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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention is based, at least in part, on the discovery of methods and compositions for the treatment of conditions associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, e.g., snoring and sleep apnea, comprising administration of a norepinephrine reuptake inhibitor (NRI) and a non myorelaxing hypnotic or 5-HT2A inverse agonist or antagonist.
• NRI norepinephrine reuptake inhibitor
• OSA Obstructive Sleep Apnea
• the present disclosure is based upon the administration of noradrenergic and non-myorelaxing hypnotic drugs to increase pharyngeal muscle activity in sleeping humans and reduce snoring and sleep apnea severity, e.g., in OSA patients.
• a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state include administering to a subject in need thereof an effective amount of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non myorelaxing hypnotic and/or 5-HT2A inverse agonist or antagonist.
• NRI norepinephrine reuptake inhibitor
• the NRI is a norepinephrine selective reuptake inhibitor (NSRI), e.g., an NSRI selected from the group consisting of Amedalin, Atomoxetine, CP-39,332, Daledalin, Edivoxetine, Esreboxetine, Lortalamine, Nisoxetine,
• NSRI norepinephrine selective reuptake inhibitor
• the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI), e.g., an NNRI selected from the group consisting of Amitriptiline, Amoxapine, Bupropion, Ciclazindol, Desipramine, Desvenlafaxine,
• NRI norepinephrine non-selective reuptake inhibitor
• the NRI is selected from the group consisting of Atomoxetine and Reboxetine.
• the NRI is Atomoxetine
• the dosage of Atomoxetine is 20 - 100 mg, e.g., 25-75 mg.
• the non myorelaxing hypnotic is a benzodiazepine hypnotic, e.g., temazepam, brotizolam, flurazepam, nitrazepam, or triazolam; or a non-benzodiazepine hypnotic, e.g., a cyclopyrrolone hypnotic, e.g., zolpidem, zopiclone or eszopiclone, a stereoisomer of zopiclone; gabapentin; trazodone;
• a benzodiazepine hypnotic e.g., temazepam, brotizolam, flurazepam, nitrazepam, or triazolam
• a non-benzodiazepine hypnotic e.g., a cyclopyrrolone hypnotic, e.g., zolpidem, zopiclone
• diphenhydramine suvorexant; tasimelteon; ramelteon; agomelatine; doxepin;
• the 5-HT2A inverse agonist is AC-90179, ketanserin, nelotanserin, eplivanserin, pimavanserin, or volinanserin; or the 5-HT2A antagonist is trazodone, mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL- 100,907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or Niaprazine.
• the 5 -HT2 A antagonist is ketanserin, iloperidone, perospirone
• the 5-HT2A inverse agonist or antagonist is pimvanserin, preferably administered at a dose of 20-40 mg, preferably 34 mg.
• the non myorelaxing hypnotic or 5-HT2A inverse agonist or antagonist is in an immediate release formulation. In some embodiments, the non myorelaxing hypnotic or 5-HT2A inverse agonist or antagonist is in an extended release formulation.
• the non myorelaxing hypnotic is zolpidem, and in specific embodiments, the dosage of zolpidem is 2-12.5 mg.
• the zolpidem is in an immediate release formulation, e.g., with a dose of 2-10 mg.
• the zolpidem is in an extended release formulation, e.g., with a dose of 5-12.5 mg.
• the disease or disorder is Obstructive Sleep Apnea (e.g., AHI of > 10 events per hour) or Simple Snoring.
• Obstructive Sleep Apnea e.g., AHI of > 10 events per hour
• Simple Snoring e.g., AHI of > 10 events per hour
• the non-fully conscious state is sleep.
• the NRI and the non myorelaxing hypnotic are administered in a single composition.
• the NRI and 5-HT2A inverse agonist or antagonist are administered in a single composition.
• the single composition is an oral administration form.
• the oral administration form is a syrup, pill, tablet, troche, or capsule.
• the single composition is a transdermal administration form, e.g., a patch.
• compositions comprising (i) a norepinephrine reuptake inhibitor (NRI) (ii) a non myorelaxing hypnotic and/or 5- HT2A inverse agonist or antagonist, and (iii) a pharmaceutically acceptable carrier.
• NRI norepinephrine reuptake inhibitor
• the NRI is a norepinephrine selective reuptake inhibitor (NSRI), e.g., selected from the group consisting of Amedalin, Atomoxetine, CP- 39,332, Daledalin, Edivoxetine, Esreboxetine, Lortalamine, Nisoxetine, Reboxetine, Talopram, Talsupram, Tandamine, and Viloxazine.
