Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals

Definitions

• Tinnitus is characterized by an auditory sensation in the absence of external sound. In many cases tinnitus is subjectively perceptual, i.e., only the subject can perceive symptoms. Symptoms of tinnitus include ringing, roaring, static, buzzing, hissing and whistling in one or both ears. The noise may be intermittent or continuous. According to the National Institute on Deafness and other Communication Disorders (NIDCD) approximately 10 percent of the US adult population, or about 25 million Americans, have experienced some degree of tinnitus. According to the American Tinnitus Association, 20 million of these sufferers struggle with burdensome chronic tinnitus, while 2 million have extreme and debilitating cases.
• NDCD National Institute on Deafness and other Communication Disorders
• tinnitus can lead to depression and other mental health challenges that severely affect the patient and the patient's family members.
• Therapies such as masking, sound therapy, electrical stimulation, and drugs have shown some benefit.
• these treatments may be insufficient and many patients continue to suffer with tinnitus. Therefore, treatment of tinnitus remains a significant need.
• Acute sensorineural hearing loss is also known as sudden sensorineural hearing loss (SSNHL), sudden deafness and acute sensory hearing loss.
• Idiopathic acute sensorineural hearing loss is a form of acute sensorineural hearing loss in which no clear cause is known.
• the terms“acute sensorineural hearing loss” or“ASNHL” will be used herein for convenience and encompasses SSNHL, sudden deafness, acute sensory hearing loss and idiopathic acute sensorineural hearing loss.
• acute sensorineural hearing loss may be defined as the onset of one-sided sensorineural hearing loss in less than 72 hours. It strikes an estimated 5-20/100,000 persons per year.
• ASNHL may occur following various inner ear injuries.
• criteria for ADHD include six or more symptoms of inattention and six or more symptoms of hyperactivity and impulsivity for children up to age 16, or 5 or more such symptoms for adolescents 17 or older and adults.
• Inattention symptoms include: 1. often failure to give close attention to details or make careless mistakes in schoolwork, at work, or with other activities, 2. often has trouble holding attention on tasks or play activities, 3. often does not seem to listen when spoken to directly,
• Medications may be administered to control some symptoms of ADHD.
• Stimulants such as methylphenidate, methamphetamine, dextroamphetamine, may be prescribed but can have adverse effects such as diminished appetite and headaches non-stimulant medications, such as atomoxetine, bupropion, guanfacine, and clonidine that may be used as alternatives, or added to stimulant therapy.
• Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences.
• Addiction is a disorder of the brain's reward system which arises through transcriptional and epigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., eating food, the use of drugs, engagement in sexual intercourse, participation in high-thrill cultural activities such as gambling, etc.).
• Classic symptoms of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, and continued use despite consequences.
• Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).
• methods of treating tinnitus include administering (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in one or more symptoms of the tinnitus.
• methods of treating tinnitus include administering (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in next day tinnitus in the subject.
• methods of treating tinnitus include administering: (lS,3S)-3-amino- 4-(difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, and (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• methods of treating tinnitus include administering to a patient in need thereof (lS,3S)-3-amino-4-(difluoromethylidene) cyclopentane- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a benzodiazepine wherein the method provides improvement in tinnitus.
• methods of treating tinnitus include administering to a patient in need thereof of (S)-3-amino-4-(difluorom ethyl enyl) cyclopent-l-ene-l- carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a benzodiazepine wherein the method provides improvement in tinnitus.
• the benzodiazepine is clobazam.
• methods of treating acute sensorineural hearing loss described herein include administering to a patient in need thereof (lS,3S)-3-amino-4- (difluoromethylidene) cyclopentane- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the method provides improvement in acute sensorineural hearing loss.
• methods of treating acute sensorineural hearing loss described herein include administering to a patient in need thereof (S)-3-amino-4-(difluoromethylenyl) cyclopent-l- ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the method provides improvement in acute sensorineural hearing loss.
• methods of treating acute sensorineural hearing loss described herein include administering to a patient in need thereof (S)-3-amino-4-(difluoromethylenyl) cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a benzodiazepine wherein the method provides improvement in acute sensorineural hearing loss.
• the benzodiazepine is clobazam.
• methods of treating Meniere's disease described herein include administering to a patient in need thereof (lS,3S)-3-amino-4-(difluoromethylidene) cyclopentane- 1- carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a benzodiazepine wherein the method provides improvement in Meniere's disease.
• methods of treating Meniere's disease described herein include administering to a patient in need thereof (S)-3-amino-4-(difluorom ethyl enyl) cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a benzodiazepine wherein the method provides improvement in Meniere's disease.
• the benzodiazepine is clobazam.
• methods of treating Tourette’s syndrome described herein include administering to a patient in need thereof (lS,3S)-3-amino-4-(difluoromethylidene) cyclopentane- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the method provides improvement in Tourette’s syndrome.
• methods of treating Tourette’s syndrome described herein include administering to a patient in need thereof (S)- 3 -amino-4-(difluorom ethyl enyl) cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the method provides improvement in Tourette’s syndrome.
