides methods for treating agitation in an agitated individual, comprising administering to the individual a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. In embodiments, the therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof is in a dosage form as described herein.

In embodiments, the present disclosure provides a method of treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. In embodiments, latromidine or a pharmaceutically acceptable salt thereof is administered (e.g., daily) for at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, or at least one year.

In embodiments, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In embodiments, the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects). In embodiments, the therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof is in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is in a dosage form as described herein. In embodiments, therapeutically effective amounts of latropyridine and dexmedetomidine or pharmaceutically acceptable salts thereof are present in the same dosage form or in separate dosage forms as described herein.

In an embodiment, the active agents dexmedetomidine and latrepyridine are administered concurrently (in the same dosage form or in separate dosage forms) to a subject for a specific period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, etc.), followed by administration of latrepyridine as a single dose to the subject for a specific period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, etc.).

The present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual oromucosally a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride). In embodiments, the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects). In embodiments, a single administration of the combination treats agitation and maintains sedation for at least 12 hours. In embodiments, the therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof is in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is in a dosage form as described herein. In embodiments, therapeutically effective amounts of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

In embodiments, agitation can be acute agitation, chronic agitation, or both.

In embodiments, agitation is caused by norepinephrine induced hyperexcitation.

In embodiments, agitation is treated without inducing any significant sedation.

In embodiments, agitation is associated with a neuropsychiatric disorder selected from schizophrenia, mania, bipolar disorder, delirium, depression, or other related neuropsychiatric disorder.

In embodiments, agitation is associated with a neurodegenerative disorder selected from Alzheimer's disease, frontotemporal dementia (or Pick's disease), dementia, dementia with Lewy bodies, post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy, or other related neurodegenerative disorders.

In embodiments, agitation is associated with alcohol withdrawal or substance abuse withdrawal including opioid withdrawal.

The present disclosure provides a method for treating chronic agitation in a subject, comprising administering to the subject via the oral mucosa a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride). In embodiments, the subject suffers from dementia. In embodiments, dementia includes Alzheimer's disease dementia (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (LBD), and Down dementia.

In embodiments, the present disclosure provides a method for treating chronic agitation in an individual, comprising administering to the individual via the oral mucosa a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for treating chronic agitation in an individual, comprising administering to the individual via the oral mucosa a dosage form comprising a combination of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the individual suffers from dementia. In embodiments, dementia includes Alzheimer's disease dementia (AD), frontotemporal dementia (FTD), vascular dementia, Lewy body disease (LBD), and Down's dementia.

In embodiments, the present disclosure provides a method of treating agitation in an agitated individual comprising administering to the individual oromucosally a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. In embodiments, agitation is caused by norepinephrine-induced hyperexcitation. In embodiments, the therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein. In embodiments, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is present in a dosage form as described herein.

In embodiments, the agitation is severe. In embodiments, the agitation is mild.

In an embodiment, the present disclosure provides a method of treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid Alzheimer's disease.

In an embodiment, the present disclosure provides a method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid Alzheimer's disease.

In an embodiment, the present disclosure provides a method of treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid dementia.

In an embodiment, the present disclosure provides a method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid dementia.

In an embodiment, the present disclosure provides a method of treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid Parkinson's disease.

In an embodiment, the present disclosure provides a method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid Parkinson's disease.

In an embodiment, the present disclosure provides a method of treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid PTSD.

In an embodiment, the present disclosure provides a method of treating agitation in an individual comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid PTSD.

In an embodiment, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid vascular cognitive impairment.

In an embodiment, the present disclosure provides a method of treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid vascular cognitive impairment.

In an embodiment, the present disclosure provides a method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid Huntington's disease.

In an embodiment, the present disclosure provides a method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid Huntington's disease.

In an embodiment, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid schizophrenia.

In an embodiment, the present disclosure provides a method of treating agitation in an individual comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid schizophrenia.

In an embodiment, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid bipolar disorder.

In an embodiment, the present disclosure provides a method of treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid bipolar disorder.

In an embodiment, the present disclosure provides a method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from comorbid depressive disorder.

In an embodiment, the present disclosure provides a method for treating agitation in an individual, comprising administering a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa, wherein the individual suffers from comorbid depressive disorder.

In an embodiment, the present disclosure provides a method of treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from dementia.

In an embodiment, the present disclosure provides a method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from agitation associated with delirium.

In an embodiment, the present disclosure provides a method for treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa: (i)   about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), and (ii)  about 0.1 mg to about 100 mg of latrazol or a pharmaceutically acceptable salt thereof.

In embodiments, agitation is treated without otherwise causing significant sedation. In embodiments, agitation is caused by norepinephrine induced hyperexcitation. In embodiments, therapeutically effective amounts of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

In an embodiment, the present disclosure provides a method for treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa: (i)   about 5 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride), and (ii)  about 5 mg to about 50 mg of latrazol or a pharmaceutically acceptable salt thereof.

In embodiments, agitation is treated without otherwise causing significant sedation. In embodiments, agitation is caused by norepinephrine induced hyperexcitation. In embodiments, therapeutically effective amounts of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof are present in the same dosage form or in separate dosage forms as described herein.

In an embodiment, the present disclosure provides a method of reducing norepinephrine-induced hyperstimulation, comprising administering to a subject via the oral mucosa a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of reducing norepinephrine-induced hyperstimulation, comprising oromucosally administering to a subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride).

In embodiments, dexmedetomidine and latrepyridine are administered together in a single dosage form. In embodiments, dexmedetomidine and latrepyridine are administered in combination in separate dosage forms. In embodiments, dexmedetomidine and latrepyridine or a pharmaceutically acceptable salt thereof are administered as a single dose via a single unit dosage form or multiple unit dosage forms administered simultaneously. In embodiments, dexmedetomidine or a salt thereof is administered in one or more unit doses of a total daily dose of up to about 0.5 micrograms to about 500 micrograms. In embodiments, latrepyridine or a salt thereof is administered in one or more unit doses of a total daily dose of up to about 1 mg to about 100 mg.

In an embodiment, the present disclosure provides a method of treatment comprising administering to a subject dexmedetomidine or a pharmaceutically acceptable salt thereof in an oromucosal dosage form that provides rapid relief of agitation and then continuing treatment with latromidine or a pharmaceutically acceptable salt thereof for an effective period of time.

In an embodiment, the present disclosure provides a method for treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. In an embodiment, the behavioral and psychological symptoms include agitation or aggression.

In an embodiment, the present disclosure provides a method for treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder, comprising oromucosal administration of a therapeutically effective amount of latromidine and dexmedetomidine or a pharmaceutically acceptable salt thereof. In an embodiment, the behavioral and psychological symptoms include agitation or aggression.

In an embodiment, the present disclosure provides a method for treating behavioral and psychological symptoms in an individual suffering from a neuropsychiatric disorder, comprising administering a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof via the oral mucosa. In an embodiment, the behavioral and psychological symptoms include agitation or aggression.

In an embodiment, the present disclosure provides a method for treating behavioral and psychological symptoms in an individual suffering from a neuropsychiatric disorder, comprising administering a therapeutically effective amount of latromidine and dexmedetomidine or a pharmaceutically acceptable salt thereof via the oral mucosa. In an embodiment, the behavioral and psychological symptoms include agitation or aggression.

In embodiments, the present disclosure provides for the use of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof for treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder.

In embodiments, the present disclosure provides for the use of therapeutically effective amounts of latromidine and dexmedetomidine, or pharmaceutically acceptable salts thereof, for treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder.

In embodiments, the present disclosure provides for the use of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof for treating behavioral and psychological symptoms in an individual suffering from a neuropsychiatric disorder.

In embodiments, the present disclosure provides for the use of therapeutically effective amounts of latromidine and dexmedetomidine or pharmaceutically acceptable salts thereof for treating behavioral and psychological symptoms in individuals suffering from a neuropsychiatric disorder.

In an embodiment, the present disclosure provides a method for treating depression in an individual in need thereof, comprising administering to the individual a dosage form comprising a therapeutically effective amount of latrapyridine or a pharmaceutically acceptable salt thereof via the oral mucosa. In an embodiment, latrapyridine is administered once a day at a dose of about 1 mg to about 100 mg. In an embodiment, latrapyridine is administered once a day at a dose of about 10 mg. In an embodiment, latrapyridine is administered once a day at a dose of about 20 mg. In an embodiment, latrapyridine is administered once a day at a dose of about 30 mg. In an embodiment, latrapyridine is administered twice a day at a dose of about 20 mg. In an embodiment, latrapyridine is administered three times a day at a dose of about 20 mg. In an embodiment, latrapyridine is administered once a day at a dose of about 30 mg. In an embodiment, latropyridine is administered twice a day at a dose of about 30 mg. In an embodiment, latropyridine is administered to a subject at a total daily dose of about 60 mg.

The present disclosure provides a method for treating depression in a subject in need thereof, comprising administering a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the subject via the oral mucosa.

The present disclosure provides a method for treating depression in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof. The present disclosure provides a method for treating depression in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof via the oral mucosa.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, comprising administering to the subject orally from about 1 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof and from about 5 μg to about 300 μg of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

In embodiments, improvements in depressive symptoms are observed as measured by the HAM-D-17 Depression subscale.

In embodiments, the subject has a HAM-D-17 total score of ≥18 at the start of treatment.

In an embodiment, a method is provided for reducing the score on the HDRS scale in a human subject suffering from depression, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latropyridine.

In an embodiment, a method is provided for reducing the score on the MADRS scale in a human subject suffering from depression, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latropyridine.

The HAM-D or HDRS is a tool used to assess symptoms of depression. The tool is administered by the clinician after a structured or unstructured interview with the patient to determine their symptoms. The total score is calculated by summing the individual scores from each question. Scores below 7 generally indicate the absence or remission of depression. Scores between 7-17 indicate mild depression. Scores between 18-24 indicate moderate depression. Scores of 25 and above indicate severe depression. Most studies on depression consider that a patient has responded to "treatment" if the score decreases by more than 50%. "Remission" should generally be understood as a score below 7.

The Montgomery-Asperger Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire that psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression, and each item produces a score from 0 to 6. The total score ranges from 0 to 60. The questionnaire includes questions about the following symptoms: 1. Obvious sadness, 2. Reports of sadness, 3. Feeling nervous, 4. Decreased sleep, 5. Decreased appetite, 6. Difficulty concentrating, 7. Fatigue, 8. Inability to feel, 9. Pessimistic thoughts, and 10. Suicidal thoughts.

In an embodiment, the unit dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latromidine is administered simultaneously at the same time or within a short period of time, usually less than 1 hour, preferably 0.5 hours, and more preferably 0.25 hours.

In an embodiment, the unit dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latromidine is administered sequentially at any time period within about 24 hours from each other, such as about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours or about 1 hour.

In an embodiment, the combination comprising latropyridine and dexmedetomidine or a salt thereof is administered once a day, twice a day, three times a day, or four, five, or six times a day, preferably once, twice, or three times a day.

In embodiments, the combination comprising latropyridine and dexmedetomidine or a salt thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

In an embodiment, the depression is moderate or severe. In an embodiment, the depression is severe depression, bipolar disorder or mixed depression.

In an embodiment, the present disclosure provides a synergistic combination comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; and (ii)  a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for treating depression in a subject in need thereof.

In embodiments, the present disclosure provides a method for treating psychosis in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof. In embodiments, latropyridine is administered once a day in a dose of about 1 mg to about 100 mg. In embodiments, latropyridine is administered once a day in a dose of about 10 mg. In embodiments, latropyridine is administered once a day in a dose of about 20 mg. In embodiments, latropyridine is administered once a day in a dose of about 30 mg. In embodiments, latropyridine is administered twice a day in a dose of about 10 mg. In embodiments, latropyridine is administered twice a day in a dose of about 20 mg. In embodiments, latropyridine is administered twice a day in a dose of about 30 mg. In an embodiment, latropyridine is administered three times a day at a dose of about 10 mg. In an embodiment, latropyridine is administered three times a day at a dose of about 20 mg. In an embodiment, latropyridine is administered three times a day at a dose of about 30 mg. In an embodiment, latropyridine is administered to a subject at a total daily dose of about 60 mg.

In an embodiment, the present disclosure provides a method for treating a psychotic disorder in a subject in need thereof, comprising administering to the subject via the oral mucosa a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

The present disclosure provides a method of treating a psychotic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latrazolidine or a pharmaceutically acceptable salt thereof.

The present disclosure provides a method for treating a psychotic disorder in a subject in need thereof, the method comprising oromucosal administration (e.g., sublingually, intrabuccally, or intragingivally) of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof to the subject.

In embodiments, treatment is effective without causing significant sedation.

In embodiments, treatment is effective without experiencing clinically significant cardiovascular effects. In embodiments, the severity of the individual's psychosis is assessed using the PANSS scale.

The Positive and Negative Syndrome Scale (PANSS) criteria have been widely used in clinical trials and are considered the "gold standard" for assessing the efficacy of antipsychotic treatment. To assess patients using the PANSS, a clinical interview of approximately 45 minutes is conducted. Patients are rated 1 to 7 for 30 different symptoms based on the interview and reports from family members or primary care hospital workers. Separate scores are usually given for positive items, negative items, and general psychopathology.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a prolonged psychotic disorder in a subject, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a sustained period of psychosis in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof to the subject.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a sustained period of psychosis in a subject, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In an embodiment, the present disclosure provides a method of achieving a reduction in PANSS scores for a sustained period of psychosis in a subject, comprising oromucosal administration to the subject of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

In embodiments, the PANSS score is reduced by at least about 20% to about 50% relative to the baseline score. In embodiments, the PANSS score is reduced by about 25% relative to the baseline score. In embodiments, the total PANSS score is reduced by about 30% relative to the baseline score. In embodiments, the total PANSS score is reduced by about 35% points relative to the baseline score. In embodiments, the total PANSS score is reduced by about 40% points relative to the baseline score. In embodiments, the total PANSS score is reduced by about 45% points relative to the baseline score. In embodiments, the total PANSS score is reduced by about 50% points relative to the baseline score.

In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the individual is agitated. In embodiments, the individual is not agitated.

In embodiments, the psychotic disorder is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia and mania or another related neuropsychiatric disorder. In embodiments, the psychotic disorder is associated with a neurodegenerative disorder.

In embodiments, the mental illness is associated with a condition such as a substance abuse disorder (e.g., alcohol, opioid and other substance withdrawal).

In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is a single episode. In embodiments, the psychosis is recurrent or includes recurrent episodes. In embodiments, acute psychosis is associated with acute psychotic episodes and/or mixed episodes. In embodiments, dexmedetomidine and latrazopyridine or a pharmaceutically acceptable salt thereof are administered by the buccal route. In embodiments, dexmedetomidine and latrazopyridine or a pharmaceutically acceptable salt thereof are administered by the sublingual route. In embodiments, dexmedetomidine and latrazopyridine or a pharmaceutically acceptable salt thereof are administered sublingually or buccally in the form of tablets or discs.

The combinations disclosed herein can be administered as long as needed to treat agitation. In embodiments, the combination is administered at least once a day (e.g., once a day or twice a day) for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer. The combinations disclosed herein can be administered as long as needed to treat depression.

The unit dose can be administered once a day, twice a day, three times a day, or four, five, or six times a day, preferably once, twice, or three times a day. The daily dose depends on the frequency of administration, preferably once or twice a day, or three or five times a day. The daily dose can be divided into two, three, four, five, or six times.

In an embodiment, the present disclosure provides a combination comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; and (ii)  a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for treating behavioral and psychological symptoms in an individual in need thereof.

In an embodiment, the present disclosure provides a synergistic combination comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, and (ii)  a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, for treating agitation in an individual in need thereof.

In an embodiment, the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

In an embodiment, the therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof is latromidine hydrochloride or dihydrochloride.