• NRI norepinephrine selective reuptake inhibitor
• the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of Amitriptiline, Amoxapine, Bupropion, Ciclazindol, Desipramine, Desvenlafaxine, Dexmethilphenidate, Diethylpropion, Doxepin, Duloxetine,
• NRI norepinephrine non-selective reuptake inhibitor
• the NRI is selected from the group consisting of Atomoxetine and Reboxetine.
• the NRI is Atomoxetine
• the dosage of Atomoxetine is 20 - 100 mg.
• the non myorelaxing hypnotic is a benzodiazepine hypnotic, e.g., temazepam, brotizolam, flurazepam, nitrazepam, or triazolam; or a non-benzodiazepine hypnotic, e.g., a cyclopyrrolone hypnotic, preferably selected from the group consisting of zolpidem, zopiclone, and eszopiclone; gabapentin;
• a benzodiazepine hypnotic e.g., temazepam, brotizolam, flurazepam, nitrazepam, or triazolam
• a non-benzodiazepine hypnotic e.g., a cyclopyrrolone hypnotic, preferably selected from the group consisting of zolpidem, zopiclone, and eszopiclone; gabap
• trazodone diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine;
• the non myorelaxing hypnotic is in an immediate release formulation. In some embodiments, the non myorelaxing hypnotic is in an extended release formulation.
• the non myorelaxing hypnotic is zolpidem.
• the zolpidem is in an immediate release formulation, e.g., with a dose of 2-10 mg.
• the zolpidem is in an extended release formulation, e.g., with a dose of 5-12.5 mg.
• the 5-HT2A inverse agonist is AC-90179, ketanserin, nelotanserin, eplivanserin, pimavanserin, or volinanserin; or the 5-HT2A antagonist is trazodone, mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL- 100,907, cyproheptadine, pizotifen, LY-367,265, 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or Niaprazine.
• the 5 -HT2 A antagonist is ketanserin, iloperidone, perospirone
• the 5-HT2A inverse agonist or antagonist is pimvanserin, present in a dose of 20-40 mg or 30-40 mg, preferably 34 mg.
• compositions described herein for use in treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state.
• the disease or disorder is sleep apnea or Simple Snoring.
• the disease or disorder is Obstructive Sleep Apnea.
• the non-fully conscious state is sleep.
• the NRI and the non myorelaxing hypnotic are administered in a single composition.
• the single composition is an oral administration form.
• the oral administration form is a pill, tablet, troche, or capsule.
• NRI norepinephrine reuptake inhibitor
• a non myorelaxing hypnotic and/or 5-HT2A inverse agonist or antagonist for use in treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state.
• kits comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non myorelaxing hypnotic and/or 5-HT2A inverse agonist or antagonist, e.g., for use in method described herein, e.g., for treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non- fully conscious state.
• the kit can comprise, e.g., separate pharmaceutical
• kit may contain (a) separate or common bottles or packets allowing potentially separate dosaging and (b) optionally a set of kit instructions.
• FIG. 1 Graphic illustration of an obstructive apnea.
• the top channel shows the electroencephalogram (EEG) pattern of sleep.
• the next channel represents airflow.
• the next three channels show ventilatory effort by movements of the rib cage and abdomen and changes in esophageal pressure, all of which reflect contraction of respiratory muscles.
• the last channel indicates oxyhemoglobin saturation.
• FIG. 2 Atomoxetine alone (Ato) and oxybutynin alone (Oxy) did not systematically reduce OSA severity (apnea hypopnea index, AHI). In contrast, there was a potent effect of these agents when administered together. White lines indicate means, boxes indicate 95% Cl.
• FIG. 3A-3B Atomoxetine is responsible for most of the ventilatory improvement. Ventilation was measured during‘passive’ condition (when ventilatory drive is close to eupneic level and the upper airway dilator muscles are relatively relaxed, 3 A) and during‘active conditions’ (when ventilatory drive is close to the arousal threshold and the upper airway muscles are close to the maximal activation possible during sleep, 3B). Vpassive is generally considered a measure of collapsibility of the upper airway. The increase in Vactive from atomoxetine to ato- oxy was likely due to an increase in arousal threshold (more time was allowed during sleep for muscle recruitment) rather than to the effect of oxybutynin.
• FIGs. 5A-B After inducing a reflex activation of the genioglossus muscle with a transient obstruction of the upper airway during sleep, the time during which the activity of the genioglossus remained elevated above baseline after the obstructive stimulus was removed was 2-fold longer during slow wave sleep (SWS) compared to NREM 2 (N2) sleep.