• methods of treating Tourette’s syndrome described herein include
• methods of treating Tourette’s syndrome described herein include administering to a patient in need thereof (S)-3-amino-4-(difluoromethylenyl) cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof in combination with risperidone, ziprasidone, haloperidol, pimozide, fluphenazine, clonidine or guanfacine, wherein the method provides improvement in Tourette’s syndrome.
• methods of treating addiction described herein include administering to a patient in need thereof (lS,3S)-3-amino-4- (difluoromethylidene) cyclopentane- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof in combination with naltrexone, disulfiram, acamprosate, topiramate, buprenorphine, methadone, gabapentin or pregabalin, wherein the method provides improvement in addiction.
• Described herein are methods and compositions for treating tinnitus which include administering to a subject in need thereof an effective amount of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing.
• compositions for treating acute sensorineural hearing loss which include administering to a subject in need thereof an effective amount of (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing.
• compositions for treating Meniere's disease which include administering to a subject in need thereof an effective amount of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing.
• compositions for treating Tourette’s syndrome which include administering to a subject in need thereof an effective amount of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing.
• ADHD Attention deficit hyperactivity disorder
• compositions for treating addiction which include administering to a subject in need thereof an effective amount of (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing.
• Described herein are methods of treating tinnitus with (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing.
• methods of treating tinnitus include administering (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in next day tinnitus symptoms of the subject.
• methods of treating tinnitus include administering (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, in combination with (S)-3-amino-4-(difluoromethylenyl)cyclopent-l- ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• embodiments include administering to a subject in need thereof an effective amount of
• methods of treating acute sensorineural hearing loss include administering to a subject in need thereof an effective amount of (S)-3 -amino-4-(difluorom ethyl enyljcy cl opent- l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof.
• methods of treating acute sensorineural hearing loss include administering (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in one or more symptoms of the acute sensorineural hearing loss.
• methods of treating acute sensorineural hearing loss include administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l- carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in next day acute sensorineural hearing loss of the subject.
• methods of treating acute sensorineural hearing loss include administering
• Methods of treating Meniere's disease include administering to a subject in need thereof an effective amount of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof.
• methods of treating Meniere's disease include administering
• methods of treating Meniere's disease include administering to a subject in need thereof an effective amount of (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof.
• methods of treating Meniere's disease include administering (S)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in one or more symptoms of the Meniere's disease.
• methods of treating Meniere's disease include administering (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in next day Meniere's disease symptoms of the subject.
• Methods of treating Tourette’s syndrome include administering to a subject in need thereof an effective amount of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof.
• methods of treating Tourette’s syndrome include administering (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or a
• methods of treating Tourette’s syndrome include administering (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in next day Tourette’s syndrome symptoms of the subject.
• methods of treating Tourette’s syndrome include administering to a subject in need thereof an effective amount of (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof.
• methods of treating Tourette’s syndrome include administering (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, in combination with (S)-3-amino-4-(difluoromethylenyl)cyclopent-l- ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Methods of treating ADHD include administering to a subject in need thereof an effective amount of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof.
• methods of treating ADHD include administering (lS,3S)-3-amino- 4-(difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in one or more symptoms of the ADHD in the subject.
• methods of treating ADHD include administering (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or a
• methods of treating ADHD include administering to a subject in need thereof an effective amount of (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof.
• methods of treating ADHD include administering (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in one or more symptoms of the ADHD.
• methods of treating ADHD include administering (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in next day ADHD symptoms of the subject.
• methods of treating ADHD include administering (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or a pharmaceutically acceptable salt thereof, in combination with (S)-3-amino-4-(difluoromethylenyl)cyclopent-l- ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• Methods of treating addiction are provided and, in embodiments, include
• methods of treating addiction include administering (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide improvement in one or more symptoms of the addiction.
• methods of treating tinnitus include
• methods of treating addiction include administering (l S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l- carboxylic acid or a pharmaceutically acceptable salt thereof, in combination with (S)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• kits for treating tinnitus including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene) cyclopentane- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluorom ethyl enyl)cy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or a combination of the foregoing, wherein the composition provides improvement in at least one symptom of the tinnitus.
• provided herein are methods of treating Meniere's disease including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene) cyclopentane- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing, wherein the composition provides improvement in at least one symptom of the Meniere's disease.
• Symptoms of Meniere's disease may include, but are not limited to, vertigo, hearing loss, tinnitus, hypersensitivity to sounds, and aural fullness in the affected ear.
• methods of treating Tourette’s syndrome including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene) cyclopentane- 1 -carboxylic acid or a
• Symptoms of Tourette’s syndrome are tics which may include eye blinking and other vision irregularities, throat clearing, grunting, facial grimacing, shoulder shrugging, and head or shoulder jerking, self-harm, and vocal tics including coprolalia or echolalia.
• Hyperactivity and impulsivity symptoms may include: 1. often fidgets with or taps hands or feet, or squirms in seat, 2. often leaves seat in situations when remaining seated is expected, 3.