In embodiments, the agitated individual has a baseline score of about 14 or greater on the PEC scale.

In embodiments, an agitated individual experiences a decrease in PEC score following administration of a dosage form of the disclosure according to the methods described herein. In embodiments, the patient achieves a change in PEC score of more than -2 points relative to baseline within 2 hours of administration of the composition. For example, the PEC score decreases by about -1, about -2, about -3, about -4, about -5, about -6, about -7, about -8, about -9, or about -10 relative to baseline. In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 micrograms to about 500 micrograms (e.g., about 30, about 60, about 80, about 90, about 120, about 180, or about 240 micrograms). In embodiments, the dosage form comprises latrolpyridine or a pharmaceutically acceptable salt thereof. In embodiments, latrolpyridine or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 mg to about 100 mg. In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and latrolpyridine or a pharmaceutically acceptable salt thereof. In embodiments, the reduction in PEC score persists for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration of the composition.

In embodiments, the agitated individual has a baseline score on the ACES score of about 3 or less.

In embodiments, an agitated subject experiences an increase in Agitation-Calmness Assessment Scale (ACES) score after administration of a dosage form of the present disclosure according to the methods described herein. In embodiments, agitation is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior) as measured by the Agitation-Calmness Assessment Scale (ACES) 2 hours after administration of the composition. For example, the ACES score is increased to about 3 (mild agitation) or 4 (normal behavior). In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 micrograms to about 500 micrograms (e.g., about 30, about 60, about 90, about 120, about 180, or about 240 micrograms). In embodiments, the dosage form comprises latrolpyridine or a pharmaceutically acceptable salt thereof. In embodiments, latrolpyridine or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 mg to about 500 mg. In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and latrolpyridine or a pharmaceutically acceptable salt thereof. In embodiments, the ACES score increase persists for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration of the composition. In embodiments, the ACES score after treatment is preferably between 3 and 7; for example, 3, 4, 5, 6, or 7. Advantageously, an elevated ACES score is obtained shortly after administration of latropyridine (alone or, preferably, with dexmedetomidine); for example, an elevated ACES score can be obtained within about 2 hours of administration of the composition. For example, an elevated ACES score can be obtained within about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes. An elevated ACES score can be obtained within about 5 minutes to about 120 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 30 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 60 minutes, about 60 minutes to about 120 minutes, about 60 minutes to about 90 minutes, or about 90 minutes to about 120 minutes after administration of the composition.

In embodiments, the agitated individual has a baseline score of about 3 or higher on the CGI-I.

In embodiments, an agitated subject experiences an increase in CGI-I score after administration of a dosage form of the present disclosure according to the methods described herein. For example, the CGI-I score increases to about 1 (substantially increased) or about 2 (much increased). In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 micrograms to about 500 micrograms (e.g., 30, 60, 90, 120, or 180 micrograms). In embodiments, the dosage form comprises latromidine or a pharmaceutically acceptable salt thereof. In embodiments, latromidine or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 mg to about 500 mg. In embodiments, latrolpyridine or a pharmaceutically acceptable salt thereof is present in an amount of about 1 mg to about 100 mg. In embodiments, latrolpyridine or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg to about 50 mg. In embodiments, the dosage form comprises dexmedetomidine or a pharmaceutically acceptable salt thereof and latrolpyridine or a pharmaceutically acceptable salt thereof. In embodiments, the increase in CGI-I score persists for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration of the composition. In embodiments, the CGI-I score is about 1.

In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered sublingually. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered buccally. In an embodiment, latrapyridine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet. In an embodiment, the tablet is lyophilized (or freeze-dried).

In an embodiment, latrolpyridine or a pharmaceutically acceptable salt thereof is administered via the oral mucosa (sublingually or via the buccal or gingival) in the form of a wafer capsule, patch or film.

In embodiments, the oral mucosal dosage form is a tablet, capsule, patch, film, sachet, rice paper capsule, powder, microtablet, pill, paste, gel, ointment, cream, drop, liquid (e.g., solution, suspension or emulsion), spray, microsphere or nanosphere, which can be formulated according to standard methods in the art. V. Medical Kit:

According to the present disclosure, a kit of parts is provided, which comprises an oromucosal lyophilized tablet dosage form, wherein the dosage form comprises: (i)   a therapeutically effective amount of latrazopyridine or a pharmaceutically acceptable salt thereof; and, as appropriate (ii)  instructions for administering (i) simultaneously, sequentially or separately to a subject in need thereof.

According to the present disclosure, a kit of parts is provided, which comprises two oral mucosal lyophilized tablet dosage forms (i) and (ii), wherein the dosage forms comprise: (i)    a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii)    a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; and, as appropriate, (iii)  instructions for administering (i) and (ii) simultaneously, sequentially, or separately to a subject in need thereof.

According to the present disclosure, there is also provided a kit of parts comprising a single oral lyophilized tablet dosage form, the dosage form comprising: (i)    a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride); (ii)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; and, if appropriate (iii)  instructions for administering the single dosage form to a subject in need thereof.

Dexmedetomidine or a pharmaceutically acceptable salt thereof and latromidine or a pharmaceutically acceptable salt thereof are each provided in a form suitable for administration in combination with the other.

In embodiments, dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof are provided as part of the same or a single dosage form.

In an embodiment, dexmedetomidine and latrazopyridine or a pharmaceutically acceptable salt thereof are provided as two separate dosage forms, with one dosage form being administered before, after, and/or simultaneously with (or as appropriate) the other dosage form. When administered sequentially, the sequential administration may be close in time or distant in time. This may include a situation where the two dosage forms are administered (or as appropriate) sufficiently close in time to allow the beneficial effect on the patient to be greater during the treatment of the related disease than when either of the two compositions is administered (or as appropriate) alone during the same treatment.

When used in this context, the terms "administered simultaneously" and "administered at the same time" include within about 24 hours, such as about 23 hours, about 22 hours, about 21 hours, about 20 hours, about 19 hours, about 18 hours, about 17 hours, about 16 hours, about 15 hours, about 14 hours, about 13 hours, about 12 hours, about 11 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 2 ... The invention relates to administering individual doses of dexmedetomidine or a pharmaceutically acceptable salt thereof and latrapyridine or a pharmaceutically acceptable salt thereof within about 1 hour, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, or less than about 1 hour (i.e., about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute).

In embodiments, dexmedetomidine and latrazopyridine or a pharmaceutically acceptable salt thereof are administered simultaneously. In embodiments, the active agents are administered together in a single dosage form. When dexmedetomidine and latrazopyridine or a pharmaceutically acceptable salt thereof are provided as separate dosage forms, each dosage form may be packaged separately for use in combination with the other in combination therapy. Alternatively, the two dosage forms may be packaged and presented together as separate components of a "combination pack" for use in combination with each other in combination therapy. Specific Embodiments

Example 1. A method for treating a disorder associated with norepinephrine-mediated hyperexcitation in a human subject, comprising administering to the human subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Example 2. A method for treating a stress-mediated neuropsychiatric disorder mediated by norepinephrine induced hyperarousal in a human subject in need thereof, the method comprising: orally administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 3. The method of embodiment 1 or 2, wherein the disease of the human subject is acute stress disorder.

Embodiment 4. The method of embodiment 1 or 2, wherein the condition of the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of anxiety, sleep disturbance, excessive startle reaction, irritability, inability to stop moving or sitting still, lack of motivation and agitation.

Embodiment 5. The method of embodiment 4, wherein the symptom is anxiety.

Embodiment 6. The method of embodiment 4, wherein the symptom is sleep disorder.

Embodiment 7. The method of embodiment 4, wherein the symptom is an excessive fright reaction.

Embodiment 8. The method of Embodiment 4, wherein the symptom is irritability.

Embodiment 9. The method of embodiment 4, wherein the symptom is an inability to stop moving or sitting still.

Embodiment 10. The method of embodiment 4, wherein the symptom is lack of motivation.

Embodiment 11. The method of Embodiment 4, wherein the symptom is agitation.

Embodiment 12. The method of embodiment 1 or 2, wherein the disease of the human individual is pan-autistic disorder.

Embodiment 13. The method of any one of embodiments 1-12, wherein the method prevents the disorder from developing into post-traumatic stress disorder.

Embodiment 14. A method for treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 15. A method of treating ASD in a subject in need thereof, comprising orally administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof as a single treatment.

Embodiment 16. A method of treating ASD in a subject in need thereof, comprising administering to the subject a dosage formulation comprising about 10 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 17. A method of treating ASD following a traumatic event in a subject in need thereof, comprising orally administering to the subject a dosage form comprising about 10 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 18. A method for preventing PTSD in an individual in need thereof, comprising administering to the individual via the oral mucosa (eg, sublingually, buccally, or gingivally) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 19. The method according to embodiments 14 to 18, wherein latromidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg.

Embodiment 20. The method according to embodiments 14 to 18, wherein latromidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg.

Embodiment 21. The method according to embodiments 14 to 18, wherein latromidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 40 mg.

Embodiment 22. The method according to embodiments 14 to 18, wherein latromidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 60 mg.

Embodiment 23. The method according to embodiments 14 to 18, wherein latromidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 80 mg.

Embodiment 24. The method according to embodiments 19 to 23, wherein latromidine or a pharmaceutically acceptable salt thereof is administered once, twice or three times a day.

Embodiment 25. The method according to any one of embodiments 14-24, wherein the dosage form comprising latromidine or a pharmaceutically acceptable salt thereof is administered immediately after the traumatic event.

Embodiment 26. The method according to any one of embodiments 14-25, wherein the dosage form comprising latromidine or a pharmaceutically acceptable salt thereof is administered within 1 minute to 48 hours after the traumatic event.

Embodiment 27. The method according to any one of embodiments 14-25, wherein the dosage form comprising latromidine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the traumatic event.

Embodiment 28. The method according to any one of embodiments 14-25, wherein the dosage form comprising latromidine or a pharmaceutically acceptable salt thereof is administered before the onset of ASD.

Embodiment 29. The method according to any one of embodiments 14-26, wherein the dosage form comprising latropyridine or a pharmaceutically acceptable salt thereof is administered in a single unit or in multiple units.

Embodiment 30. The method according to any one of embodiments 14-29, wherein latromidine or a pharmaceutically acceptable salt thereof is administered orally.

Embodiment 31. The method according to any one of embodiments 14-29, wherein latromidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally.

Embodiment 32. The method according to embodiment 31, wherein latromidine or a pharmaceutically acceptable salt thereof is administered sublingually or intrabuccally in the form of tablets.

Embodiment 33. The method according to embodiment 32, wherein the tablet is freeze-dried (or lyophilized).

Embodiment 34. The method according to embodiment 31, wherein latromidine or a pharmaceutically acceptable salt thereof is administered in the form of a wafer capsule, a patch or a film.

Embodiment 35. The method according to any one of the preceding embodiments, wherein one or more symptoms of ASD are selected from increased anxiety, difficulty sleeping; excessive startle reactions, lack of motivation, irritability, and inability to stop moving or sitting still.

Embodiment 36. A method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 37. A method of preventing PTSD in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 38. A method of treating ASD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 39. A method of treating ASD occurring following a traumatic event in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 40. A method of treating ASD in an individual in need thereof, comprising administering to the individual about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 41. The method according to any one of embodiments 36-40, wherein the dosage form comprising dexmedetomidine and/or latromidine or a pharmaceutically acceptable salt thereof is administered immediately after the traumatic event.

Embodiment 42. The method according to any one of embodiments 36-40, wherein the dosage form comprising dexmedetomidine and/or latromidine or a pharmaceutically acceptable salt thereof is administered within 1 to 48 hours of the traumatic event.

Embodiment 43. The method according to any one of embodiments 36-40, wherein the dosage form comprising dexmedetomidine and/or latromidine or a pharmaceutically acceptable salt thereof is administered within 24 hours of the ASD.

Embodiment 44. The method according to any one of embodiments 36-40, wherein dexmedetomidine and/or latromidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple units.

Embodiment 45. The method according to embodiment 44, wherein about 20 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment 46. The method according to embodiment 44, wherein about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment 47. The method according to embodiment 44, wherein about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment 48. The method according to embodiment 44, wherein about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment 49. The method according to embodiment 43, wherein about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment 50. The method according to embodiment 43, wherein about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment 51. The method according to any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, or four, five, or six times a day.

Embodiment 52. The method according to any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally.

Embodiment 53. The method according to embodiment 52, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of tablets, wafers, patches or films.

Embodiment 54. The method according to embodiment 53, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or intrabuccally in the form of a film.

Embodiment 55. The method according to embodiment 53, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or intrabuccally in the form of tablets.

Embodiment 56. The method according to embodiment 55, wherein the tablet is lyophilized.

Embodiment 57. The method according to any one of embodiments 14-56, wherein the dosage form comprising latromidine and/or dexmedetomidine or a pharmaceutically acceptable salt thereof is administered immediately prior to an anticipated event that may lead to the development of PTSD.

Embodiment 58. The method according to any one of embodiments 14-56, wherein the dosage form comprising latromidine and/or dexmedetomidine or a pharmaceutically acceptable salt thereof is continuously administered during the PTSD-inducing event and/or for a period of time after the PTSD-inducing event.

Embodiment 59. The method according to any of the preceding embodiments, wherein the traumatic event is directly and personally experienced by the individual.

Embodiment 60. The method according to any of the preceding embodiments, wherein the traumatic event is witnessed by the individual.

Example 61. A kit of parts comprising an oromucosal lyophilized tablet dosage form comprising: (i)   a therapeutically effective amount of latrazopyridine or a pharmaceutically acceptable salt thereof; and, as appropriate (ii)  instructions for administering (i) simultaneously, sequentially or separately to a subject in need thereof.

Embodiment 62. The kit according to Embodiment 61, wherein latropyridine or a pharmaceutically acceptable salt thereof is latropyridine dihydrochloride.

Embodiment 63. A method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof as a single therapy.

Embodiment 64. A method of treating pan-autistic disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of dexmedetomidine alone or in combination with latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 65. The method of embodiment 63 or 64, wherein latromidine or a pharmaceutically acceptable salt thereof is administered orally and dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet, wafer, patch or film.

Embodiment 66. The method of any one of Embodiments 63 or 64, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually or buccally in the form of a tablet.

Embodiment 67. The method of Embodiment 66, wherein the tablet is lyophilized (or freeze-dried).

Embodiment 68. The method of embodiment 63 or 64, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a membrane.

Embodiment 69. The method of embodiment 63 or 64, wherein latromidine or dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in a single or multiple unit dosage form.

Embodiment 70. The method of Embodiment 69, wherein the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latromidine are administered simultaneously at the same time or within a short period of time.

Embodiment 71. The method of embodiment 69, wherein the unit dosage forms comprising dexmedetomidine or a pharmaceutically acceptable salt thereof and latromidine are administered sequentially within a time period of about 24 hours.

Embodiment 72. The method of Embodiment 69, wherein dexmedetomidine and latropyridine are administered concurrently to the subject.

Embodiment 73. The method of Embodiment 69, wherein the unit dosage forms comprising latropyridine and dexmedetomidine or a salt thereof are administered for at least 7 days, at least 10 days, at least 30 days, at least 60 days, at least 180 days, at least 365 days or longer.

Embodiment 74. The method of any one of the aforementioned embodiments, wherein the severity of the symptoms of general autism disorder is assessed by the Child Autism Rating Scale (CARS), the Child Autism Rating Scale 2-Standard Form (CARS2-ST), the Child Autism Rating Scale 2-High Functioning (CARS2-HF), the Aberrant Behavior Checklist (ABC), the Social Responsiveness Scale (SRS), and the Vineland Adaptive Behavior Scale II (VABS-II).