• SWS slow wave sleep
• FIG. 6 The effect of the combination of Atomoxetine-Pimavanserin (Ato- Pima) on OSA severity (apnea hypopnea index, AHI), on the arousal index, the upper airway collapsibility (ventilation at low ventilatory drive, Vpassive) and the arousal threshold.
• Atomoxetine-Pimavanserin Atomoxetine-Pimavanserin
• the pharyngeal airway region has no bone or cartilage support, and it is held open by muscles. When these muscles relax during sleep, the pharynx can collapse resulting in cessation of airflow.
• ventilatory effort continues and increases in an attempt to overcome the obstruction, shown by an increase in the amplitude of esophageal pressure swings.
• Rib cage and abdominal movements are in the opposite direction as a result of the diaphragm contracting against an occluded airway, forcing the abdominal wall to distend out and the chest wall to cave inward.
• apnea- hypopnea index (AHI), which is the combined average number of apneas (cessation of breathing for at least ten seconds) and hypopneas (reduced airflow and oxygen saturation) that occur per hour of sleep. See, for example, Ruehland et al, The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2): 150-157.
• OSA When a stringent definition of OS A is used (an AHI of > 15 events per hour or AHI > 5 events per hour with daytime sleepiness), the estimated prevalence is approximately 15 percent in males and 5 percent in females. An estimated 30 million individuals in the United States have OSA, of which approximately 6 million have been diagnosed. The prevalence of OSA in the United States appears to be increasing due to aging and increasing rates of obesity. OSA is associated with major comorbidities and economic costs, including: hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue/lost productivity. See, for example, Young et al, WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013; 177:1006.
• CPAP continuous positive airway pressure
• noradrenergic drugs such as norepinephrine reuptake inhibitors only mildly reduce OSA severity, and only in selected patients. See, e.g., Proia and Hudgel, Chest. 1991 Aug; 100(2):416-21;
• the selective norepinephrine reuptake inhibitor atomoxetine was tested by Bart-Sangal et al (2008, supra) in a prospective observational study of 15 patients with mild OSA. The drug did not improve AHI but did significantly improve daytime sleepiness. As shown herein, atomoxetine administered alone did not improve OSA severity in a sample of 9 moderate-to-severe OSA patients (Taranto-Montemurro et al. Am J Respir Crit Care Med 2019; 199: 1267-1276).
• noradrenergic withdrawal in the central nervous system plays a primary role in determining the upper airway dilator muscles hypotonia during sleep.
• Translational work performed recently in our laboratory showed that drugs with noradrenergic properties such as desipramine can increase genioglossus muscle activity 3 and can reduce upper airway collapsibility during sleep in humans 4 .
• noradrenergic drugs taken alone cannot reduce OSA severity.
• Protriptyline 5 ⁇ 6 , desipramine 4 and atomoxetine 7 have been tested in patients with OSA without success in reducing the AHI.
• a second possible mechanism at work in the combination of atomoxetine and oxybutynin is that oxybutynin could act as a hypnotic by increasing the arousal threshold and consolidating sleep, thus contrasting the wake-promoting effects of atomoxetine.
• Previous literature reported that antimuscarinics administered at low doses have mild sedative effects 12 and induce sleepiness 13 . Moreover, and consistently with this hypothesis, it has been also recently shown that oxybutynin can improve sleep quality by reducing symptoms of nocturia 14 .
• a low respiratory arousal threshold (wake up easily in response to upper airway obstruction) can limit neuromuscular compensation of the upper airway and contribute to the development of sleep-related hypopneas and apneas in many individuals.
• apnea/hypopnea leads to a buildup in CCh that increases ventilatory drive that can activate the pharyngeal muscles and reduce upper airway resistance by making the upper airway stiffer.
• a low respiratory arousal threshold can preempt this important compensatory mechanism. Therefore, while for people with high arousal threshold the arousal is a life-saving mechanism to protect them from asphyxia during sleep, it may be destabilizing for patients with a low arousal threshold, because the premature awakening can perpetuate the cycle of repetitive upper airway collapse.
• preventing arousals with medications with specific profiles in patients taking a wake-activating drug like atomoxetine that induces a low arousal threshold could yield more stable breathing and less OSA.
• Atomoxetine was responsible for a reduction in the arousal threshold (waking up more easily), likely because of its adrenergic properties.