• kits for treating addiction including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene) cyclopentane- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof, or (S)-3-amino-4-(difluorom ethyl enyl)cy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or combinations of the foregoing, wherein the composition provides improvement in at least one symptom of the addiction.
• Symptoms of addiction may include, but are not limited to, compulsive engagement in rewarding stimuli despite adverse consequences, impaired control over substances or behavior, preoccupation with substance or behavior, continued use despite consequences, immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).
• drug and behavioral addictions include alcoholism, amphetamine addiction, cocaine addiction, nicotine addiction, opiate addiction, benzodiazepine addiction, food addiction, gambling addiction, and sexual addiction.
• the terms “effective amount” or“therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and/or physiologic effect in connection with Tourette’s syndrome.
• the terms “effective amount” or“therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and/or physiologic effect in connection with ADHD.
• the terms “effective amount” or“therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and/or physiologic effect in connection with addiction.
• An effective amount of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or a pharmaceutically acceptable salt thereof is used to treat a subject having Meniere's disease.
• An effective amount of (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is used to treat a subject having tinnitus.
• An effective amount of (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is used to treat a subject having acute sensorineural hearing loss.
• An effective amount of (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is used to treat a subject having acute sensorineural hearing loss.
• An effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l- carboxylic acid or a pharmaceutically acceptable salt thereof is used to treat a subject having Tourette’s syndrome.
• An effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent- l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is used to treat a subject having ADHD.
• the subject may be an animal, e.g., mammal, e.g., human, etc.
• the terms“treat”,“treatment” or“treating” encompass any manner in which the symptoms or pathology of a condition, disorder or disease associated with tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction are ameliorated or otherwise beneficially altered.
• “treat”,“treatment” or“treating” can refer to inhibiting a disease or condition, e.g., arresting or reducing its development or at least one clinical or subclinical symptom thereof.
• “treat”,“treatment” or“treating” can refer to relieving the disease or condition, e.g., causing regression of the disease or condition or at least one of its clinical or subclinical symptoms.
• the benefit to a subject being treated may be statistically significant, mathematically significant, or at least perceptible to the subject and/or the physician.
• the effective amount can vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system, health, etc.), the disease or disorder being treated, as well as the route of administration and the pharmacokinetics of the agent being administered.
• (difluoromethylidene)cyclopentane-l -carboxylic acid is between about 4 to 6 hours. C max increases in a dose proportional manner over a range of 5 mg - 500 mg; whereas there is a greater than proportional increase in AUCs in the dose range.
• (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid is between 9 and 10 times more potent as an inactivator of GAB A- AT than (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid and may exhibit similar
• (1S, 3 S)-3-amino-4-(difluoromethylidene)cy cl opentane-l -carboxylic acid may be provided as an acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.
• (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid may be provided as an acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.
• Acid addition salts include but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acid addition salts, as well as the 8-halotheophyllines, for example 8- bromo-theophylline.
• inorganic acid addition salts including but not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acid addition salt
• methods include treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction by administering to a subject in need thereof about 0.5 mg to about 1000 mg of (lS,3S)-3-amino-4-difluoromethylenyl-l- cyclopentanoic acid or a pharmaceutically acceptable salt thereof, e.g., a hydrochloride salt thereof.
• the amount of (lS,3S)-3-amino-4-difluoromethylenyl-l- cyclopentanoic acid or a pharmaceutically acceptable salt thereof, e.g., a hydrochloride salt thereof, can be between 0.1 and 1500 mg/day, or 0.01 mg/kg/day to 15 mg/kg/day, for treatment of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction.
• the amount of (lS,3S)-3-amino-4- difluorom ethyl enyl-l-cy cl opentanoic acid or a pharmaceutically acceptable salt thereof, e.g., a hydrochloride salt thereof, can be between 0.1 and 1000 mg/day for treatment of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction.