Embodiment 75. A method for reducing the score of a human subject suffering from pan-autistic disorder on the Childhood Autism Rating Scale (CARS), comprising oromucosal administration of an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 76. A method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 77. A method for reducing a score on the Childhood Autism Rating Scale (CARS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 78. A method for reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 79. A method for reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human subject suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 80. A method of reducing a score on the Childhood Autism Rating Scale 2-Standard Form (CARS2-ST) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 81. A method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 82. A method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 83. A method of reducing a score on the Childhood Autism Rating Scale 2-Standardized Form (CARS2-HF) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 84. A method for reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 85. A method for reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 86. A method of reducing a score on the Aberrant Behavior Checklist (ABC) in a human subject suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 87. A method for reducing a score on a Social Responsiveness Scale (SRS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 88. A method for reducing a score on a Social Responsiveness Scale (SRS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 89. A method for reducing a score on a Social Responsiveness Scale (SRS) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 90. A method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 91. A method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 92. A method for reducing a score on the Vineland Adaptive Behavior Scale II (VABS-II) in a human individual suffering from pan-autistic disorder, comprising administering an effective amount of dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 93. The method of any one of embodiments 75-92, wherein the treatment causes a decrease in the score by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% compared to the score before the treatment.

Embodiment 94. The method of any one of Embodiments 75-92, wherein the reduction in score is achieved after at least 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks or more of treatment.

Embodiment 95. The method of any one of Embodiments 75-92, wherein the treatment inhibits the progression of autism or reduces the severity of one or more symptoms thereof.

Embodiment 96. The method of any one of Embodiments 75-92, wherein the treatment inhibits the progression of Asperger's disorder or reduces the severity of one or more symptoms thereof.

Embodiment 97. The method of any one of Embodiments 75-92, wherein the treatment inhibits the progression of Rett's disorder or reduces the severity of one or more symptoms thereof.

Embodiment 98. The method of any one of Embodiments 75-92, wherein the treatment inhibits the progression of, or reduces the severity of, one or more symptoms of, childhood disintegrative disorder.

Embodiment 99. The method of any one of embodiments 75-92, wherein the treatment inhibits the progression of or reduces the severity of one or more symptoms of pervasive developmental disorder, unclassified.

Embodiment 100. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 1 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 101. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 10 mg to about 60 mg of latromidine or a pharmaceutically acceptable salt thereof, for example, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg, including all ranges and values therebetween).

Embodiment 102. The method of any one of Embodiments 75-92, wherein latropyridine or a pharmaceutically acceptable salt thereof is administered once, twice or three times a day.

Embodiment 103. The method of any one of Embodiments 75-92, wherein a total daily dose of about 10 mg of latromidine or a pharmaceutically acceptable salt thereof is administered to the subject.

Embodiment 104. The method of any one of Embodiments 75-92, wherein a total daily dose of about 20 mg of latromidine or a pharmaceutically acceptable salt thereof is administered to the subject.

Embodiment 105. The method of any one of Embodiments 75-92, wherein a total daily dose of about 30 mg of latromidine or a pharmaceutically acceptable salt thereof is administered to the subject.

Embodiment 106. The method of any one of Embodiments 75-92, wherein a total daily dose of about 40 mg of latromidine or a pharmaceutically acceptable salt thereof is administered to the subject.

Embodiment 107. The method of any one of Embodiments 75-92, wherein a total daily dose of about 60 mg of latromidine or a pharmaceutically acceptable salt thereof is administered to the subject.

Embodiment 108. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof for administration to the subject.

Embodiment 109. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof for administration to the subject.

Embodiment 110. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof for administration to the subject.

Embodiment 111. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof for administration to the subject.

Embodiment 112. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof for administration to the subject.

Embodiment 113. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof for administration to the subject.

Embodiment 114. The method of any one of Embodiments 75-92, wherein the dosage form comprises about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof for administration to the subject.

Embodiment 115. A method of treating agitation in an agitated individual, comprising administering to the individual a therapeutic amount of latromidine or a pharmaceutically acceptable salt thereof and a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 116. A method of treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 117. A method for treating agitation in an agitated individual, comprising administering to the individual a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Example 118. A method for treating agitation in an agitated individual, comprising administering to the individual via the oral mucosa a dosage form comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, and (ii)  a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 119. A method for treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 120. A method of treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder comprising oromucosal administration of a therapeutically effective amount of latromidine and dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 121. A method for treating behavioral and psychological symptoms in an individual suffering from a neuropsychiatric disorder, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 122. A method for treating behavioral and psychological symptoms in an individual suffering from a neuropsychiatric disorder, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof.

Example 123. Use of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof for treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder.

Example 124. Use of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof for treating behavioral and psychological symptoms in an individual suffering from a neuropsychiatric disorder.

Embodiment 125. Use of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof for treating behavioral and psychological symptoms in an individual suffering from a neurodegenerative disorder.

Embodiment 126. Use of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof for treating behavioral and psychological symptoms in an individual suffering from a neuropsychiatric disorder.

Embodiment 127. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid Alzheimer's disease.

Embodiment 128. A method for treating chronic agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from concomitant dementia.

Embodiment 129. A method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from idiopathic Parkinson's disease (Parkinson's disease).

Embodiment 130. A method of treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid PTSD.

Embodiment 131. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid vascular cognitive impairment.

Embodiment 132. A method of treating agitation in a subject comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from idiopathic Huntington's disease (Huntington's disease).

Embodiment 133. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid schizophrenia.

Embodiment 134. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid bipolar disorder.

Embodiment 135. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid depressive disorder.

Embodiment 136. A method for treating agitation in a subject, comprising oromucosal administration of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof, wherein the subject suffers from idiopathic delirium.

Embodiment 137. A method of treating agitation in an individual comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid Alzheimer's disease.

Embodiment 138. A method for treating chronic agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid dementia.

Embodiment 139. A method of treating agitation in an individual comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid Parkinson's disease.

Embodiment 140. A method of treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid PTSD.

Embodiment 141. A method of treating agitation in an individual comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid Huntington's disease.

Embodiment 142. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid schizophrenia.

Embodiment 143. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid bipolar disorder.

Embodiment 144. A method for treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid depressive disorder.

Embodiment 145. A method of treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from comorbid vascular cognitive impairment.

Embodiment 146. A method of treating agitation in an individual, comprising oromucosal administration of a therapeutically effective amount of a combination of latromidine or a pharmaceutically acceptable salt thereof and dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the individual suffers from idiopathic delirium.

Embodiment 147. The method according to any one of the preceding embodiments, wherein the agitation is severe.

Embodiment 148. The method according to any one of the preceding embodiments, wherein the agitation is mild or moderate.

Embodiment 149. The method according to any one of the preceding embodiments, wherein latropyridine is administered once a day in a dose of about 10 mg.

Embodiment 150. The method according to any one of the preceding embodiments, wherein latropyridine is administered once a day in a dose of about 20 mg.

Embodiment 151. The method according to any one of the preceding embodiments, wherein latropyridine is administered twice a day in a dose of about 10 mg.

Embodiment 152. The method according to any one of the preceding embodiments, wherein latropyridine is administered three times a day in a dose of about 10 mg.

Example 153. A method according to any of the preceding embodiments, wherein latropyridine is administered twice a day in a dose of about 20 mg.

Embodiment 154. The method according to any one of the preceding embodiments, wherein latropyridine is administered to the subject in a total daily dose of about 60 mg.

Embodiment 155. A method of treating agitation in an agitated individual comprising administering to the individual about 0.1 mg to about 500 mg of latromidine or a pharmaceutically acceptable salt thereof and about 0.5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 156. A method of treating agitation in an agitated individual, comprising oromucosally administering to the individual about 0.1 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 157. A method of treating agitation in an agitated individual comprising oromucosally administering to the individual about 5 mg to about 60 mg of latromidine or a pharmaceutically acceptable salt thereof and about 20 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 158. A method of treating agitation in an agitated individual comprising oromucosally administering to the individual about 1 mg to about 40 mg of latromidine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 200 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 159. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 160. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 161. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 162. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 163. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 164. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 165. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 166. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 167. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 168. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 169. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 170. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 171. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 172. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 173. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 174. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 175. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 176. A method of treating agitation in an agitated individual comprising administering to the individual about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 177. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 178. A method of treating agitation in an agitated individual comprising administering to the individual about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is caused by norepinephrine induced overexcitation.

Embodiment 179. A method for treating depression in a subject in need thereof, comprising administering to the subject via the oral mucosa a dosage form comprising a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 180. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa a dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 181. A method for treating depression in a subject in need thereof, the method comprising administering to the subject a dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 182. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa a dosage form comprising a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof in combination.

Embodiment 183. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 5 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof and about 10 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 184. The method according to embodiments 179-183, wherein the depression is moderate or severe.

Embodiment 185. The method according to embodiments 179-183, wherein the depression is severe depression.

Embodiment 186. The method according to embodiments 179-183, wherein the depression is mixed depression.

Embodiment 187. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 188. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 189. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 190. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 30 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 191. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 40 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 192. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 193. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 194. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 10 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 195. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 20 mg of latromidine or a pharmaceutically acceptable salt thereof and about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 196. A method for reducing the score on the HDRS scale in a human subject suffering from depression, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latromidine.

Embodiment 197. A method for reducing the score on the MADRS scale in a human subject suffering from depression, comprising oromucosal administration of an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof, alone or in combination with latropyridine.

Embodiment 198. The method according to any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof (eg, hydrochloride) and latromidine are administered in two separate dosage forms simultaneously or sequentially.

Embodiment 199. The method according to any of the preceding claims, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof and latropyridine are administered simultaneously in a single unit dosage form.

Embodiment 200. The method according to embodiment 199, wherein the two separate dosage forms are administered sequentially at a specific time interval, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes, or 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours.

Embodiment 201. The method according to any one of the preceding embodiments, wherein the dosage form is lyophilized.

Embodiment 202. The method according to any one of the preceding embodiments, wherein the dosage form is administered sublingually or buccally.

Embodiment 203. The method according to any of the preceding embodiments, wherein the dosage form disintegrates within not less than about 1 minute after contact with the oral mucosa.

Embodiment 204. The method according to any of the preceding embodiments, wherein the dosage form is mucoadhesive.

Embodiment 205. The method according to embodiment 88, wherein dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof is administered via the oral mucosa in a dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet and liquid drops.

Embodiment 206. The method according to embodiment 205, wherein the dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof are administered sublingually or intrabuccally in the form of a tablet.

Embodiment 207. The method according to any of the preceding embodiments, wherein the agitation is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy and progressive supranuclear palsy.

Embodiment 208. The method according to any one of the preceding embodiments, wherein the agitation is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, mania, bipolar disorder, delirium and depression.

Embodiment 209. The method according to any one of the preceding embodiments, wherein the agitation is associated with alcohol withdrawal, opioid use disorder, opioid withdrawal, and substance abuse withdrawal.

Embodiment 210. The method according to any of the preceding embodiments, wherein the agitation is associated with an OPD/IPD procedure (eg, MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedure).

Embodiment 211. The method according to any one of the preceding embodiments, wherein the agitation is acute.

Embodiment 212. The method according to any one of the preceding embodiments, wherein the agitation is chronic.

Embodiment 213. The method according to any one of the preceding embodiments, wherein the agitation is caused by norepinephrine-induced hyperexcitation.

Embodiment 214. The method according to any of the preceding embodiments, wherein the agitation is treated without causing significant sedation.

Embodiment 215. The method according to any one of the preceding embodiments, wherein latromidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.5 mg to about 500 mg.

Embodiment 216. The method according to embodiment 102, wherein the latropyridine or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg to about 100 mg.

Embodiment 217. The method according to any one of the preceding embodiments, wherein the dexmedetomidine is present in an amount of about 0.5 micrograms to about 300 micrograms.

Embodiment 218. The method according to embodiment 104, wherein the dexmedetomidine is present in an amount of about 10 micrograms to about 300 micrograms.

Embodiment 219. The method according to any one of the preceding embodiments, wherein the dosage form(s) are administered multiple times a day.

Embodiment 220. The method according to any one of the preceding embodiments, wherein the dosage form(s) is administered once a day.

Embodiment 221. The method according to any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 222. A method according to any one of the preceding embodiments, wherein latropyridine or a pharmaceutically acceptable salt thereof is latropyridine hydrochloride (or dihydrochloride).

Example 223. An oral mucosal dosage form comprising: (i)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)  one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within not less than about 1 minute after contact with the oral mucosa.

Example 224. An oral mucosal dosage form comprising: (i)   a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii)  one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within not less than about 1 minute after contact with the oral mucosa.

Example 225. An oral mucosal dosage form comprising: (i)    a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii)   a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii)  one or more mucosal adhesives; and (iv)  one or more pharmaceutically acceptable excipients or carriers; wherein the dosage form disintegrates within not less than about 1 minute after contact with the oral mucosa.

Embodiment 226. The oral mucosal dosage form according to Embodiment 224 or 225, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 227. The oral mucosal dosage form according to any one of Embodiments 224-226, wherein latromidine or a pharmaceutically acceptable salt thereof is latromidine hydrochloride or dihydrochloride.

Embodiment 228. The oral mucosal dosage form according to embodiment 224 or 225, wherein the therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride) is about 5 μg to about 300 μg per unit dose, such as about 20 μg to about 200 μg per unit dose, about 30 μg to about 100 μg per unit dose, or about 10 μg to about 50 μg per unit dose.

Embodiment 229. The oral mucosal dosage form according to Embodiment 225, wherein the therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms or about 180 micrograms.

Embodiment 230. The oral mucosal dosage form according to embodiments 224 to 225, wherein the therapeutic amount of latromidine or a pharmaceutically acceptable salt thereof is about 0.5 mg to about 100 mg per unit dose.

Embodiment 231. The oral mucosal dosage form according to embodiments 224 to 225, wherein the therapeutic amount of latromidine or a pharmaceutically acceptable salt thereof is about 10 mg to about 100 mg per unit dose.

Embodiment 232. The oral mucosal dosage form according to embodiments 224 to 225, wherein the one or more mucosal adhesives are selected from the group consisting of: polyacrylic acid polymers, methacrylic acid polymers, cellulose derivatives such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), ethyl hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, sodium carboxymethyl cellulose, thiolated carboxymethyl cellulose; polysaccharides, xanthan gum, karaya gum, tragacanth gum, propylene glycol, propylene glycol alginate, sodium alginate, polyethylene oxide, microcrystalline cellulose (Avicel), cross-linked carboxymethyl cellulose and mixtures thereof.

Embodiment 233. The oral mucosal dosage form according to embodiment 232, wherein the one or more mucoadhesive agents are present in an amount of about 0.5% to about 20% w/w.

Embodiment 234. The oral mucosal dosage form according to Embodiment 232, wherein the polyacrylic acid polymer is carbomer, polycarbophil or a combination thereof.

Embodiment 235. The oral mucosal dosage form according to Embodiment 232, wherein the polysaccharide is pectin, chitosan or a combination thereof.

Embodiment 236. An oral mucosal dosage form according to the aforementioned embodiment, wherein one or more of the pharmaceutically acceptable excipients or carriers are selected from the group consisting of: disintegrants, fillers/diluents (matrix formers), binders, glidants, lubricants, plasticizers, pH adjusters, colorants, flavoring agents, taste masking agents, viscosity enhancers, sweeteners and combinations thereof.

Embodiment 237. An oral mucosal dosage form according to any of the preceding embodiments, wherein the dosage form has a mucoadhesion peak force greater than about 50 g (e.g., about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g, or about 1500 g).

Embodiment 238. The oral mucosal dosage form according to any one of the preceding embodiments, wherein the dosage form is prepared by spray drying, sublimation, nano-ization, granulation, direct compression or freeze drying, preferably freeze drying.

Embodiment 239. The oral mucosal dosage form according to any one of the preceding embodiments, wherein the dosage form is a sublingual tablet.