• the reduction in arousal threshold with the combination was a non-statistically-significant 7% (p>0.7, Figure 4).
• oxybutynin could be replaced by non myorelaxing hypnotics with a more powerful effect on the arousal threshold such as z-drugs (i.e. zolpidem, zopiclone) or agents enhancing sleep depth and slow wave sleep (i.e. gabapentin, tiagabine).
• zolpidem and other commonly used hypnotics zopiclone, temazepam
• drugs that increase sleep depth such as tiagabine or gabapentin could help the resolution of OS A.
• SWS slow wave sleep
• EEG showed an increase in slow wave activity by 16% suggesting that the drug mildly increased sleep depth.
• the pharmacological increase in slow wave sleep (SWS) could be an ideal mechanism for raising the arousal threshold to treat OSA, particularly since SWS seems to be a“protective state” against OSA.
• Ratnavadivel et al. found that 82% of patients with moderate to severe OSA achieve an AHK15 events/hr in SWS 18 .
• the reason for improvement likely relates to changes in the non-anatomical factors that contribute to OSA during SWS such as reduced arousability, thereby enabling a higher activation of upper airway dilator muscles. Furthermore, we recently showed that, after inducing a reflex activation of the genioglossus muscle with a transient obstruction of the upper airway during sleep, the time during which the activity of the genioglossus remained elevated above baseline after the obstructive stimulus was removed (also called after-discharge, see Figure 5) was 2-fold longer during SWS compared to NREM 2 sleep.
• Serotonin neurons in the brainstem are critical for producing both the cortical and respiratory motor response to hypercapnia.
• Serotonin neuron deficient mice have an impaired hypercapnic ventilatory response (HCVR) 26 and lack the ability to arouse from sleep in response to CO2 27 .
• HCVR hypercapnic ventilatory response
• Buchanan was able to restore the EEG arousal in these mice with 5 -HT2 A receptor stimulation, suggesting that this specific sub receptor is responsible for activating the central nervous system in response to chemosensory (respiratory) stimuli. This notion is supported by human data; Heinzer et al.
• trazodone lOOmg a 5-HT2A antagonist
• OSA hypercapnia
• Eckert et al. 29 showed that trazodone could improve arousal threshold by 30% in seven patients with a low arousal threshold, but it did not affect the AHI compared to placebo.
• Smales et al. 30 showed that trazodone 100 mg reduced the AHI by 26% in 15 unselected OSA patients.
• the methods described herein include methods for the treatment of disorders associated with pharyngeal airway muscle collapse during sleep.
• the disorder is Obstructive Sleep Apnea (OSA) (defined as an AHI of > 10 events per hour) or Simple Snoring.
• OSA Obstructive Sleep Apnea
• the methods include administering a therapeutically effective amount of (i) a norepinephrine reuptake inhibitor and (ii) a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist as known in the art and/or described herein, to a subject who is in need of, or who has been determined to be in need of, such treatment.
• to“treat” means to ameliorate at least one symptom of the disorder associated with pharyngeal airway collapse.
• pharyngeal airway collapse during sleep results in snoring and/or an interruption in breathing (apnea or hypopnea), arousal from sleep, and reduced oxygenation (hypoxemia); thus, a treatment can result in a reduction in one or more of snoring, apneas/hypopneas, sleep fragmentation, and hypoxemia.
• a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5- HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, such as OSA, will result in decreased AHI.
• the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, such as OSA, will result in decreased AHI by 50% or more.
• the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, such as OSA, will result in decreased AHI by 75% or more.
• the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, such as OSA, will result in increased ventilation.
• a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, such as OSA, will result in increased ventilation.
• OSA non-fully conscious state
• a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, such as OSA, will result in increased oxygen blood levels.
• the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state will result in improved total sleep time, reduced AHI, increased oxygenation, less sleep fragmentation, increased total sleep time, and/or improved subjective sleep quality.
• An effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent can be administered in one or more administrations, applications or dosages, simultaneously or separately.
• a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist can be formulated as a single dosage form, e.g., a capsule, tablet or solution, containing both a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent, or as separate dosage forms, e.g., one a capsule, tablet or solution, containing a norepinephrine reuptake inhibitor and another capsule, tablet or solution containing a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist.
• Each of the norepinephrine reuptake inhibitor and the non myorelaxing hypnotic agents and/or 5-HT2A inverse agonist or antagonist can be administered, simultaneously or separately from one or more times per day to one or more times per week; including once every other day.