• the daily dosage can be, e.g., in the range of about 0.1 to 1500 mg,
• 50 to 125 mg 50 to 100 mg, 50 to 75 mg, 75 to 1500 mg, 75 to 1000 mg, 75 to 500 mg, 75 to 300 mg, 75 to 250 mg, 75 to 200 mg, 75 to 175 mg, 75 to 150 mg, 75 to 125 mg, 75 to 100 mg, 100 to 1500 mg, 100 to 1000 mg, 100 to 500 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg, 100 to 175 mg, 100 to 150 mg, 100 to 125 mg, 125 to 1500 mg, 125 to 1000 mg, 125 to 500 mg, 125 to 300 mg, 125 to 250 mg, 125 to 200 mg, 125 to 175 mg, 125 to 150 mg, 150 to 1500 mg, 150 to 1000 mg, 150 to 500 mg, 150 to 300 mg, 150 to 250 mg, 150 to 200 mg, 150 to 175 mg, 175 to 500 mg, 175 to 300 mg, 175 to 250 mg, 175 to 200 mg, 200 to 1500 mg, 200 to 1000 mg, 200 to 500 mg, 200 to 300 mg,
• compositions may include (l S,3S)-3-amino- 4-difluoromethylenyl-l-cyclopentanoic acid or a pharmaceutically acceptable salt thereof in an amount of, e.g., about 0.01 to 500 mg, 0.1 to 500 mg, 0.1 to 450 mg, 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 175 mg, 0.1 to 150 mg, 0.1 to 125 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 30 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to lmg, 0.5 to 500 mg, 0.5 to 450 mg, 0.5 to 300 mg, 0.5 to 250 mg, 0.5 to 200 mg, 0.5 to 175 mg, 0.5 to 150 mg, 0.5 to 125 mg, 0.5 to 100 mg, 0.5 to 75 mg, 0.5 to 50 mg, 0.5 to 30 mg
• 1 to 125 mg 1 to 100 mg, 1 to 75 mg, 1 to 50 mg, 1 to 30 mg, 1 to 25 mg, 1 to 20 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 500 mg, 5 to 450 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 175 mg, 5 to 150 mg, 5 to 125 mg, 5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 10 to 500 mg, 10 to 450 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 175 mg, 10 to 150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 75 mg, 10 to 50 mg, 10 to 30 mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 15 to 500 mg, 15 to 450 mg, 15 to 300 mg, 15 to 250 mg, 15 to 200 mg, 15 to 175 mg, 15 to 150 mg, 15 to 125 mg,
• 150 to 450 mg 150 to 300 mg, 150 to 250 mg, 150 to 200 mg, 200 to 500 mg, 200 to 450 mg,
• (l S,3S)-3-amino-4-difluoromethylenyl-l- cyclopentanoic acid or a pharmaceutically acceptable salt thereof is administered to a subject 100 mg/per day, 95 mg/per day, 90 mg/per day, 85 mg/per day, 80 mg/per day, 75 mg/per day, 70 mg/per day, 65 mg/per day, 60 mg/per day, 55 mg/per day, 50 mg/per day, 45 mg/per day, 40 mg/per day, 35 mg/per day, 30 mg/per day, 25 mg/per day, 20 mg/per day, 15 mg/per day, 10 mg/per day, 5 mg/per day, 4 mg/per day, 3 mg/per day, 2 mg/per day, 1 mg/per day, in one or more doses.
• an adult dose for treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction can be about 5 to 80 mg per day and can be increased to 150 mg per day. Dosages can be lower for infants and children than for adults.
• a pediatric dose for treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction can be about 0.1 to 50 mg per day once or in 2, 3 or 4 divided doses.
• a pediatric dose for treating tinnitus can be 0.75 mg/kg/day to 1.5 mg/kg/day.
• compositions also referred to simply as compositions
• dosage forms encompass unit doses.
• various dosage forms including conventional formulations and modified release formulations can be administered one or more times daily. Any suitable route of
• Suitable dosage forms include tablets, capsules, oral liquids, powders, aerosols, transdermal modalities such as topical liquids, patches, creams and ointments, parenteral formulations and suppositories.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4-difluoromethylenyl-l- cyclopentanoic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 2 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 2 hours after administration to the subject.
• sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction are provided which include administering to a subject in need thereof a pharmaceutical composition including (l S,3S)-3-amino-4-difluoromethylenyl-l-cyclopentanoic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 3 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-difluorom ethyl enyl-l-cy cl opentanoic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 4 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4-difluoromethylenyl-l- cyclopentanoic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 6 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 6 hours after administration to the subject.
• sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction are provided which include administering to a subject in need thereof a pharmaceutical composition including (l S,3S)-3-amino-4-difluoromethylenyl-l-cyclopentanoic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject.
• the pharmaceutical compositions provide improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction the next day after administration to the subject.
• the pharmaceutical compositions may provide improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration at bedtime or earlier, and waking from a night of sleep.
• (lS,3S)-3-amino-4-difluoromethylenyl-l-cyclopentanoic acid or a pharmaceutically acceptable salt thereof is administered to a subject having tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction in combination with (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof.
• (lS,3S)-3-amino-4- difluorom ethyl enyl-l-cy cl opentanoic acid or a pharmaceutically acceptable salt thereof may be administered to a subject having tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction in separate dosage forms or combined in one dosage form.
• methods include treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction by administering to a subject in need thereof about 0.005 mg to about 750 mg of (S)-3-amino-4-
• the amount of (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, e.g., hydrochloride salt can be between 0.005 and 1000 mg/day, or 0.005 mg/kg/day to 14 mg/kg/day, for treatment of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction.