Embodiment 240. The oral mucosal dosage form according to any one of the preceding embodiments, wherein the dosage form is a buccal tablet.

Embodiment 241. An oral mucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii) xanthan gum; (iii) sodium cross-linked carboxymethyl cellulose (or) sodium starch glycolate; (iv) sucralose; (v) magnesium stearate and/or silicon dioxide; (vi) lactose monohydrate; (or) mannitol and, as appropriate, other pharmaceutically acceptable excipients; wherein the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

Embodiment 242. An oral mucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) sodium alginate; (iii) sodium cross-linked carboxymethyl cellulose; (or) sodium starch glycolate; (iv) sucralose; (v) magnesium stearate and/or silicon dioxide; (vi) lactose monohydrate or mannitol and, as appropriate, other pharmaceutically acceptable excipients; wherein the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

Embodiment 243. An oral mucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) a therapeutically effective amount of latropyridine or a pharmaceutically acceptable salt thereof; (ii) carbomer; (iii) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (iv) sucralose; (v) magnesium stearate and/or silicon dioxide; (vi) lactose monohydrate or mannitol and, as appropriate, other pharmaceutically acceptable excipients; wherein the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

Embodiment 244. An oral mucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyethylene oxide; (iv) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (v) sucralose; (vi) magnesium stearate and/or silicon dioxide; (vii) lactose or mannitol; and (viii) other pharmaceutically acceptable excipients as appropriate; wherein the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

Embodiment 245. An oral mucosal (e.g., sublingual or buccal) lyophilized tablet comprising: (i) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iii) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyethylene oxide; (iv) sodium cross-linked carboxymethyl cellulose or sodium starch glycolate; (v) sucralose; (vi) magnesium stearate and/or silicon dioxide; (vii) lactose or mannitol; and (viii) other pharmaceutically acceptable excipients as appropriate; wherein the tablet disintegrates within not less than about 1 minute after contact with the oral mucosa.

Embodiment 246. The oral mucosal lyophilized tablet according to Embodiments 241 to 245, wherein the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 10 micrograms to about 300 micrograms.

Embodiment 247. The oral mucosal lyophilized tablet according to Embodiment 246, wherein the therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 30 micrograms, about 60 micrograms, about 90 micrograms, about 120 micrograms, about 180 micrograms or about 240 micrograms.

Embodiment 248. The oral mucosal lyophilized tablet according to Embodiments 241-245, wherein the therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof is about 10 mg to about 100 mg.

Embodiment 249. The oral mucosal lyophilized tablet according to Embodiment 247, wherein the therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof is about 30 mg.

Embodiment 250. An oromucosal dosage form according to any one of the preceding embodiments, which is administered to treat agitation caused by norepinephrine induced hyperstimulation.

Embodiment 251. An oromucosal dosage form according to embodiment 250, wherein the agitation caused by norepinephrine stimulant overexcitation is associated with a neurodegenerative disorder selected from the group consisting of dementia, Alzheimer's disease, frontotemporal dementia, Parkinsonism, sunset syndrome in Alzheimer's disease/dementia, or other neurodegenerative disorders.

Embodiment 252. The oromucosal dosage form according to embodiment 250, wherein the agitation caused by norepinephrine induced hyperstimulation is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, mania, bipolar disorder, delirium, depression or another related neuropsychiatric disorder.

Embodiment 253. The oral mucosal dosage form according to embodiment 250, wherein the agitation caused by norepinephrine stimulant overexcitation is associated with alcohol withdrawal, opioid use disorder, opioid withdrawal and substance abuse withdrawal.

Embodiment 254. The oromucosal dosage form according to any one of the preceding embodiments, wherein dexmedetomidine and latromidine or pharmaceutically acceptable salts thereof are provided in a single unit dosage form or in separate dosage forms.

Embodiment 255. A pharmaceutical composition for treating agitation caused by norepinephrine-induced overexcitation, comprising a therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof (eg, hydrochloride) and a therapeutic amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 256. The combination according to embodiment 255, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 257. According to the combination of Embodiment 255, wherein latropyridine or a pharmaceutically acceptable salt thereof is latropyridine hydrochloride.

Embodiment 258. The combination according to embodiment 255, wherein the therapeutic amount of dexmedetomidine or a pharmaceutically acceptable salt thereof comprises about 5 micrograms to about 300 micrograms per unit dose.

Embodiment 259. The combination according to embodiment 255, wherein the therapeutic amount of latromidine or a pharmaceutically acceptable salt thereof comprises about 10 mg to about 100 mg per unit dose.

Embodiment 260. The combination according to embodiment 255, wherein dexmedetomidine and latromidine or pharmaceutically acceptable salts thereof are administered sublingually or intrabuccally in a dosage form selected from the group consisting of: film, wafer capsule, patch, buccal tablet, gel, spray, troche and liquid drops.

Embodiment 261. The combination according to Embodiment 260, wherein dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof are administered sublingually in the form of a tablet.

Embodiment 262. The combination according to embodiment 260, wherein dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof are administered buccally in the form of tablets.

Embodiment 263. According to the combination of embodiments 260-262, wherein the tablet disintegrates within not less than 1 minute after contacting with the oral mucosa.

Embodiment 264. The combination according to embodiment 255, wherein dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof are administered simultaneously in a single dosage form.

Embodiment 265. The combination according to embodiment 255, wherein dexmedetomidine and latromidine or pharmaceutically acceptable salts thereof are administered concurrently or sequentially in separate dosage forms.

Embodiment 266. The combination according to embodiment 255, wherein dexmedetomidine and latromidine or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, four times a day, five times a day or six times a day.

Example 267. A kit of parts comprising at least two separate oral mucosal lyophilized tablet dosage forms (a) and (b), wherein the dosage forms comprise: (a) a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (b) a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; and, as appropriate, (c) instructions for administering (a) and (b) simultaneously, sequentially, or separately to a subject in need thereof.

Example 268. A kit of parts comprising a single oral lyophilized tablet dosage form comprising: (i)    a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii)   a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof; and, if appropriate (iii)  instructions for administering the single dosage form to a subject in need thereof.

Embodiment 269. The kit according to embodiments 267-268, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 270. The kit according to embodiments 267-268, wherein latromidine or a pharmaceutically acceptable salt thereof is latromidine hydrochloride.

Embodiment 271. The kit according to embodiments 267-268, wherein latromidine or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg to about 100 mg.

Embodiment 272. The kit embodiment according to 268, wherein dexmedetomidine and latromidine or pharmaceutically acceptable salts thereof are administered once a day, twice a day, three times a day, four times a day, five times a day or six times a day in a single unit dose.

Embodiment 274. The kit according to any one of embodiments 267 to 272, wherein dexmedetomidine and latromidine or pharmaceutically acceptable salts thereof are administered together or separately as sublingual or buccal tablets.

Embodiment 275. According to the kit embodiment of 274, wherein the tablet disintegrates within no less than about 1 minute after contacting the oral mucosa.

Embodiment 276. The kit according to any one of embodiments 267-275, wherein dexmedetomidine and latromidine or pharmaceutically acceptable salts thereof are administered to treat agitation caused by norepinephrine induced hyperstimulation.

Embodiment 277. The kit according to embodiment 276, wherein the agitation is acute or chronic.

Embodiment 278. A kit according to embodiment 276, wherein the agitation caused by norepinephrine stimulant overexcitation is associated with a neurodegenerative disorder selected from the group consisting of: dementia, Alzheimer's disease, frontotemporal dementia, Parkinson's disease, agitation associated with Sundown syndrome in Alzheimer's disease/dementia, or agitation/agitation symptoms associated with other neurodegenerative disorders.

Embodiment 279. The kit according to embodiment 276, wherein the agitation caused by norepinephrine induced hyperexcitation is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, mania, bipolar disorder, delirium, depression or another related neuropsychiatric disorder.

Embodiment 280. A kit according to embodiment 276, wherein the agitation caused by norepinephrine-induced overexcitation is associated with alcohol withdrawal, opioid use disorder, opioid withdrawal, substance abuse withdrawal, or an OPD/IPD procedure (e.g., MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy, tooth extraction or other dental procedure).

Embodiment 281. The kit according to any one of embodiments 267-280, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 10 μg to 300 μg (including about 30 μg, about 60 μg, about 90 μg, about 120 μg, about 180 μg, about 240 μg).

Embodiment 282. The method/dosage form/combination or kit according to any one of the preceding embodiments, wherein the agitation in the individual is treated without causing significant sedation.

Embodiment 283. The method/dosage form/combination or kit according to any one of the preceding embodiments, wherein the agitation in the subject is treated without causing cardiovascular effects.

Example 284. A method for treating a psychotic illness in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 285. The treatment method according to Embodiment 284, wherein the latropyridine is administered in a dosage of about 1 mg to about 100 mg once a day, about 10 mg once a day, about 20 mg once a day, about 30 mg once a day, about 20 mg twice a day, about 20 mg three times a day, about 30 mg once a day, about 30 mg twice a day, or about 60 mg once a day.

Embodiment 286. A method for treating a psychotic disorder in a subject in need thereof, comprising administering to the subject via the oral mucosa a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 287. A method of treating a psychotic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 288. A method for treating a psychotic disorder in a subject in need thereof, the method comprising oromucosally administering to the subject a therapeutically effective amount of a combination of dexmedetomidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 289. A method for treating depression in a subject in need thereof, the method comprising administering to the subject via the oral mucosa about 1 mg to about 100 mg of latromidine or a pharmaceutically acceptable salt thereof and about 5 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

Embodiment 290. The method according to embodiments 284-289, wherein the treatment is effective without causing significant sedation.

Embodiment 291. The method according to embodiments 284-289, wherein the treatment is effective without experiencing clinically significant cardiovascular effects.

Embodiment 292. The method according to embodiments 284-289, wherein the severity of the individual's mental illness is assessed using the PANSS scale.

Embodiment 293. The method according to embodiments 284-289, wherein the psychosis is acute.

Embodiment 294. The method according to embodiments 284-289, wherein the mental illness is chronic.

Embodiment 295. The method according to embodiments 284-289, wherein the subject is agitated.

Embodiment 296. The method according to embodiments 284-289, wherein the subject is non-agitated.

Embodiment 297. A method of achieving a reduction in PANSS scores for a sustained period of psychosis in an individual, comprising oromucosal administration to the individual of a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 298. A method of achieving a reduction in PANSS scores for a sustained period of psychosis in an individual, comprising oromucosal administration to the individual of a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of latromidine or a pharmaceutically acceptable salt thereof.

Embodiment 299. The method according to embodiments 297-298, wherein the PANSS score is reduced by at least about 20% to about 50% relative to the baseline score.

Embodiment 300. The method according to embodiment 299, wherein the PANSS score is reduced by about 25% relative to the baseline score.

Embodiment 301. The method according to embodiment 299, wherein the PANSS score is reduced by about 50% points relative to the baseline score.

Embodiment 302. The method according to any one of embodiments 298-301, wherein the mental illness is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia and manic depression or another related neuropsychiatric disorder.

Embodiment 303. The method according to any one of embodiments 284-301, wherein the psychosis is associated with a neurodegenerative disorder.

Embodiment 304. The method according to any one of embodiments 284-301, wherein the mental illness is associated with a condition such as a substance abuse disorder (e.g., alcohol, opioid and other substance withdrawal).

Embodiment 305. The method according to any one of embodiments 284-301, wherein the psychosis is a single, recurrent or mixed episode.

Embodiment 306. A method for establishing the relevance of norepinephrine agonist signaling to psychiatric disorders such as acute stress, PTSD, depression, substance withdrawal, substance craving, agitation, panic disorder, and anxiety by using preclinical animal models.

Embodiment 307. The method according to embodiment 306, wherein the preclinical animal models include a resident intruder assay, a forced swim test, a yohimbine-induced anxiety model, and a CCK-induced panic model.

Embodiment 308. The method of embodiment 306 or 307, wherein the preclinical animal models unexpectedly demonstrate that latromidine unexpectedly reduces the severity of symptoms in stress-related psychiatric disorders including acute stress disorder, PTSD, depression, substance withdrawal, substance use cravings, agitation, panic disorder, and anxiety.

Embodiment 309. The method of embodiment 306 or 307, wherein the preclinical models relate norepinephrine agonist signaling to ADHD.

Embodiment 310. The method of any one of embodiments 306-309, wherein by reducing the extent of said symptoms, the patient improves their clinical outcome due to increased compliance with basic therapeutic treatment, including adherence to medication regimen and participation in therapy.

Embodiment 311. The method of embodiment 310, wherein the improved clinical outcomes may result from patients with reduced symptoms being able to interact more effectively in social contexts, reducing aggression and panic symptoms that may result from lack of social interaction, as seen in disorders such as autism.

Embodiment 312. The method of any of Embodiments 306-311, wherein effective symptom management prevents disease progression, such as when acute stress disorder progresses to PTSD.

Embodiment 313. The method of any one of Embodiments 306-311, wherein latrapyridine treats and prevents symptoms such as acute stress and pan-autistic disorder from getting worse over time.

The details of the present disclosure, its objects and advantages are explained in more detail below with respect to non-limiting exemplary illustrations. Examples: Example 1. Sublingual / buccal / gingival tablets of latrexopridine dihydrochloride hydrate and dexmedetomidine hydrochloride with mucoadhesive properties : Table 1 : Latrexopridine oral mucosal tablets (A to F) Element Example A Example B Example C Example D Example E Example F Latropyridine 30 mg 30 mg 30 mg 30 mg 30 mg 30 mg Hydroxypropyl methylcellulose (lower viscosity grade, such as K100L or 4000cps or less 3.0 mg Hydroxypropyl cellulose (MW <150K Dalton, lower viscosity grade) 2.5 mg Polyethylene oxide 2.5 mg Xanthan gum (or) sodium alginate 2.5 mg Carbomer (lower viscosity grade) 2.0 mg Cross-linked carboxymethyl cellulose sodium (or) sodium starch hydroxyacetate 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg Sucralose 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Magnesium stearate (and)/(or) silicon dioxide 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Lactose monohydrate (or) mannitol 24.4 mg 24.9 mg 24.9 mg 24.9 mg 25.4 mg 25.4 mg Tablet weight 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg Table 2 : Latrepidine Oromucosal Tablets (G to L) Element Example G Example H Example I Example J Example K Example L Latropyridine 30 mg 30 mg 30 mg 30 mg 30 mg 30 mg Hydroxypropyl methylcellulose (lower viscosity grade, such as K100L or 4000cps or less 3.0 mg Hydroxypropyl cellulose (MW <150K Dalton, lower viscosity grade) 2.5 mg Polyethylene oxide 2.5 mg Xanthan gum (or) sodium alginate 2.5 mg Carbomer (lower viscosity grade) 2.0 mg Gelatin (low viscosity) 1.5 mg 1.5 mg 1.5 mg 1.5 mg 1.5 mg 1.5 mg Cross-linked carboxymethyl cellulose sodium (or) sodium starch hydroxyacetate 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg Sucralose 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Magnesium stearate (and)/(or) silicon dioxide 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Lactose monohydrate (or) mannitol 24.4 mg 24.9 mg 24.9 mg 24.9 mg 25.4 mg 25.4 mg Tablet weight 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg Table 3 : Dexmedetomidine and Latrepidine Oromucosal Tablets (M to R) Element Example M Example N Example O Example P Example Q Example R Dexmedetomidine 120 mcg 120 mcg 120 mcg 120 mcg 120 mcg Latropyridine 30 mg 30 mg 30 mg 30 mg 30 mg Hydroxypropyl methylcellulose (lower viscosity grade, such as K100L or 4000cps or less 3.0 mg Hydroxypropyl cellulose (MW <150K Dalton, lower viscosity grade) 2.5 mg Polyethylene oxide 2.5 mg Xanthan gum (or) sodium alginate 2.5 mg Carbomer (lower viscosity grade) 2.0 mg Cross-linked carboxymethyl cellulose sodium (or) sodium starch hydroxyacetate 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg Sucralose 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Magnesium stearate (and)/(or) silicon dioxide 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Lactose monohydrate (or) mannitol 24.4 mg 24.9 mg 24.9 mg 24.9 mg 25.4 mg 25.4 mg Tablet weight 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg Table 4 : Dexmedetomidine and Latrepidine Oromucosal Tablets (S to X) Element Example S Example T Example U Example V Example W Example X Dexmedetomidine 120 mcg 120 mcg 120 mcg 120 mcg 120 mcg Latropyridine 30 mg 30 mg 30 mg 30 mg 30 mg Hydroxypropyl methylcellulose (lower viscosity grade, such as K100L or 4000cps or less 3.0 mg Hydroxypropyl cellulose (MW <150K Dalton, lower viscosity grade) 2.5 mg Polyethylene oxide 2.5 mg Xanthan gum (or) sodium alginate 2.5 mg Carbomer (lower viscosity grade) 2.0 mg Gelatin (low viscosity) 1.5 mg 1.5 mg 1.5 mg 1.5 mg 1.5 mg 1.5 mg Cross-linked carboxymethyl cellulose sodium (or) sodium starch hydroxyacetate 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg 2.0 mg Sucralose 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Magnesium stearate (and)/(or) silicon dioxide 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg Lactose monohydrate (or) mannitol 24.4 mg 24.9 mg 24.9 mg 24.9 mg 25.4 mg 25.4 mg Tablet weight 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg 60.0 mg