• the norepinephrine reuptake inhibitor and the non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist are administered daily.
• the agents are administered less than 60, 45, 30, 20, or 15 minutes before a subject wishes or intends to fall asleep.
• certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
• treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments.
• Dosage, toxicity and therapeutic efficacy of the therapeutic compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
• the data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans.
• the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
• the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
• the therapeutically effective dose can be estimated initially from cell culture assays.
• a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture.
• IC50 i.e., the concentration of the test compound which achieves a half- maximal inhibition of symptoms
• levels in plasma can be measured, for example, by high performance liquid chromatography.
• the methods include administering a dose of 20-100 mg Atomoxetine (or a dose equivalent thereof of another NRI) and a dose of 2-12.5 mg zolpidem, e.g., extended release zolpidem (or a dose equivalent thereof of another non myorelaxing hypnotic).
• the methods include administering 80 mg Atomoxetine /12.5 mg zolpidem; 75 mg Atomoxetine /10 mg zolpidem; 75 mg Atomoxetine /8 mg zolpidem; 50 mg Atomoxetine /6 mg zolpidem; or 25 mg Atomoxetine/4 mg zolpidem.
• the methods include administering a dose of 20-100 mg Atomoxetine (or a dose equivalent thereof of another NRI) and a dose of 2-12 mg zolpidem (or a dose equivalent thereof of another non myorelaxing hypnotic) within an hour of sleep time. In some embodiments, the methods include administering 80 mg Atomoxetine /12 mg zolpidem; 75 mg
• Atomoxetine /10 mg zolpidem; 75 mg Atomoxetine /8 mg zolpidem; 50 mg
• Atomoxetine /6 mg zolpidem; or 25 mg Atomoxetine/4 mg zolpidem, 15-10 minutes before sleep time.
• the methods include administering Atomoxetine/ zolpidem in a 6.5 to 1 ratio by weight. In other embodiments, the methods include administering Atomoxetine/ zolpidem in a 6.5 to 1 ratio by weight at 15-10 minutes before sleep time.
• Gabapentin e.g., 600 mg gabapentin
• pimvanserin e.g., 20-40 mg, e.g., 34 mg pimvanserin, is used in addition to or in place of zolpidem.
• compositions comprising a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5-HT2A inverse agonist or antagonist as active ingredients.
• norepinephrine reuptake inhibitor and non myorelaxing hypnotic agent and/or 5- HT2A inverse agonist or antagonist can be administered in a single composition or in separate compositions.
• the methods include administering a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and/or 5- HT2A inverse agonist or antagonist, and no other active ingredients, i.e., the norepinephrine reuptake inhibitor and the non myorelaxing hypnotic agent and/or 5- HT2A inverse agonist or antagonist are the sole active agents.
• NRIs norepinephrine reuptake inhibitors
• NRIs include the selective NRIs, e.g., Amedalin (UK-3540-1), Atomoxetine (Strattera), CP-39,332, Daledalin (UK-3557-15), Edivoxetine (LY-2216684), Esreboxetine, Lortalamine (LM-1404), Nisoxetine (LY-94,939), Reboxetine (Edronax, Vestra), Talopram (Lu 3-010), Talsupram (Lu 5-005), Tandamine (AY-23,946), Viloxazine (Vivalan); and the non- selective NRIs, e.g., Amitriptiline, Amoxapine, Bupropion, Ciclazindol, Desipramine, Desvenlafaxine, Dexmethilphenidate, Diethylpropion, Doxepin, Duloxetine,
• NRIs e.g.,
• non myorelaxing hypnotics include a benzodiazepine hypnotic, e.g., temazepam, brotizolam, flurazepam, nitrazepam, or triazolam; or a non-benzodiazepine hypnotic, e.g., a cyclopyrrolone hypnotic, preferably selected from the group consisting of zolpidem, zopiclone, and
• eszopiclone gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine.
• Exemplary 5-HT2A inverse agonists include AC-90179 (Weiner et al, The Journal of Pharmacology and Experimental Therapeutics. 299 (1): 268-76), ketanserin, nelotanserin, eplivanserin, pimavanserin, and volinanserin; antagonists include Trazodone, Mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL-100,907, cyproheptadine, pizotifen, LY-367,265, 2-alky 1-4-aryl-tetrahydro-pyrimido-azepines, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, and niaprazine.
• the 5-HT2A AC-
• the norepinephrine reuptake inhibitor is Atomoxetine.
• the non myorelaxing hypnotic is zolpidem.