• compositions may include (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of, e.g., about 0.001 to 500 mg, 0.01 to 500 mg, 0.01 to 450 mg, 0.01 to 300 mg, 0.01 to 250 mg, 0.01 to 200 mg, 0.01 to 175 mg, 0.01 to 150 mg, 0.01 to 125 mg, 0.01 to 100 mg, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30 mg, 0.01 to 25 mg, 0.01 to 20 mg, 0.01 to 15 mg, 0.01 to 10 mg, 0.01 to 5 mg, 0.01 to lmg, 0.025 to 500 mg, 0.025 to 450 mg, 0.025 to 300 mg, 0.025 to 250 mg, 0.025 to 200 mg, 0.025 to 175 mg, 0.025 to 150 mg, 0.025 to 125 mg, 0.025 to 100 mg, 0.0
• dosages may be administered to a subject once, twice, three or four times daily, every other day, once weekly, or once a month.
• (S)-3-amino-4- (difluoromethylenyl) cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject twice a day, (e.g., morning and evening), or three times a day (e.g., at breakfast, lunch, and dinner), at a dose of 0.01-50 mg/administration.
• (S)-3-amino-4-(difluorom ethyl enyl)cy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject 75 mg/per day, 70 mg/per day, 65 mg/per day, 60 mg/per day, 55 mg/per day, 50 mg/per day, 45 mg/per day, 40 mg/per day, 35 mg/per day, 30 mg/per day, 25 mg/per day, 20 mg/per day, 15 mg/per day, 10 mg/per day, 7.5 mg/per day, 5.5 mg/per day, 5 mg/per day, 4.5 mg/per day, 4 mg/per day, 3.5 mg/per day, 3 mg/per day, 2.5 mg/per day, 2 mg/per day, 1.5 mg/per day, 1 mg/per day, 0.5 mg/per day, 0.25 mg/per day, in one or more doses.
• an adult dose for treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction can be about 0.5 to 50 mg per day and can be increased to 75 mg per day. Dosages can be lower for children than for adults.
• a pediatric dose for treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction can be from about 0.01 to 10 mg per day once or in 2, 3 or 4 divided doses.
• a pediatric dose for treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction can be 0.075 mg/kg/day to 1.0 mg/kg/day.
• the subject may be started at a low dose and the dosage is escalated over time.
• (S)-3-amino-4-(difluoromethylenyl)cy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof is administered via a pharmaceutical composition.
• various dosage forms including conventional formulations and modified release formulations containing (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof can be administered one or more times daily.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (S)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 1 hour after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 2 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (S)-3 -amino-4-(difluorom ethyl enyljcy cl opent-l-ene- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 3 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 3 hours after administration to the subject.
• sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction are provided which include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 4 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (S)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 6 hours after administration to the subject.
• methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction include administering to a subject in need thereof a pharmaceutical composition including (S)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject.
• the pharmaceutical compositions provide improvement of next day functioning of the subject.
• the pharmaceutical compositions may provide improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration at bedtime or earlier, and waking from a night of sleep.
• (S)-3-amino-4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof is administered to a subject having tinnitus, acute sensorineural hearing loss,
• (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof may be administered to a subject having tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction in separate dosage forms or combined in one dosage form.
• (S)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid or a pharmaceutically acceptable salt thereof, or (l S,3S)-3-amino-4-difluoromethylenyl-l- cyclopentanoic acid or a pharmaceutically acceptable salt thereof, may be administered to a subject having tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction simultaneously or at spaced apart intervals.
• provided herein are methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction including administering to a subject in need thereof (l S,3S)-3-amino-4-
• Extended release dosage forms have extended release profiles and are those that allow a reduction in dosing frequency as compared to that presented by a conventional dosage form, e.g., a solution or unmodified release dosage form. ERDFs provide a sustained duration of action of a drug. Suitable formulations which provide extended release profiles are well-known in the art.
• one or both of (l S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l- carboxylic acid or (L')-3 -ami no-4-(difluorom ethyl enyl)cyclopent- l -ene- 1 -carboxylic acid (KT- II-115), or a pharmaceutically acceptable salt of any of the preceding, is incorporated into an ion-exchange resin to provide a delayed release profile. Delayed action may result from a predetermined rate of release of the drug from the resin when the drug-resin complex contacts gastrointestinal fluids and the ionic constituents dissolved therein.
• compositions for parenteral administration may include one or more excipients, e.g. , solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, stabilizers or antimicrobial preservatives.
• excipients e.g. , solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, stabilizers or antimicrobial preservatives.
• compositions including one or both of (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, provide an in vivo plasma profile having a Cmax, individually or combined, less than about, e.g, 2000 ng/ml, 1000 ng/ml, 850 ng/ml, 800 ng/ml, 750 ng/ml, 700 ng/ml, 650 ng/ml, 600 ng/ml, 550 ng/ml, 450 ng/ml, 400 ng/ml 350 ng/ml, or 300 ng/ml and wherein the composition provides improvement in symptoms of tinnitus, acute sensorineural hearing
• the composition provides an in vivo plasma profile having a AUCo- ⁇ , individually or combined, of less than about, e.g. , 400 ng » hr/ml, 350 ng # hr/ml, 300 ng # hr/ml, 250 ng # hr/ml, or 200 ng # hr/ml.