Tablets described in this example can be prepared according to the process described herein (see Tables 1 to 4). A representative process is described below. 1. Disperse the API (latropyridine and/or dexmedetomidine), binder, sweetener in water. 2. Prepare and sift the blend of the remaining ingredients except magnesium stearate/silicon dioxide. 3. Granulate the blend by using the solution of step 1 in a suitable rapid mixer granulator. 4. Dry the granules in a suitable fluidized bed dryer. 5. Size the dried granules appropriately in a quadro-co-mill or multimill and load into a suitable blender such as a V-type blender. 6. Lubricate with magnesium stearate/silicon dioxide and compress the final lubricated blend into tablets of a specific size using appropriate tools. Example 2. Effect of Latropyridine Dihydrochloride Hydrate on Yohimbe-Induced Norepinephrine-Mediated Hyperexcitation in Weiss Rats

Background: Yohimbine is an α2-adrenaline agonist reported to induce panic attacks in healthy volunteers and exacerbate symptoms in patients with panic disorder (Charney et al., 1992 Acta Psychiatr Scand., Vol. 86(4): 273-282). Peripheral administration of yohimbine induces norepinephrine agonist-mediated hyperexcitation in rats as assessed by the EPM paradigm.

Rationale: The drug yohimbine is a natural product used to test for hyperexcitation of a specific pathway mediated by norepinephrine agonism. Yohimbine is known to be an α2-adrenaline agonist receptor antagonist and activates the locus coeruleus (LC) and increases norepinephrine agonist signaling (in contrast to α2-adrenaline agonists such as dexmedetomidine and clonidine). Increased LC activity and norepinephrine agonist signaling make animals anxious and agitated, which can be measured using the elevated plus maze. In the elevated plus maze, rodents are in the closed arms and explore the open arms depending on their anxiety and agitation (rats and mice normally explore their environment extensively when at rest). With the administration of yohimbine, animals typically remain in the closed arms and do not explore the open arms. This behavior is associated with increased levels of anxiety caused by overexcitation mediated by norepinephrine agonism. Any pharmacological intervention that demonstrates an anxiolytic effect (increased time spent in the open arms of the EPM) would effectively address the increased levels of anxiety symptoms in ASD.

Animal Groups: Male: Weiss rats were used in this study and randomly divided into different experimental groups (12 animals/group).

Acclimation: Animals were numbered and acclimated for a period of 5-7 days prior to the start of the experiment. During the acclimation period, male Weiss rats were regularly examined, handled and weighed to ensure adequate health and suitability.

Diet and Water: Animals were fed normal chewing animal chow ad libitum and had free access to fresh autoclaved potable water.

All experiments on animals were conducted according to the guidelines of the Council for the Control and Supervision of Animal Experimentation (CPCSEA), Government of India, and the International Association for Accreditation and Accreditation of Laboratory Animal Care (AAALAC).

Study Drugs: Four test drugs with different mechanisms of action related to agitation were selected to find drugs that are effective in reducing yohimbine-induced agitation: (1) Fluvoxamine (selective serotonin reuptake inhibitor), (2) Dextromethorphan (modulator of NMDA signaling), (3) Diazepam (GABA modulator as positive control), and (4) Latropyridine (complex pharmacology). Table 5. Treatment Group Details: Group No. handle* Dosage and route n pieces/group 1 Medium 1 salt water; 12 2 Medium 2 Saline + 30% ethanol; im 12 3 Latropyridine dihydrochloride hydrate 3 mg/kg; im 12 4 Latropyridine dihydrochloride hydrate 10 mg/kg; im 12 5 Dextromethorphan hydrobromide 10 mg/kg; im 12 6 Fluvoxamine citric acid salt 10 mg/kg; im 12 7 stable 1 mg/kg; ip 12 *Weight calculated based on free base. IM = intramuscular; IP: intraperitoneal. All treatment groups were pretreated with Yohimbe 2.5 mg/kg.

Test drugs were obtained from Sigma or Tocris. Dextromethorphan was from Sigma Aldrich, catalog number D9684; latromidine was from Sigma Aldrich, catalog number D6196 or Tocris, catalog number 3201; diazepam and fluvoxamine were from Sigma Aldrich, catalog number F2802 or Tocris, catalog number 1033. All of these test drugs were prepared in sufficient amounts in 0.9% saline, except fluvoxamine, which was prepared in 0.9% saline containing 30% ethanol.

Apparatus: An elevated plus maze (EPM) (Fig. 1) was used. The maze consisted of two closed arms and two open arms forming a cross, with a square central platform. All visible surfaces were made of black acrylic. The arms of the maze were placed on support columns above the floor. An antistatic black vinyl curtain was used to surround the EPM to form an enclosure.

Study Design and Dosing: Yohimbe was administered by intraperitoneal injection (i.p.) at a dose of 2.5 mg/kg (30 minutes before the study) to induce agitation, and the effect was assessed 30 minutes after the yohimbe injection by measuring the number of open arm entries and the exploration time in the EPM. The test drugs fluvoxamine, dextromethorphan and laprolidine dihydrochloride hydrate were administered by the intramuscular route, and diazepam was administered by the intraperitoneal route into the hind leg thigh muscle of rats (60 minutes before the study; 30 minutes before yohimbe administration). Diazepam was injected intraperitoneally 30 minutes before the assay, i.e., injected together with the yohimbe administration. The study design is shown in Figure 2 and Table 5.

After test drug administration, rats were placed on the platform opposite the closed arms. The number of entries and the time spent in each arm were recorded during a 5-minute period. An animal was considered to have entered an arm when it placed all four of its paws in the arm.

Statistical analysis: Analysis of variance (ANOVA) was performed on the result data. Fisher's PLSD was used for pairwise comparisons and p value ≤ 0.05 was considered significant.

Results: Unexpectedly, it was found that pretreatment of animals with latromidine dihydrochloride hydrate (3 mg/kg and 10 mg/kg, intramuscularly) for 1 hour reduced norepinephrine-induced hyperexcitation, as indicated by a significantly increased number of open-arm entries and increased exploration time. In other words, latromidine dihydrochloride hydrate reversed yohimbine-induced norepinephrine-induced hyperexcitation. The reduction effect of latromidine dihydrochloride hydrate on norepinephrine-induced hyperexcitation was unique, as pretreatment of animals with dextromethorphan (at 10 mg/kg, intramuscularly) or fluvoxamine (at 10 mg/kg, intramuscularly) was ineffective. Pretreatment with diazepam (at 1 mg/kg, ip) served as a positive control.

Figures 3 and 4 show that lapropyridine dihydrochloride hydrate significantly increased the number of entries into the open arms and the time spent in the open arms (seconds) comparable to diazepam (at 1 mg/kg, ip). The other tested drugs, dextromethorphan (at 10 mg/kg, IM) and fluvoxamine (at 10 mg/kg, IM), showed no effect.

Conclusion: Latrapyridine dihydrochloride hydrate is able to reduce behaviors associated with hyper-norepinephrine agonist signaling and its pretreatment reverses anxious behaviors induced by selective α2-adrenaline agonist antagonism in rats, providing support for a putative pleiotropic pharmacological approach with compounds acting via α-2 adrenaline agonist agonism in hyperarousal-related disorders. Therefore, Latrapyridine dihydrochloride hydrate should be effective in patients with hyperarousal mediated by associated hyper-norepinephrine agonism, such as ASD. Example 3. Evaluation of the effects of different doses of Latrapyridine dihydrochloride hydrate on yohimbine-induced norepinephrine agonist hyperarousal in Weiss rats.

Background: Yohimbine is an α2-adrenaline agonist reported to induce panic attacks in healthy volunteers and exacerbate symptoms in patients with panic disorder (Charney et al., 1992 Acta Psychiatr Scand., Vol. 86(4): 273-282). Peripheral administration of yohimbine induces norepinephrine agonist-mediated hyperexcitation in rats as assessed by the EPM paradigm.

Rationale: The drug yohimbine is a natural product used to test for hyperexcitation of a specific pathway mediated by norepinephrine agonism. Yohimbine is recognized as an α2-adrenaline agonist receptor antagonist and activates the locus coeruleus (LC) and increases norepinephrine agonist signaling (in contrast to α2-adrenaline agonists such as dexmedetomidine and clonidine). Increased LC activity and norepinephrine agonist signaling make animals anxious and agitated, which can be measured by using an elevated plus maze. In the elevated plus maze, rodents are in a closed arm and explore the open arm depending on their anxiety and agitation (rats and mice normally explore their environment extensively when at rest). With the administration of yohimbine, animals typically remain in the closed arms and do not explore the open arms. This behavior is associated with increased levels of anxiety caused by overexcitation mediated by norepinephrine agonism. Any pharmacological intervention that demonstrates an anxiolytic effect (increased time spent in the open arms of the EPM) would effectively address the increased levels of anxiety symptoms in ASD.

Animal Groups: Rats were assigned to 9 different experimental groups with 12 rats in each group as shown in Table 6. Each experimental group was also coded so that the experimenter became blind to the true experimental group during the EPM test. The dose, route, and pretreatment time are also provided in Table 6.

Adaptation: Male Weiss rats (Janvier; Le Genest St Isle - France) were used for the study. Rats were purchased with a body weight of 150 g and reached a body weight of approximately 220 g at the time of use. They were group housed (3-4 rats/cage) and maintained in a room with a controlled temperature (21°C-22°C) and an inverted light-dark cycle (12h/12h; lights on: 17:30 - 05:30; lights off: 05:30 - 17:30).

Food and Water: Animals had food and water available ad libitum.

Drug preparation: All compounds/drugs were prepared in physiological saline (0.9% NaCl).

Yohimbe was prepared as a 2.5 mg/mL solution, which yielded a dose of 2.5 mg/kg when injected intraperitoneally in a dose volume of 1 mL/kg. Diazepam was prepared as a 1 mg/mL solution, which yielded a dose of 1 mg/kg when injected intraperitoneally in a dose volume of 1 mL/kg. Latrexopyridine dihydrochloride hydrate was prepared as 7.5, 2.5, 0.75, and 0.25 mg/mL solutions, which yielded doses of 3, 1, 0.3, and 0.1 mg/kg, respectively, when injected intramuscularly in a volume of 100 µL in a 250 g rat. Latrepidine dihydrochloride hydrate was also prepared at 0.3 mg/mL, which yielded a dose of 3 mg/kg when administered intraperitoneally at a dose volume of 1 mL/kg. Table 6. Treatment Group Details Group No. n Name/Description 1 12 Saline (intraperitoneal, 30 minutes)/vehicle (intraperitoneal, 60 minutes) 2 12 Yohimbin hydrochloride (2.5 mg/kg/mL; ip, 30 min)/vehicle (im, 60 min) 3 12 Yohimbe hydrochloride (2.5 mg/kg/mL; ip, 30 minutes)/diazepam (1 mg/kg, ip, 30 minutes) 4 12 Saline (intraperitoneal, 30 minutes)/laproxine dihydrochloride hydrate (3 mg/kg; intramuscular, 60 minutes) 5 12 Yohimbe hydrochloride (2.5 mg/kg/mL; ip, 30 min)/laproxine dihydrochloride hydrate (3 mg/kg; ip, 60 min) 6 12 Yohimbe hydrochloride (2.5 mg/kg/mL; intraperitoneal, 30 minutes)/lapropyridine dihydrochloride hydrate (0.1 mg/kg; intramuscular, 60 minutes) 7 12 Yohimbe hydrochloride (2.5 mg/kg/mL; intraperitoneal, 30 minutes)/lapropyridine dihydrochloride hydrate (0.3 mg/kg; intramuscular, 60 minutes) 8 12 Yohimbe hydrochloride (2.5 mg/kg/mL; ip, 30 min)/lapropyridine dihydrochloride hydrate (1 mg/kg; IM, 60 min) 9 12 Yohimbe hydrochloride (2.5 mg/kg/mL; intraperitoneal, 30 minutes)/lapropyridine dihydrochloride hydrate (3 mg/kg; intramuscular, 60 minutes) *Weight calculated based on free base.

Experimental Procedure: Rats were randomly assigned to one of the different experimental groups. Each animal was identified by its group name, cage number, experimental series (days) and a number (1 to 9) written in permanent ink on its tail. It was manipulated by the experimenter for about 3 minutes daily during 1 week before the day of the EPM test. The apparatus was a PVC maze covered with resin glass (Plexiglas) and was subdivided into four identical exploration arms (40 × 10 cm) that were interconnected by small platforms (10 × 10 cm). The apparatus was placed 65 cm above the floor. Two arms were open and the other two arms were closed with a wall (height: 10 cm). After compound administration, the rat was placed on the platform opposite the closed arm. The number of entries and the time spent in each arm were recorded during the 5-minute period. An animal was considered to have entered an arm when it placed all four of its paws in the arm. The equipment was cleaned between animals using alcohol (70%). Urine and feces were removed from the maze. During the test, animal handling and operator visibility were minimized as much as possible.

Statistical analysis: Analysis of variance (ANOVA) was performed on the resulting data. Fisher's PLSD was used for pairwise comparisons and p-values ≤ 0.05 were considered significant. For comparison purposes, changes in EPM potency in Yohimbin rats were expressed as a percentage increase/decrease in the level recorded in the reference vehicle (set to 0% change). Therefore, for each of the EPM parameters, the following formula was used: [potency of a given group - potency of the vehicle group] / [potency of the vehicle group] × 100. Results:

General Health: No signs of macroscopically observable adverse effects associated with treatment with the compound were observed.