• the 5-HT2A inverse agonist is pimvanserin.
• Pharmaceutical compositions typically include a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions, however the present compositions do not include an antimuscarinic agent (e.g., as described in WO 2018/200775).
• compositions are typically formulated to be compatible with their intended route of administration.
• routes of administration include systemic oral or transdermal administration.
• oral compositions generally include an inert diluent or an edible carrier.
• the active compound(s) can be incorporated with excipients and used in the form of pills, tablets, troches, or capsules, e.g., gelatin capsules.
• Oral compositions can also be prepared using a fluid carrier. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
• the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
• a lubricant such as magnesium stearate or Sterotes
• a glidant such as colloidal silicon dioxide
• Systemic administration of one or both of the compounds as described herein can also be by transdermal means, e.g., using a patch, gel, lotion, or thin film, to be applied to the skin.
• transdermal administration penetrants appropriate to the permeation of the epidermal barrier can be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal
• the active compounds can be formulated into ointments, salves, gels, or creams as generally known in the art.
• the gel and/or lotion can be provided in individual sachets, or via a metered-dose pump that is applied daily; see, e.g., Cohn et al, Ther Adv Urol. 2016 Apr; 8(2): 83-90.
• the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• a controlled release formulation including implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid.
• Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc.
• Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
• compositions can be included in a container, pack, or dispenser together with instructions for administration or use in a method described herein.
• OSA subjects with a broad range of apnea severity (10 to >60/hr) are studied in a double blinded, placebo controlled, crossover trial. Treated OSA patients are enrolled, since we do not want to delay treatment to perform these experiments.
• Subjects are instrumented with standard polysomnography (PSG) recording sensors. Sleep stage and arousals are measured with electrodes pasted on to the scalp, face, chin, and chest (EEG, EOG, EKG, chin EMG). Paste-on EMG electrodes are placed over the anterior tibialis muscle to detect leg movements. Respiratory effort belts are placed around the chest and abdomen to measure breathing movements. Oxygen saturation is measured continuously with a pulse oximetry probe placed on the fingertip. Snoring is detected with a small microphone positioned over the suprasternal notch. Body position is recorded with a sensor taped to the thoracic belt. Each of these devices is standard for diagnostic PSG and should not be
• a standard CPAP mask is placed over the mouth and the nose and held in place with straps.
• the mask allows monitoring of breathing (inspiratory flow by pneumotachograph that can be integrated to yeld tidal volume) and expired carbon dioxide levels (PCC ) using a calibrated infrared CC analyzer (Capnograph/Oximeter Monitor).
• Apneas, hypopneas, arousals, and sleep stages are scored using standard American Academy of Sleep Medicine guidelines 22 by a registered polysomnographic technologist (RPSGT) blinded to the treatment allocation.
• Hypopneas are defined as reduction in flow >30% from baseline, lasting at least 10 seconds and associated with an arousal from sleep or an oxyhemoglobin desaturation > 3%.
• Phenotypic traits (Vpassive, Vactive, arousal threshold, loop gain) on placebo and on drug nights are automatically calculated from the polysomnography using the algorithms developed and tested in our lab 23 ⁇ 24 .
• the main outcome of the trial is the change in AHI and it is compared between the arms using a one-way anova followed by post-hoc analysis to compare each treatment arm with placebo, with p ⁇ 0.025 considered as statistically significant in order to correct for multiple comparisons.
• Each individual requires four studies (baseline + 3 trial nights).
• the drugs combinations tested are evaluated for a meaningful reduction in in OSA severity (AHI), an increase in oxygen levels (SaC ), and a reduction in collapsibility (Vpassive and Vactive) in both NREM and REM sleep.
• AHI OSA severity
• SaC oxygen levels
• Vpassive and Vactive reduction in collapsibility
• the results are interpreted to determine whether it is possible to improve sleep apnea severity and sleep quality with a combination of systemically administered drugs in sleeping humans.
• the analysis of the phenotypic traits during the baseline night provides information on what group of patients is likely to have the best response on the drugs, the phenotypic analysis on the placebo and drugs night will inform about the mechanisms of action of these combinations.
• pimavenserin was administered together with atomoxetine, a wake-promoting drug that, as described above, caused a reduction in arousal threshold by -18% compared to placebo in OSA patients in a previous trial. This means that pimavanserin could actually increase the respiratory arousal threshold by -50%.
• Trazodone increases the arousal threshold in obstructive sleep apnea patients with a low arousal threshold. Sleep 2014; 37:811-819

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