• the composition provides an in vivo plasma profile having a AUCo- ⁇ , individually or combined, of less than about, e.g. , 400 ng » hr/ml, 350 ng # hr/ml, 300 ng # hr/ml, 250 ng # hr/ml, or 200 ng # hr/ml.
• the composition provides an in vivo plasma profile having a AUCo- ⁇ , individually or combined, of less than about, e.g. , 400 ng » hr/ml, 350 ng # hr/ml, 300 ng #
• tinnitus in embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction including administering to a subject in need thereof a first pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane- l-carboxylic acid or (L')-3 -ami no-4-(difluorom ethyl enyl)cyclopent-l -ene- 1 -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, and a second pharmaceutical composition including one or both of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-en
• compositions may provide improvement in one or more symptoms for more than about, e.g .,
• tinnitus in embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction including administering to a subject in need thereof a first pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, and a second pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane- l-carboxylic acid or (L')-3 -ami no-4-(difluorom ethyl enyl)cyclopent- l -ene- 1
• the second pharmaceutical composition provides an in vivo plasma profile having a AUCo- ⁇ of less than about, e.g., 550 ng ⁇ hr/ml, 500 ng*hr/ml, 450 ng*hr/ml, 400 ng ⁇ hr/ml, or 350 ng*hr/ml.
• the second pharmaceutical composition provides an in vivo plasma profile having a AUCo- ⁇ of less than about, e.g, 300 ng*hr/ml, 250 ng ⁇ hr/ml, 200 ng*hr/ml, 150 ng ⁇ hr/ml, or 100 ng ⁇ hr/ml.
• the first and second pharmaceutical composition are administered wherein the compositions provide improvement in symptoms of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction the next day following administration in the subject.
• the first pharmaceutical composition provides improvement in one or more symptom for more than, e.g, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration of the first pharmaceutical composition.
• tinnitus in embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction including administering to a subject in need thereof a first pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, and a second pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane- l-carboxylic acid or (L')-3 -ami no-4-(difluorom ethyl enyl)cyclopent-l -ene-
• the Tmax of the first pharmaceutical composition is less than 3 hours. In embodiments, the Tmax of the first pharmaceutical composition is less than 2.5 hours. In embodiments, the Tmax of the first pharmaceutical composition is less than 2 hours. In embodiments, the T max of the first pharmaceutical composition is less than 1.5 hours. In embodiments, the T max of the first pharmaceutical composition is less than 1 hour. In embodiments, the T max of the first pharmaceutical composition is less than 0.5 hour. In embodiments, the T max of the first pharmaceutical composition is less than 0.25 hour. In embodiments, the T max of the second pharmaceutical composition is less than 3 hours. In embodiments, the Tmax of the second pharmaceutical composition is less than 2.5 hours. In embodiments, the Tmax of the second pharmaceutical composition is less than 2 hours.
• the first and second pharmaceutical compositions may administered within, e.g ., 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc.
• the first and second pharmaceutical compositions may administered separated by at least, e.g. , 15 minutes, 30 minutes, 1 hour, 2 hours, 12 hours, 18 hours, 24 hours, etc.
• improvement in at least one symptom of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction for more than 8 hours after administration to the subject is provided.
• improvement for more than about, e.g. , 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 30 hours, 36 hours, 42 hours or 48 hours after administration to the subject is provided.
• the administration of the first and second pharmaceutical is provided.
• tinnitus in embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction including administering to a subject in need thereof a first pharmaceutical dosage including a sub- therapeutic amount of one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane- l-carboxylic acid or (L')-3 -ami no-4-(difluorom ethyl enyl)cyclopent- l -ene- 1 -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding.
• a first pharmaceutical dosage including a sub- therapeutic amount of one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane- l-carboxylic acid or (L')-3 -ami no-4-(d
• treating tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction includes administering to a subject in need thereof a first pharmaceutical dosage including a sub-therapeutic amount of one or both of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in one or more symptoms of tinnitus, acute sensorineural hearing loss or Meniere's disease for more than 6 hours after administration.
• the first and/or the second pharmaceutical compositions contain sub- therapeutic dosages.
• a sub -therapeutic dosage is an amount of active substance, e.g ., one or both of (l S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or (S)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, that is less than the amount typically required for a therapeutic effect.
• the second composition contains a sub-therapeutic dose of one or both of (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding.
• the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction.
• the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of tinnitus, acute sensorineural hearing loss, Meniere's disease, Tourette’s syndrome, ADHD or addiction.
• a first pharmaceutical composition including a first pharmaceutical dosage of, e.g., one or both of (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, wherein the first pharmaceutical dosage provides improvement for more than 6 hours after administration, and a second pharmaceutical composition including a sub-therapeutic dosage of one or both of (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-
• the first or the second pharmaceutical composition are provided to the subject once in the evening and once in the morning.
• the total amount of one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or (ri)-3-amino-4-(difluorom ethyl enyljcy cl opent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, administered to a subject in a 24- hour period is any of the respective amounts described herein.