Behavior in the EPM: Figures 5 and 6 show the mean performance of each experimental group in terms of the number of entries into the open arms and the time spent therein, respectively. Table 7 provides the percentage change (decrease or increase) in the EPM parameters with reference to the vehicle performance level (set as 0% change). As shown in Figures 5 and 6, the vehicle-treated yohimbine-administered rats showed a significantly reduced number of visits to the open arms and the time spent therein compared to the vehicle-treated saline rats. This indicates the occurrence of yohimbine-induced norepinephrine-mediated hyperexcitation, as assessed in the EPM paradigm. Diazepam treatment at 1 mg/kg reversed the norepinephrine-mediated hyperexcitation induced by yohimbine, as shown by a significant increase in the number of visits to the open arms and the time spent therein (294% and 642% increase, respectively) (Table 7). In addition, lapropyridine dihydrochloride hydrate induced a dose-dependent increase in the number of visits to the open arms and the time spent therein in yohimbine-administered rats, and the effects were significant at doses of 1 and 3 mg/kg, as shown in Table 7 and Figures 5 and 6. It was also observed that the EPM potency of yohimbine rats treated with latromidine dihydrochloride hydrate (3 mg/kg, IM) was comparable to that of the ip treated samples, indicating that intramuscular (im) latromidine dihydrochloride hydrate is as effective as administration via the ip route (see Table 7 and Figures 5 and 6). Notably, latromidine dihydrochloride hydrate (3 mg/kg, IM) did not significantly alter the EPM potency of saline treated rats (null yohimbine rats), indicating that latromidine dihydrochloride hydrate did not induce any significant anti-agitation behavior in null yohimbine rats (see Table 7 and Figures 5 and 6). Table 7. Changes in behavioral potency during the EPM test Name/Description Percentage increase in reference medium level Enter time Saline (intraperitoneal, 30 minutes)/vehicle (intraperitoneal, 60 minutes) 233 525 Yohimbin hydrochloride (2.5 mg/kg/mL; ip, 30 min)/vehicle (im, 60 min) 0 0 Yohimbe hydrochloride (2.5 mg/kg/mL; ip, 30 minutes)/diazepam (1 mg/kg, ip, 30 minutes) 294 642 Saline (intraperitoneal, 30 min)/laproxine dihydrochloride hydrate (3 mg/kg; intramuscular, 60 min) 167 377 Yohimbe hydrochloride (2.5 mg/kg/mL; ip, 30 minutes)/laproxine dihydrochloride hydrate (3 mg/kg; ip, 60 minutes) 183 486 Yohimbe hydrochloride (2.5 mg/kg/mL; intraperitoneal, 30 minutes)/lapropyridine dihydrochloride hydrate (0.1 mg/kg; intramuscular, 60 minutes) twenty one twenty one Yohimbe hydrochloride (2.5 mg/kg/mL; intraperitoneal, 30 minutes)/lapropyridine dihydrochloride hydrate (0.3 mg/kg; intramuscular, 60 minutes) 11 73 Yohimbe hydrochloride (2.5 mg/kg/mL; intraperitoneal, 30 minutes)/lapropyridine dihydrochloride hydrate (1 mg/kg; intramuscular, 60 minutes) 106 274 Yohimbe hydrochloride (2.5 mg/kg/mL; intraperitoneal, 30 minutes)/lapropyridine dihydrochloride hydrate (3 mg/kg; intramuscular, 60 minutes) 172 392

Conclusion: The results showed that latromidine dihydrochloride hydrate (at 1 and 3 mg/kg) significantly reduced norepinephrine-mediated hyperexcitation in yohimbine-administered rats in a dose-dependent manner (see Table 7 and Figures 5 and 6). Example 4. Evaluation of the antidepressant effect of the combination of dexmedetomidine hydrochloride and latromidine dihydrochloride hydrate in the rat forced swim test model during the dark phase.

Animal groups: Male Sprague-Dawley (SD) rats (8-10 weeks of age) were housed in groups of 2 in standard animal cages with access to pelleted food and drinking water in polycarbonate bottles with stainless steel straws. During the experimental period, the animals were housed in a single experimental room. The rats were assigned to 7 different experimental groups with 9-12 rats per group, as shown in Table 8. Animals were assigned to different groups based on body weight data. Each experimental group was also coded so that the experimenter became unaware of the true experimental group during the EPM test. Dosage, route, and pretreatment time are also provided in Table 8.

Animal source: Hylasco Biotechnology Pvt. Ltd. 4B, MNPark, Turkaplly (Vil), Shameerpet (Mdl), Medchal Dist, -500078 Table 8. Treatment details: Group No. handle* Dosage and route n pieces/group Dosage volume Frequency 1 Medium 0.9% saline; im 9 100 μl/site Single dose, 60 minutes before the second swim 2 Desipramine hydrochloride 30 mg/kg in 0.9% saline; po 9 10 mL/kg Single dose, 60 minutes before the second swim 3 Dexmedetomidine hydrochloride 1 µg/kg in 0.9% saline; im 12 100 μl/site Single dose, 60 minutes before the second swim 4 Dexmedetomidine hydrochloride 5 µg/kg in 0.9% saline; im 12 100 μl/site Single dose, 60 minutes before the second swim 5 Latropyridine dihydrochloride hydrate 1 mg/kg in 0.9% saline; im 12 100 μl/site Single dose, 60 minutes before the second swim 6 Latrepidine dihydrochloride hydrate + dexmedetomidine hydrochloride 1 mg/kg in 0.9% saline; im; 1 µg/kg in 0.9% saline; im 12 50 μl/site Latropyridine + 50 μl/site Dexmedetomidine Single dose, 60 minutes before the second swim 7 Latrepidine dihydrochloride hydrate + dexmedetomidine hydrochloride 1 mg/kg in 0.9% saline; im; 5 µg/kg in 0.9% saline; im 12 50 μl/site Latropyridine + 50 μl/site Dexmedetomidine Single dose, 60 minutes before the second swim *Weight calculated based on free base. im = intramuscular; po = oral

Acclimation: After the quarantine period, animals were allowed to acclimate for 7 days. The body weight variation between groups was ensured to be minimal and not to exceed ±10% of the mean body weight of the entire group.

The animals were housed in an environmentally controlled room at 22°C ± 3°C and a relative humidity of 30% to 70%. A 12/12 light/dark cycle was maintained during the study period. The lights in the acclimatization area were turned off at 06:00 PM. All experiments were conducted at ambient temperature during the dark phase of the light (between 06:00 PM and 06:00 AM). Adequate fresh air supply of 12-15 air changes/hour was maintained in the experimental room. The maximum and minimum temperatures and relative humidity in the experimental room were recorded once daily. The relative humidity in the experimental room was calculated daily based on the dry-bulb and wet-bulb temperature records.

Diet and Water: All animals were provided with a standard rodent diet ad libitum. Animals were provided with bore-well water passed through an activated carbon filter and exposed to UV radiation in an Aquaguard water filter-cum-purifier manufactured by Eureka Forbes Ltd., Mumbai - 400 001, India ad libitum. Study Design:

The first swim takes place between 18:30 and 21:30.

The second swim was performed between 19:30 and 21:30. Animals were administered test compounds 60 min prior to FST 2 in a staggered fashion starting at 18:30.

After the intramuscular injection, the animals were observed for any adverse effects caused by the intramuscular injection.

During the first and second swim procedures, the experimental room was equipped with a 50-watt red light bulb. Forced Swim Test:

The forced swim test was performed during the dark phase.

On day 1, animals were trained in the forced swim test, lasting 15 min (1st swim) and on day 2, after treatment, a 2nd swim was performed.

On day 2, animals were given the corresponding treatment 60 min before the FST.

The forced swim test (2nd swim) was scored manually without video recording.

The forced swim test (FST) is used to study depressive-like behavior in rodents. The test is conducted in a transparent cylindrical glass container measuring 46 cm in height and 20 cm in diameter.

The container was filled with water (23°C - 25°C) to a depth of 30 cm.

Clean drying cages, heat lamps and heat pads are used to complete the procedure to prevent hypothermia in the animals.

All animals were manipulated for approximately 2 minutes daily for 5 days prior to beginning the experimental procedure.

There are 2 swim sessions, 24 hours apart. Session 1, swim 1 is the pre-test/training session (15 minutes), while session 2, swim 2 is the test session (8 minutes).

In the second swim , the first 1 minute of data was excluded from the analysis and the remaining 7 minutes of data were considered. Within the 7 minutes of data, it was divided into 5 minutes and 2 minutes.

Rats were placed in a water-filled cylinder for 15 min (1st swim).

After 15 minutes had elapsed, the rats were removed from the cylinders and placed in a temporary drying cage with a heat lamp above and a heat pad below for 15 minutes.

After the first pretest swim and a 15-min drying period, the animals were returned to their cages.

The water was changed after each session to avoid any influence on the following rats.

Twenty-four hours after the start of the first swim, conduct the test swim (second swim).

Rats were placed in a water-filled cylinder for 8 minutes (2nd swim).

After 8 minutes had passed, the rats were retrieved from the container and placed in a temporary drying cage with a heat lamp above and a heat pad below for 15 minutes. The rats were closely and continuously monitored while recovering in this cage.

The water was changed after each session to avoid any influence on the following rats.

During the second swim, animals were observed to float in the absence of any movement (stationary), climbing, and swimming.

The duration of static, swimming and climbing activities was observed by observers who were unaware of the treatment groups. Observation criteria:

Quiescent period: Rats were judged to be quiescent when they remained floating in the water without struggling and performing only those movements necessary to keep their heads above the water.

Swimming behavior: Rats were judged to be swimming if they displayed active horizontal (swimming) movements beyond that necessary to simply keep their head above water (e.g., moving around a cylinder).

Climbing behavior: Rats were judged to be climbing when they displayed active vertical movements of their front paws in and out of the water, usually pointing toward a wall.

Statistical analysis: One-way ANOVA Dunnet's multiple comparison test was applied relative to vehicle saline, and Tukey's multiple comparison test was applied to compare data between groups using GraphPad Prism version 9 software. Results:

The effects of treatment drugs (desipramine hydrochloride, dexmedetomidine hydrochloride, and latromidine dihydrochloride hydrate) on immobility, swimming, and climbing are shown in FIGS. 7A-7D .

The standard antidepressant drug, desipramine hydrochloride (30 mg/kg, po) showed a significant decrease in the immobility time and an increase in the climbing time compared to the vehicle saline group during the 5-minute observation period on the FST test day. However, the treatment of desipramine hydrochloride (30 mg/kg, po) failed to show any significant effect on the swimming time, suggesting that the norepinephrine agonist mechanism is involved in the antidepressant effect mediated by desipramine in the FST rat model (Detke et al., 1995) (see Figure 7A-7D).

Treatment with dexmedetomidine hydrochloride (1 and 5 μg/kg, intramuscularly) significantly reduced the immobility time compared to the vehicle saline group. In addition, dexmedetomidine hydrochloride (1 μg/kg, intramuscularly) significantly increased the climbing time compared to the vehicle saline group. In addition, dexmedetomidine hydrochloride (5 μg/kg, intramuscularly) significantly increased the swimming time, indicating that it produces an antidepressant effect (see Figure 7C).

Treatment with the combination of dexmedetomidine hydrochloride (1 μg/kg, IM) and latropyridine dihydrochloride hydrate (1 mg/kg, IM) significantly increased swimming time (approximately 64.3%) compared to the vehicle saline group, while the increase in swimming time for the individual drugs compared to vehicle saline was approximately 1.6% for dexmedetomidine hydrochloride (1 μg/kg, IM) and 9.8% for latropyridine dihydrochloride hydrate (1 mg/kg, IM), indicating a synergistic interaction between the two drugs at the specific dose combination. The effects of combined drug treatment on swimming behavior can be attributed to an increase in brain serotonin levels, a neurotransmitter known to have mood-elevating effects (see FIG. 7B ).

Conclusion: It can be concluded that the synergistic effects observed between dexmedetomidine hydrochloride and lapropyridine dihydrochloride hydrate at specific doses (1 μg/kg and 1 mg/kg, respectively) are caused by the specific brain norepinephrine (NE) and serotonin levels achieved by those doses of the drugs.

The above study evaluated the antidepressant-like effects of dexmedetomidine hydrochloride (1 and 5 μg/kg, intramuscularly) alone or in combination with latropyridine dihydrochloride hydrate (1 mg/kg, intramuscularly) in the dark phase using the forced swim test rat model. The combination resulted in a significant increase in swimming behavior, which even exceeded the increase of 5 μg/kg, intramuscular dexmedetomidine hydrochloride, thereby showing the synergistic effects of two suboptimal doses of dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate, respectively. Example 5. Evaluation of the effects of dexmedetomidine hydrochloride, latropyridine dihydrochloride hydrate and their combination on the attacking behavior of male Swiss albino mice in the resident intruder task.

Animal groups: Swiss albino male mice were assigned to 13 different experimental groups with 6-14 rats per group as shown in Table 9. Each experimental group was also coded so that the experimenter became blinded to the true experimental group during RI analysis.

Background: Stress is a contributing factor to mental vulnerability, and the neural substrates and systems that mediate stress responses have been implicated in affective disorders.

Rationale: Occupant-intruder stress is a behaviorally relevant model to investigate the mechanisms underlying stress-related psychiatric disorders. In male rats, a single occupant-intruder exposure activates LC neurons. Considered as a primary stress response system, LC-NE activation is critical in maintaining responses to acute stress provocations.

Animal source: Vivo Bio Tech Ltd. Hyderabad, Telangana, India

Total number of animals and age at time of study: 280 males and 140 females; 3-6 weeks of age.

Weight range: about 25-40 g (140 resident males) / about 10-20 g (140 invader males) / 15-25 g (140 females).

Acclimation: After health check, animals were acclimated to the test conditions for a period of one week. Only animals without any visible signs of disease were used for the study. Standard laboratory conditions, with a 12 h light/dark cycle (lights on between 07:00-19:00 h), temperature was maintained between 21°C ± 3°C and relative humidity between 30%-70%.

All resident mice were housed individually (1 animal/cage) and intruder mice were socially housed (5 animals/cage) in sterile solid bottom polycarbonate cages (dimensions 17 inches (L) x 10 inches (W) x 8 inches (H), with stainless steel grate top, facilities for food and water bottles, and clean corn cob bedding). Cages were hung on stainless steel frames. Table 9. Treatment Group Details: Group No. n Processing Group Dosage and route 1 14 Medium 10 mL/kg, ip 2 11 Dexmedetomidine hydrochloride 4 μg/kg, ip (10 mL/kg, ip) 3 7 Dexmedetomidine hydrochloride 10 μg/kg, ip (10 mL/kg, ip) 4 9 Latropyridine dihydrochloride hydrate 0.3 mg/kg, ip (10 mL/kg, ip) 5 9 Latropyridine dihydrochloride hydrate 1 mg/kg, ip (10 mL/kg, ip) 6 7 Latropyridine dihydrochloride hydrate 3 mg/kg ip (10 mL/kg ip) 7 7 Latropyridine dihydrochloride hydrate 10 mg/kg, ip (10 mL/kg, ip) 8 9 Dexmedetomidine hydrochloride + Latrepidine dihydrochloride hydrate 4 µg/kg ip + 0.3 mg/kg ip (10 mL/kg ip) 9 9 Dexmedetomidine hydrochloride + Latrepidine dihydrochloride hydrate 4 µg/kg ip + 1 mg/kg ip (10 mL/kg ip) 10 7 Dexmedetomidine hydrochloride + Latrepidine dihydrochloride hydrate 4 µg/kg ip + 3 mg/kg ip (10 mL/kg ip) 11 7 Dexmedetomidine hydrochloride + Latrepidine dihydrochloride hydrate 4 µg/kg ip + 10 mg/kg ip (10 mL/kg ip) 12 6 Dexmedetomidine hydrochloride + Latrepidine dihydrochloride hydrate 10 µg/kg ip + 1 mg/kg ip (10 mL/kg ip) 13 10 Sodium valproate 300 mg/kg ip (10 mL/kg ip) *Weight calculated based on free base.

Diet and Water: SAFETM laboratory diet for rodents manufactured by SAFE, France was provided in pelleted form. Drinking water was provided ad libitum in polycarbonate bottles with stainless steel straws through a water filtration system.

Study Drugs: Test substances (dexmedetomidine hydrochloride, lapropiridine dihydrochloride hydrate, and sodium valproate) were dissolved in 0.9% saline solution as a vehicle. β-Estradiol was dissolved in 0.9% saline solution.

*Note on Latropyridine: Vortexing and sonication for 5 minutes may be used to obtain a clear solution.

All formulations were prepared fresh on the day of treatment. Dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate formulations were stored at 4°C, protected from light until administration.

Experimental Design and Dosing: Bilateral ovariectomy was performed in female Swiss albino mice at 3-4 weeks of age according to standard methods (Alagwu and Nneli, 2005). Animals were anesthetized with Avertin (2,2,2-tribromoethanol) at 250 mg/kg, intraperitoneally and laid on the operating table and secured with tape. A midline incision was made below the ribs and on the dorsal area 1 cm lateral to either side of the midline, and a small incision was made in the fascia to separate the fat supporting the ovaries. By slowly pulling out the adipose tissue, the ovaries were identified and removed following ligation of the uterine horns with silk sutures. The fascia was covered with sutures and a similar procedure was repeated on the other side. The superficial epidermis was sutured, and gentamicin (80 mg/kg, subcutaneously) was given as an antibiotic and meloxicam (4 mg/kg, subcutaneously) was given as an analgesic, after which povidone-iodine was applied to the superficial epidermis. Polyethylene glycol (PEG) was applied to prevent eyeball dryness and a 3-week recovery period was maintained (surgery was performed by a single experimenter). Male Swiss albino mice (25-40 g, resident animals) were housed individually (i.e., 1 animal/cage), with ovariectomized female Swiss albino mice for a period of three weeks (isolation adaptation). During this adaptation period, female mice were treated with β-estradiol at a dose of 0.2 mg/kg subcutaneously. Male Swiss albino mice (10-20 g, intruder animals) were housed 5 animals/cage for a period of five days (social adaptation). On the day of exposure, the animals were brought into the experimental room 60 minutes before the start of the experiment to acclimate them to the experimental conditions. On days 1 and 2, the intruder was placed in the housing cage of the resident animal for a period of 10 minutes and returned to its housing cage. During this 10-minute exposure period, the attack behavior of the resident animal (tail clicking, chasing, biting, lateral attack, grappling attack) was considered as the attack duration and attack latency. During this exposure period, female mice were removed from the resident cage (choice phase performed by 3 experimenters between 9 AM and 1 PM).

Animals meeting the following criteria were selected for treatment: The average attack duration of the resident animals (day 1 and day 2) should be greater than 30 seconds. The selected animals were randomly divided into different groups based on their attack duration.

On the 4th day from the initial exposure, the resident animals were administered test article/vehicle/sodium valproate, and the same intruders were exposed to the same resident animals 60 minutes prior to testing. Sodium valproate was administered to the resident animals 30 minutes prior to testing.

Statistical analysis: The obtained data were compared with the baseline score by using Student's paired two tailed t-test. The duration of attack and latency to attack between the groups were analyzed using one-way ANOVA followed by Bonferroni's posthoc test. All statistical analyses were performed using Graph pad prism software package (version 7 or higher), and p values less than 0.05 were considered significant.

Results: Latrolpyridine dihydrochloride hydrate was found to reduce agitation/aggression in resident mice. Latrolpyridine dihydrochloride hydrate (1 mg/kg, 3 mg/kg, and 10 mg/kg; ip) significantly reduced the duration of attacks (Figures 8A and 8B). Similarly, the combination of dexmedetomidine hydrochloride and latrolpyridine dihydrochloride hydrate (dexmedetomidine 4 mcg/kg, ip + latrolpyridine 3 mg/kg, ip; dexmedetomidine 4 mcg/kg, ip + latrolpyridine 10 mg/kg, ip; and dexmedetomidine 10 mcg/kg, ip + latrolpyridine 1 mg/kg, ip) was found to have a significant effect on the reduction of the duration of attacks compared to vehicle (Figures 9A and 9B). Both combinations of dexmedetomidine and latrepyridine (i.e., dexmedetomidine 4 µg/kg, ip + latrepyridine 3 mg/kg, ip and dexmedetomidine 10 µg/kg, ip + latrepyridine 1 mg/kg, ip) showed almost the same efficacy as latrepyridine 10 mg/kg, ip in reducing attack duration, with mean attack durations of 42.58 seconds, 40.73 seconds, and 36.87 seconds, respectively (Figure 10). From a drug safety perspective, achieving similar efficacy with reduced doses of each individual component of the combination instead of higher doses of a single compound provides particular value.

Conclusion: Latrapyridine is able to reduce agitation/aggression associated with high norepinephrine agonist signaling. Therefore, latrapyridine should be effective in those patients with associated high norepinephrine agonist tone or sympathetic overexcitation. This finding suggests that latrapyridine may work well in combination with other modulators of this pathway, including alpha-2 adrenergic agonists such as dexmedetomidine. Example 6 : Antipsychotic effects of dexmedetomidine hydrochloride and latrapyridine in mice were obtained using the Smart-cube system.

Dexmedetomidine and lapropyridine have antipsychotic effects when tested in the SmartCube® system (Psychogenics, Inc., Paramus, NJ; see also U.S. Pat. No. 7,580,798, which is incorporated herein by reference in its entirety). This system uses features derived from mouse behavioral data to first classify mice that have taken the compound versus the vehicle. This measure indicates how well the system can distinguish mice that have taken the compound from mice that have taken the vehicle. Second, by comparing the features to a proprietary reference database of behavioral feature sets, SmartCube® is a behavioral assignment feature that is associated with classes of commercially available drugs known to treat neuropsychiatric symptoms. Thus, the high system can be used as a model to identify both the activity and psychiatric effects of a compound by comparing the compound's effects relative to the drug to known validated effects.

By comparing the animals' responses to known drugs, test drugs can be classified according to their function; for example, hallucinogens, anxiogenics, analgesics, cognitive enhancers, psychostimulants, mood stabilizers, high-dose antipsychotics, antipsychotics, sedatives/hypnotics, anxiolytics, high-dose antidepressants, antidepressants.

Once all features are extracted from the raw data by an automated pipeline, a proprietary bioinformatics algorithm is used to decorrelate the feature sets and find the combination of values that best separates the different groups of interest. For each compound, at each dose, the system provides the probability that the drug is active and breaks down this putative activity into different classes of interest.

The SmartCube references used in this article include antipsychotics and antidepressants tested at several dose ranges. As indicated in the legend, "Antipsychotic" and "High-dose Antipsychotic" reflect the concept that the antipsychotic references are dose-dependent. Antipsychotics may engage additional receptor systems when administered at higher doses and therefore affect mouse behavior differently. The same applies to different doses of antidepressants. Materials and Methods:

Animals: Male C57/BL6 mice (N=12/group) from Taconic Laboratories were used. Upon receipt, mice were housed in groups of 4 mice per cage in OPTI mouse ventilated cages. Mice were acclimated to group housing for at least one week prior to testing and were then tested at approximately 8-9 weeks of age. All animals were examined, handled, and weighed prior to the start of the study to ensure adequate health and suitability and to minimize nonspecific stress associated with handling.

During the study, a 12/12 light/dark cycle was maintained. Room temperature was maintained between 20°C and 23°C, with relative humidity maintained between approximately 30% and 70%. Food and water were provided ad libitum for the duration of the study.

Animals were acclimated to the holding room for up to one week prior to the start of the study. Room temperature and humidity were recorded continuously in a fixed room. Experimenters were blinded to treatment assignments. Behavioral testing was performed according to established protocols approved by the IACUC committee and PGI's standard operating procedures (SOPs). Standard safety precautions were applied to all studies. Personnel working in the animal room and laboratory wore protective clothing. Treatments: 8 groups (N=12/group)

All compounds tested were formulated in NP3 (vehicle solution): 5% Pharmasolve; 30% P3 (1:1:1 PEG200:PEG400:propylene glycol); 65% saline; pH 5.1-6. All SmartCube operations were performed using NP3 as the vehicle and under the same environment. Test groups: ●    Vehicle: NP3 ●    0.005 and 0.010 mg/kg of dexmedetomidine ●    1 and 10 mg/kg of latrazopyridine ●    Combination of dexmedetomidine and latrazopyridine (in mg/kg): 0.005/1.0; 0.005/10; 0.010/1.0; 0.010/10

Test compounds were injected intraperitoneally (IP) for 15 minutes before the animals were placed in the SmartCube for evaluation. Explanation of SmartCube legend:

Vehicle: Activity profile (NPS) of mice injected intraperitoneally (IP) with vehicle

Antipsychotics: SmartCube classifies the behavior of mice treated with test compounds as similar to treatment with commercial antipsychotics at therapeutically relevant doses.

High doses of antipsychotics: SmartCube classified the behavior of mice dosed with the test compound as similar to treatment with a commercial antipsychotic at doses considered highly therapeutic. High doses of antipsychotics typically cause sedation.

Antidepressants: SmartCube categorizes the behavior of mice treated with test compounds as similar to treatment with commercial antidepressants at therapeutically relevant doses.

High-dose antidepressants: SmartCube classified the behavior of mice dosed with the test compound as similar to treatment with a commercial antidepressant at a dose considered highly therapeutic.

Mood Stabilizers: SmartCube classified the behavior of mice dosed with the test compound as similar to treatment with a commercially available mood stabilizer at a dose considered highly therapeutic. Results:

The results of the class analysis are presented as a normalized bar graph where the percentages for each dose sum to 100. The percentages indicate how likely the classifier is to distinguish between the vehicle and test groups. The pattern indicates which class feature is assigned.

Dexmedetomidine has an antipsychotic profile in the SmartCube.

Smart-Cube acquired signatures from mice administered (IP mg/kg; N=12/group) with 2 doses (0.005 and 0.010 mg/kg) of dexmedetomidine, an α2-adrenaline agonist (Figure 11). The Smart-Cube deep learning classifier assigned active signatures by comparing the phenotypic behavior of mice injected with dexmedetomidine to a reference library obtained with known compounds. At 0.005 and 0.010 mg/kg, Smart-Cube classified the dexmedetomidine group with increased accuracy (compared to vehicle) and assigned antipsychotic signatures.

Latropyridine has antipsychotic properties in the SmartCube.

Smart-Cube acquired signatures from mice administered 2 doses (1.0 and 10 mg/kg) of latrepyridine (IP mg/kg; N=12/group) (Figure 11). The Smart-Cube deep learning classifier assigned active signatures by comparing the phenotypic behavior of mice injected with latrepyridine to a reference library obtained with known compounds. At 1 and 10 mg/kg, Smart-Cube classified the latrepyridine group with increased accuracy (compared to vehicle) and assigned antipsychotic signatures.

There is a synergistic effect at 0.010 mg/kg dexmedetomidine and 1 mg/kg latromidine.

Smart-Cube acquired signatures from mice administered (IP mg/kg; N=12/group) with the combination of dexmedetomidine and latrogpyridine: 0.005/1.0; 0.005/10; 0.010/1.0; 0.010/10 (dexmedetomidine/latrogpyridine; mg/kg; Figure 11). The Smart-Cube deep learning classifier assigned active signatures by comparing the phenotypic behavior of mice injected with the combination of dexmedetomidine and latrogpyridine with a reference library obtained with known compounds. At a dose of 0.005/1.0 (dexmedetomidine/latrepyridine in mg/kg): Smart-Cube distributes antipsychotic profile and total activity, which is approximately the sum of the individual doses (9% and 20% of individual doses of dexmedetomidine and latrepyridine, respectively) (25%). At a dose of 0.005/10 (dexmedetomidine/latrepyridine in mg/kg): Smart-Cube distributes high dose antipsychotic profile and total activity, which is approximately the sum of the individual doses (9% and 80% of individual doses of dexmedetomidine and latrepyridine, respectively) (90%). At a dose of 0.010/1.0 (dexmedetomidine/latrepyridine in mg/kg): Smart-Cube dispenses antipsychotic profiles, plus some high-dose antipsychotic profiles, with total activity greater than the sum of the individual doses (40% and 20% of the individual doses of dexmedetomidine and latrepyridine, respectively). The sum is 60%, but the dose combination effect is 76%. At a dose of 0.01/10 (dexmedetomidine/latrepyridine in mg/kg): Smart-Cube dispenses high-dose antipsychotic profiles and up to 95% of total activity.

These data indicate that at suboptimal doses, dexmedetomidine (at 0.010 mg/kg) and latromidine (at 1 mg/kg) act synergistically while largely retaining antipsychotic properties. Example 7. Evaluation of the effects of dexmedetomidine hydrochloride, latromidine dihydrochloride hydrate, and combinations thereof on locomotor activity ( movement ) and sedation behavior of male Swiss albino mice in the field test .

Rationale: Spontaneous locomotor activity is measured in relation to total distance travelled in an open field test. Relatively short distance travelled would indicate less locomotor activity or sedation.

Animal groups: Swiss albino male mice (6-7 weeks of age, 25-40 g in weight) were assigned to 10 different experimental groups of 12 rats each, as shown in Table 10. Each experimental group was also coded so that the experimenter became blind to the true experimental group during the open-field test.

Acclimation: After health check, animals were acclimated to the test conditions for a period of one week. Only animals without any visible signs of disease were used for the study. Standard laboratory conditions, with a 12 h light/dark cycle (lights on between 07:00-19:00 h), temperature was maintained between 21°C ± 3°C and relative humidity between 30%-70%. Table 10. Treatment groups: Group No. N pieces/group Processing Group Dosage/Route/Volume of administration 1 12 Medium 10 mL/kg, ip 2 12 Dexmedetomidine hydrochloride (4 μg/kg, intraperitoneal) (10 mL/kg, intraperitoneal) 3 12 Dexmedetomidine hydrochloride (10 μg/kg, intraperitoneal) (10 mL/kg, intraperitoneal) 4 12 Dexmedetomidine hydrochloride (20 μg/kg, intraperitoneal) (10 mL/kg, intraperitoneal) 5 12 Dexmedetomidine hydrochloride (30 μg/kg, intraperitoneal) (10 mL/kg, intraperitoneal) 6 12 Latropyridine dihydrochloride hydrate (1 mg/kg, ip) (10 mL/kg, ip) 7 12 Latropyridine dihydrochloride hydrate (3 mg/kg, ip) (10 mL/kg, ip) 8 12 Latropyridine dihydrochloride hydrate (10 mg/kg, ip) (10 mL/kg, ip) 9 12 Dexmedetomidine hydrochloride + Latrepidine dihydrochloride hydrate (4 μg/kg, intraperitoneal) + (10 mg/kg, intraperitoneal) 10 12 Dexmedetomidine hydrochloride + Latrepidine dihydrochloride hydrate (10 μg/kg, intraperitoneal) + (1 mg/kg, intraperitoneal)

All mice were housed in groups of 4 (dimensions 17 inches (L) x 10 inches (W) x 8 inches (H), with a stainless steel grate top, facilities for food and water bottles, and clean corn cob bedding). The cages were hung on a stainless steel frame.

Diet and Water: SAFE ^™ laboratory diet for rodents manufactured by SAFE, France was provided in pelleted form. Drinking water was provided ad libitum in polycarbonate bottles with stainless steel straws through a water filtration system.

Study Drugs: Test substances (dexmedetomidine hydrochloride and lapropyridine dihydrochloride hydrate) were dissolved in 0.9% saline as a vehicle.

*Note on Latropyridine: Vortexing and sonication for 5 minutes may be used to obtain a clear solution.

All formulations were prepared fresh on the day of treatment. Dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate formulations were stored at 4°C, protected from light until administration.

Study design and dosing: Mice were brought into the laboratory and acclimated to the environment for at least 7 days. The field test was performed under the lighting conditions of 40 lux light. Mice were dosed according to the groups in Table 10. After a 60-minute post-dose interval, 4 mice from a certain group were placed in the field and their movements were tracked over a 30-minute period. Once the test was over, the mice were removed from the field and the field was cleaned. After this, the next group of 4 mice were placed in the field and tracked.