• the first and/or the second pharmaceutical compositions may be provided with conventional release or modified release profiles.
• the first and second pharmaceutical compositions may be provided at the same time or separated by an interval of time, e.g ., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, etc.
• the first and the second pharmaceutical compositions may be provided with different drug release profiles to create a two-phase release profile.
• the first pharmaceutical composition may be provided with an immediate release profile, e.g., ODDF, parenteral, etc.
• the second pharmaceutical composition may provide an extended release profile.
• one or both of the first and second pharmaceutical compositions may be provided with an extended release or delayed release profile.
• compositions may be provided as pulsatile formulations, multilayer tablets or capsules containing tablets, beads, granules, etc.
• the first pharmaceutical composition is an immediate release composition.
• the second pharmaceutical composition is an immediate release composition.
• the first and second pharmaceutical compositions are provided as separate immediate release compositions, e.g. , film, tablets or capsules. In embodiments the first and second pharmaceutical compositions are provided 12 hours apart.
• a co-therapy of (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid and fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding is effective to reduce frequency or severity of symptoms in the subject greater than any of the compounds administered alone.
• the co-therapy produces a more than additive result compared to compounds administered individually.
• the subject may be started at a low dose and the dosage is escalated. In this manner, it can be determined if the drug is well tolerated in the subject. Dosages can be lower for children than for adults.
• kits for treating tinnitus including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with a second pharmaceutically active agent.
• a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with a second pharmaceutically active agent.
• kits for treating ASNHL including administering to a patient in need thereof a pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino- 4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with a second pharmaceutically active agent.
• a pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino- 4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with a second pharmaceutical
• a pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino- 4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with a second pharmaceutically active agent.
• a pharmaceutical composition including one or both of (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino- 4-(difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with a second pharmaceutically active agent.
• the second pharmaceutically active agent may include analgesics, anti-inflammatory agents, antidepressants, calcium channel antagonists, glutamate receptor antagonists, CGRP agonists, CGRP antagonists, anticonvulsants (e.g., baclofen type), osmoregulators, sodium channel blockers, anticonvulsants, antiarrhythmics, and neuroprotectives.
• analgesics may include opioids, non-steroidal analgesics, gabapentin, and alpha-adrenergic agonists.
• the second active agent may include a sulfonamide, for example, acetazol amide, azosemide, bumetanide, chlorthalidone, clopamide, furosemide,
• hydrochlorothiazide HCT, HCTZ, HZT
• indapamide mefruside, metolazone, piretanide, tripamide xipamide, dichlorphenamide (DCP), dorzolamide, ethoxzolamide, sultiame, or zonisamide.
• the second active agent may include a thiazide, for example, bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlor-methiazide, chlorthalidone, indapamide, metolazone or quinethazone.
• a thiazide for example, bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlor-methiazide, chlorthalidone, indapamide, metolazone or quinethazone.
• the second active agent may include a NKl receptor antagonist, for example, 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-l -carboxylic acid [l-(R)-(3,5-bis- trifluoromethyl-phenyl)-ethyl]-methyl-arnide or pharmaceutically acceptable salts or solvates thereof, 4-(S)-(4-acetyl-piperazin-l-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-l- carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, and 2-(R)-(4-fluoro-2-methyl-phenyl)- 4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[l,2- -a]-pyrazin
• the second active agent may include risperidone, ziprasidone, haloperidol, pimozide, fluphenazine, clonidine or guanfacine.
• the second active agent may include methylphenidate, methamphetamine, dextroamphetamine, atomoxetine, bupropion, guanfacine, or clonidine.
• the second active agent may include naltrexone, disulfiram, acamprosate, topiramate, buprenorphine, methadone, gabapentin or pregabalin.
• the second active agent may include a benzodiazepine.
• the benzodiazepine may include diazepam, alprazolam, estazolam, clobazam, clonazepam, clorazepate, chlordiazepoxide, flurazepam, triazolam, temazepam, midazolam, halazepam, quazepam, lorazepam, oxazepam, derivatives thereof, or pharmaceutically acceptable salts thereof
• the second active agent may include clonazepam and/or clobazam.
• kits for treating tinnitus including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts described above and clonazepam.
• a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts
• kits for treating tinnitus including administering to a patient in need thereof a pharmaceutical composition including ((lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding in any of the amounts described above and clobazam.
• a pharmaceutical composition including ((lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding in any of the amounts described above and clobazam
• kits for treating ASNHL including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts described above and clonazepam.
• a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts described above and
• kits for treating ASNHL including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts described above and clobazam.
• a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts described above and clobazam.
• provided herein are methods of treating Meniere’s disease including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts described above and clobazam.
• a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in any of the amounts described
• the disclosed combinations may provide improved treatment compared to either active agent alone.
• the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of subjective tinnitus.
• the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of ASNHL.
• the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of Meniere’s disease.
• the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of Tourette’s syndrome.
• the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of ADHD.
• the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of addiction.
• the pharmaceutical compositions include 0.1 mg to 30 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg clobazam or a pharmaceutically acceptable salt thereof.
• the pharmaceutical compositions include 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg clobazam or a pharmaceutically acceptable salt thereof.
• the pharmaceutical compositions include 0.1 mg, 0.25 mg, 0.5 mg, 1 mg,
• the pharmaceutical compositions include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg clobazam or a pharmaceutically acceptable salt thereof.
• the adult dose of clobazam may be 5-60 mg daily in divided doses or as a single dose given at night.
• the adult dose of clobazam may be 5-10 mg, 5- 20 mg, 5-25 mg, 5-30 mg, 5-35 mg, 5-40 mg, 5-50 mg, 5-55 mg, 10-15 mg, 10-20 mg, 10-25 mg, 10-30 mg, 10-35 mg, 10-40 mg, 10-45 mg, 10-50 mg, 10-55 mg, 10-60 mg, 15-20 mg,
• kits for treating tinnitus including administering to a patient in need thereof (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, and clobazam or a pharmaceutically acceptable salt thereof, together or separately, wherein the patient experiences improvement of at least one tinnitus symptom for more than 4 hours after administration of the pharmaceutical composition to the patient.
• the improvement of at least one tinnitus symptom for more than 6 hours after administration of the (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, and the clobazam or a pharmaceutically acceptable salt thereof to the patient is provided in accordance with the present disclosure.
• kits for treating ASNHL including administering to a patient in need thereof (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, and clobazam or a pharmaceutically acceptable salt thereof, together or separately, wherein the patient experiences improvement of at least one ASNHL symptom for more than 4 hours after administration of the pharmaceutical composition to the patient.
• the improvement of at least one ASNHL symptom for more than 6 hours after administration of the (l S,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, and the clobazam or a pharmaceutically acceptable salt thereof to the patient is provided in accordance with the present disclosure.
• improvement in at least one Meniere’s disease symptom for at least e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of the (l S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or S)-3-amino-4-(difluorom ethyl enyl)cy cl opent-l-ene-l -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, and the clobazam or a
• kits for treating tinnitus including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof wherein the composition provides improvement of at least one tinnitus symptom for more than 4 hours after administration of the pharmaceutical composition to the patient.
• a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxy
• the improvement of at least one tinnitus symptom for more than 6 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement of at least one tinnitus symptom for more than, e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement in at least one tinnitus symptom for at least e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement in at least one tinnitus symptom for 12 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• kits for treating ASNHL including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof wherein the composition provides improvement of at least one ASNHL symptom for more than 4 hours after administration of the pharmaceutical composition to the patient.
• a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-I
• the improvement of at least one ASNHL symptom for more than 6 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement in at least one ASNHL symptom for at least e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement in at least one ASNHL symptom for 12 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• the improvement of at least one Meniere’s disease symptom for more than 6 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement of at least one Meniere’s disease symptom for more than, e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement in at least one Meniere’s disease symptom for at least e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• improvement in at least one Meniere’s disease symptom for 12 hours after administration of the pharmaceutical composition to the patient is provided in accordance with the present disclosure.
• methods of treating tinnitus including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in tinnitus the next day.
• a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement
• methods of treating ASNHL including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3- amino-4-(difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in ASNHL the next day.
• methods of treating Meniere’s disease including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in Meniere’s disease the next day.
• a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in Meniere’s disease
• kits for treating Tourette’s syndrome including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in Tourette’s syndrome the next day.
• a pharmaceutical composition including (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition
• methods of treating ADHD including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in ADHD the next day.
• a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in ADHD the next day.
• methods of treating addiction including administering to a patient in need thereof a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in addiction the next day.
• a pharmaceutical composition including (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l-carboxylic acid or fV)-3- amino-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, wherein the composition provides improvement in addiction the next day.
• methods of treating tinnitus including administering to a patient in need thereof (lS,3S)-3-amino-4-(difluoromethylidene)cyclopentane-l- carboxylic acid or (L')-3 -ami no-4-(difluorom ethyl enyl)cyclopent- l -ene- 1 -carboxylic acid (KT-II-l 15), or a pharmaceutically acceptable salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in tinnitus the next day.
• kits for treating Tourette’s syndrome including administering to a patient in need thereof (lS,3S)-3-amino-4- (difluoromethylidene)cyclopentane-l -carboxylic acid or fV)-3-amino-4- (difluoromethylenyl)cyclopent-l-ene-l-carboxylic acid (KT-II-115), or a pharmaceutically acceptable salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in Tourette’s syndrome the next day.
• TST total sleep time (TST) of time in bed (TIB). Additional evaluation of sleep may include analysis of parent/caregiver logs of sleep patterns that may include: (1) bed time; (2) time of sleep onset; (3) number and duration of awakenings; (4) number of disruptive behavior; (5) time of last awakening; and (6) daytime sleepiness.

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• 2019
  • 2019-02-08 CA CA3090258A patent/CA3090258A1/en active Pending
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