Statistical Analysis: Distance traveled in 30-minute bins was analyzed in 5-minute bins and compared to the distance traveled in the vehicle group using one-way ANOVA followed by Dunnett's test. All statistical analyses were performed using Graph pad prism software package (version 7 or higher) and p values less than 0.05 were considered significant. Results:

Dexmedetomidine hydrochloride (at 4 μg/kg, 10 μg/kg, and 20 μg/kg) did not show any significant reduction in the distance traveled (Figure 12). In addition, latropyridine dihydrochloride hydrate tested at 1 mg/kg, 3 mg/kg, and 10 mg/kg did not show any significant reduction in the distance traveled. Furthermore, the combination of dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate (4 μg/kg + 10 mg/kg and 10 μg/kg + 1 mg/kg, respectively) also did not show any significant reduction in the distance traveled. However, only dexmedetomidine hydrochloride at 30 μg/kg showed a significant reduction in the distance traveled.

Conclusion: Latrapyridine significantly reduced agitation/aggression in resident mice, as observed in a decrease in the duration of attacks in the resident intruder assay (from Example 5). However, it did not cause any decrease in locomotion, nor did it cause sedation, as the distance traveled in the open field remained unchanged. Therefore, it can be concluded that latrapyridine is effective in reducing agitation/aggression, without causing sedation. Example 8. Effect of latrapyridine dihydrochloride hydrate in CCK-4-induced panic anxiety in rats.

Background: CCK4 (Cholecystokinin tetrapeptide) has been reported to trigger panic attacks in healthy volunteers (Eser et al., Panic Induction with Cholecystokinin-Tetrapeptide (CCK-4) Increases Plasma Concentrations of the Neuroactive Steroid 3α, 5α Tetrahydrodeoxycorticosterone (3α, 5α-THDOC) in Healthy Volunteers. Neuropsychopharmacol 30, 192-195, 2005) and enhance panic rates in patients with panic disorder (Bradwejn et al., Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings. Arch Gen Psychiatry. 1991 Jul;48(7):603-10). Peripheral administration of CCK4 induces anxiety-like effects in rats as assessed in the EPM paradigm (Rex et al., Effects of cholecystokinin tetrapeptide and sulfated cholecystokinin octapeptide in rat models of anxiety. Neurosci Lett. 1994 May 19; 172(1-2):139-42).

Rationale: Cholecystokinin-tetrapeptide (CCK-4) induction as an experimental model of human anxiety disorders has become the focus of intensive research over the past two decades. CCK-4 is a synthetic analog of the endogenous neuropeptide cholecystokinin (CCK) found in different brain regions. In particular, high concentrations of CCK have been detected in regions involved in mediating panic attacks, such as the cerebral cortex, amygdala, hippocampus, and brain stem nuclei. CCK-4 dose-dependently induces panic attacks in healthy controls. Therefore, it has been assumed that CCK-4 meets the criteria for an ideal and effective panic-inducing agent. In addition, several studies have demonstrated that successful treatment with anti-panic drugs, such as imipramine, fluvoxamine, citalopram, or benzodiazepine, attenuates CCK-4-induced panic attacks. Therefore, the CCK-4 challenge paradigm can be used as a useful tool to evaluate the anti-panic potential of novel anti-anxiety compounds.

Animal Groups: Male Weiss rats weighing 150 g were purchased and reached a weight of approximately 220 g at the time of use. Animals were assigned to 6 different experimental groups with 12 rats in each group as shown in Table 11. Each experimental group was also coded so that the experimenter became unaware of the true experimental group during the EPM test. Dosage, route, and pretreatment time are also provided in Table 11. Table 11. Treatment Group Details: Group No. N/ each group Management ( dose, route of administration, time of administration before EPM ) 1 12 CCK4 (0.2 mg/kg; ip, -30 minutes)/vehicle (im, -60 minutes) 2 12 CCK4 (0.2 mg/kg; ip, -30 minutes)/diazepam (1 mg/kg, im, -60 minutes) 3 12 CCK4 (0.2 mg/kg; ip, -30 minutes)/LAT (1 mg/kg; im, -60 minutes) 4 12 CCK4 (0.2 mg/kg; ip, -30 minutes)/LAT (3 mg/kg; im, -60 minutes) 5 12 CCK4 (0.2 mg/kg; ip, -30 minutes)/LAT (10 mg/kg; im, -60 minutes) 6 12 CCK4 (0.2 mg/kg; ip, -30 minutes)/LAT (15 mg/kg; im, -60 minutes) *Weights calculated based on free base. im = intramuscular; ip = intraperitoneal

Acclimation: They were group housed (3-4 rats/cage) and maintained in a room with controlled temperature (21°C-22°C) and inverted light-dark cycle (12h/12h; lights on: 17:30 - 05:30; lights off: 05:30 - 17:30).

Food and Water: Animals had food and water available ad libitum.

Study Drugs: All compounds/drugs were prepared in physiological saline (0.9% NaCl).

CCK-4 was prepared as a 0.2 mg/ml solution which, when injected intraperitoneally in a dose volume of 1 ml/kg, yielded a dose of 0.2 mg/kg.

Diazepam was prepared as a 1 mg/ml solution which, when injected intraperitoneally in a dose volume of 1 ml/kg, yielded a dose of 1 mg/kg.

Latrolpyridine was prepared at concentrations of 2.5, 7.5, 25, and 37.5 mg/ml, which yielded doses of 1, 3, 10, and 15 mg/kg, respectively, when injected intramuscularly in a volume of 100 µL into 250 g rats.

Study Design and Dosing: Rats were randomly assigned to one of the different experimental groups. Each animal was identified by its group name, cage number, experimental series (days), and a number (1 to 4) written in permanent ink on its tail. It was manipulated by the experimenter for approximately 3 minutes daily during 1 week before the day of the EPM test.

The apparatus is a PVC maze covered with resin glass and is subdivided into four equal exploration arms (40 × 10 cm) interconnected by small platforms (10 × 10 cm). The apparatus is placed 65 cm above the floor. Two arms are open and the other two are closed with a wall (height: 10 cm).

After compound administration, rats were placed on the platform opposite the closed arms. The number of entries and the time spent in each arm were recorded during a 5-minute period. An animal was considered to have entered an arm when it placed all four of its paws in the arm.

Clean the equipment with alcohol (70°) between animals. Remove urine and feces from the maze.

During testing, animal handling and operator visibility were minimized as much as possible.

Statistical analysis: Data were analyzed using one-way ANOVA followed by Dunnett's test. All statistical analyses were performed using Graph pad prism software package (version 9), and p values less than 0.05 were considered significant.

Results: Figures 13 and 14 show the average performance of each experimental group in terms of the number of entries into the open arms and the time spent in them. Table 12 : Changes in behavioral performance during the EPM test Processing Group Entries (number) Mean ± SEM (% increase compared to CCK-4/vehicle) Time (sec) Mean ± SEM (% increase compared to CCK-4/vehicle) CCK4 (0.2 mg/kg)/vehicle 1.9 ± 0.3 (0.00) 13.2 ± 2.3 (0.00) CCK4 (0.2 mg/kg)/diazepam (1 mg/kg) 9.5 ± 0.5 (400.00) **** 99.3 ± 3.8 (652.27) **** CCK4 (0.2 mg/kg)/LAT (1 mg/kg) 2.8 ± 0.4 (47.37) 24.2 ± 4.7 (83.33) CCK4 (0.2 mg/kg)/LAT (3 mg/kg) 2.5 ± 0.2 (31.58) 26.2 ± 3.3 (98.48) CCK4 (0.2 mg/kg)/LAT (10 mg/kg) 3.3 ± 0.3 (73.68) * 34.1 ± 3.4 (158.33) ** CCK4 (0.2 mg/kg)/LAT (15 mg/kg) 4.3 ± 0.4 (126.32) *** 48.4 ± 5.3 (266.67) ****

The vehicle-treated CCK-4 rats entered the open arms 1.9±0.3 times and spent 13.2±2.3 seconds in them (Table 12). Treatment with 1 mg/kg diazepam reversed the panic anxiety induced by CCK-4, as shown by a significant increase in the number of entries into the open arms and the time spent in the open arms (9.5±0.5 in Figure 13 and 99.3±3.8 seconds in Figure 14, respectively).

The results showed that latromidine as a monotherapy induced an increase in the number of entries into the open arms and the time spent in the open arms in CCK-4 treated rats. The effect of latromidine was dose dependent, with the maximum effect obtained at 15 mg/kg. The effect of latromidine was significant at doses of 10 and 15 mg/kg (Table 12).

Conclusions: In sequential CCK-4 and EPM analyses, latromidine acutely reduced stress-mediated anxiety and agitation as measured in the EPM analysis (increased number of entries and time spent in the open arm) following CCK-4 administration. These data support the use of latromidine for the treatment of stress-induced symptoms in humans following traumatic events.

1: Open arm 2: Closed arm 3: Platform 4: Lifting frame

Figure 1: Depicts the elevated plus maze apparatus. According to Example 2, the maze consists of two closed arms and two open arms forming a cross, with a square center platform. Figure 2: Depicts the study design and administration time points for various drugs according to Example 2. Figure 3: Depicts the time (in seconds) spent in the open arms of the elevated plus maze by Wistar rats after administration of latropyridine dihydrochloride hydrate (3 mg/kg and 10 mg/kg) to rats administered with yohimbine hydrochloride (2.5 mg/kg) according to Example 2. Figure 4: Depicts the number of entries into the open arms of the elevated plus maze by Weiss rats after administration of latromidine (3 mg/kg and 10 mg/kg) to rats administered with yohimbine hydrochloride (2.5 mg/kg) according to Example 2, compared to dextromethorphan hydrobromide (10 mg/kg) and fluvoxamine citrate (10 mg/kg). Figure 5: Depicts the time (in seconds) spent in the open arms of the elevated plus maze by Weiss rats after administration of laprolidine dihydrochloride hydrate (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg and 3 mg/kg) to rats administered with yohimbine hydrochloride (2.5 mg/kg), where laprolidine dihydrochloride hydrate (3 mg/kg + saline) was treated as itself, according to Example 3. Figure 6: Depicts the number of entries into the open arms of the elevated plus maze in Weiss rats after administration of laprolidine dihydrochloride hydrate (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg and 3 mg/kg) to rats administered with yohimbine hydrochloride (2.5 mg/kg), where laprolidine dihydrochloride hydrate (3 mg/kg + saline) was used as the self-treatment according to Example 3. Figure 7: Depicts the effects of dexmedetomidine hydrochloride (1 μg/kg and 5 μg/kg), latropyridine dihydrochloride hydrate (1 mg/kg), and the combination of dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate (1 μg/kg + 1 mg/kg and 5 μg/kg + 1 mg/kg, respectively) on the immobility (7A), swimming (7B), climbing (7C), and total activity (7D) behaviors (in seconds) during a 5-minute FST test in Sprague-Dawley (SD) rats in the dark phase according to Example 4. Figure 8A and Figure 8B: Depict the effects of dexmedetomidine hydrochloride (4 μg/kg and 10 μg/kg) and latropyridine dihydrochloride hydrate (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) on the duration of attacks (in seconds) of Swiss albino mice in the resident intruder task according to Example 5. Figures 9A and 9B: Depict the effects of the combination of dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate (4 μg/kg + 0.3 mg/kg, 4 μg/kg + 1 mg/kg, 4 μg/kg + 3 mg/kg, 4 μg/kg + 10 mg/kg, and 10 μg/kg + 1 mg/kg, respectively) on the duration of attack (in seconds) of Swiss albino mice in the resident intruder task according to Example 5. Figure 10: Depicts the effect of dexmedetomidine hydrochloride (4 μg/kg and 10 μg/kg), latropyridine dihydrochloride hydrate (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) and the combination of dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate (4 μg/kg + 0.3 mg/kg, 4 μg/kg + 1 mg/kg, 4 μg/kg + 3 mg/kg, 4 μg/kg + 10 mg/kg and 10 μg/kg + 1 mg/kg, respectively) on the duration of strikes (in seconds) in Swiss albino mice in the resident intruder task according to Example 5. FIG. 11 : shows the SMARTCUBE features of dexmedetomidine hydrochloride, latropyridine, and the combination of dexmedetomidine hydrochloride and latropyridine for antipsychotic behavior according to Example 6. FIG. 12 : depicts the effects of dexmedetomidine hydrochloride (4 μg/kg, 10 μg/kg, 20 μg/kg, and 30 μg/kg), latropyridine dihydrochloride hydrate (1 mg/kg, 3 mg/kg, and 10 mg/kg), and the combination of dexmedetomidine hydrochloride and latropyridine dihydrochloride hydrate (4 μg/kg + 10 mg/kg and 10 μg/kg + 1 mg/kg, respectively) on the distance traveled (in centimeters) of Swiss albino mice in the open field test according to Example 7. Figure 13: Depicts the number of entries into the open arms after administration of latropyridine dihydrochloride hydrate (1, 3, 10, and 15 mg/kg) to rats administered with CCK-4 according to Example 8. Figure 14: Depicts the time spent in the open arms after administration of latropyridine dihydrochloride hydrate (1, 3, 10, and 15 mg/kg) to rats administered with CCK-4 according to Example 8.

Claims (32)

A method for treating a disorder associated with norepinephrine-induced overexcitation in a human subject comprises administering to the human subject a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof, optionally in combination with a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the disease is acute stress disorder. The method of claim 2, wherein the human subject has one or more symptoms associated with acute stress disorder selected from the group consisting of anxiety, sleep disturbance, excessive startle reaction, irritability, inability to stop moving or sitting still, lack of motivation, and agitation. The method of claim 3, wherein the symptom is anxiety. The method of claim 3, wherein the symptom is sleep disorder. The method of claim 3, wherein the symptom is an excessive fright reaction. The method of claim 3, wherein the symptom is irritability. The method of claim 3, wherein the symptom is an inability to stop moving or sitting still. The method of claim 3, wherein the symptom is lack of motivation. The method of claim 3, wherein the symptom is agitation. The method of any one of claims 1 to 10, wherein the method prevents the condition from developing into post-traumatic stress disorder. The method of claim 1, wherein the disease is pan-autistic disorder. The method of any one of claims 1 to 12, wherein the condition is caused by a traumatic event experienced by the human individual. The method of any one of claims 1 to 13, wherein the latropyridine is administered once a day. The method of any one of claims 1 to 13, wherein the latripridine is administered twice a day. The method of any one of claims 1 to 13, wherein the latropyridine is administered three times a day. The method of claim 13, wherein the latripridine is administered within 4 weeks of the traumatic event. The method of claim 13, wherein the latripridine is administered within 2 weeks of the traumatic event. The method of claim 13, wherein the latripridine is administered within 1 week of the traumatic event. The method of claim 13, wherein the latropyridine is administered within 3 days of the traumatic event. The method of claim 13, wherein the latropyridine is administered within 1 day of the traumatic event. The method of claim 13, wherein the latropyridine is administered within 12 hours of the traumatic event. The method of claim 13, wherein the latropyridine is administered within 6 hours of the traumatic event. The method of claim 13, wherein the latropyridine is administered within 4 hours of the traumatic event. The method of any of the preceding claims, wherein the therapeutically effective amount of latromidine is in the range of about 5 mg to about 300 mg per day. The method of any of the preceding claims, wherein the therapeutically effective amount of latromidine is in the range of about 10 mg to about 200 mg per day. The method of any of the preceding claims, wherein the therapeutically effective amount of latromidine is in the range of about 10 mg to about 100 mg per day. The method of any of the preceding claims, wherein the therapeutically effective amount of latromidine is in the range of about 10 mg to about 80 mg per day. The method of any of the preceding claims, wherein the therapeutically effective amount of latromidine is in the range of about 15 mg to about 60 mg per day. The method of any of the preceding claims, wherein the therapeutically effective amount of latromidine is in the range of about 30 mg to about 45 mg per day. The method of any of the preceding claims, wherein the therapeutically effective amount of latropyridine is evenly distributed over two daily administrations or three daily administrations. The method of any of the preceding claims, wherein the latropyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially or intermittently.