Combination pharmacological interventions for obstructive sleep apnea

Abstract

Provided herein are methods of treating sleep apnea in a subject, the method comprising: identifying a subject as having sleep apnea; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and nonbenzodiazepine sedative-hypnotic, optionally including a selective serotonin-norepinephrine reuptake inhibitor.

Description

[0001] COMBINATION PHARMACOLOGICAL INTERVENTIONS

[0002] FOR OBSTRUCTIVE SLEEP APNEA

[0003] CLAIM OF PRIORITY

[0004] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 569,963, filed on March 26, 2024. The entire contents of the foregoing are incorporated herein by reference.

[0005] TECHNICAL FIELD

[0006] This invention relates to pharmaceutical compositions for use in treatment or prevention of obstructive sleep apnea.

[0007] BACKGROUND

[0008] Obstructive sleep apnea (OSA) is characterized by a repetitive collapse of the upper airway during sleep leading to intermittent hypoxemia and arousals from sleep, affecting up to 1 billion people worldwide. Untreated OSA has been associated with many adverse health outcomes, including neurocognitive and cardiovascular sequelae resulting in costs of more than 150 billion dollars per year in the United States alone.

[0009] There are currently no medications specifically approved for the treatment of OSA, and available options may not be suitable or effective for all individuals wi th the disorder. There is great need in developing a drug therapy for treating OSA.

[0010] SUMMARY

[0011] Provided herein are methods of treating sleep apnea in a subject, the method comprising identifying a subject as having sleep apnea; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

[0012] Provided herein are methods of decreasing sleep disturbances in a subject, the method comprising identifying a subject as having breathing-related sleep disturbances; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

[0013] Also provided herein are methods of increasing total sleep time and / or sleep efficiency in a subject, the method comprising identifying a subject as having sleep apnea-related reduction of total sleep time and / or sleep efficiency; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

[0014] In some embodiments, the sleep apnea and / or breathing-related sleep disturbances comprises obstructive sleep apnea (OSA), central sleep apnea (CSA), or complex sleep apnea syndrome. In some embodiments, the sleep apnea is OSA. In some embodiments, the OSA is moderate or severe untreated OSA. In some embodiments, the subject has an apnea hypopnea index of about 15 / h or more. In some embodiments, the subject has a body mass index (BMI) less than about 40 kg / m2and a fraction of hypopneas more than about 25%.

[0015] In some embodiments, the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sultiame, benzolamide, and any combination thereof. In some embodiments, the carbonic anhydrase inhibitor is acetazolamide. In some embodiments, acetazolamide is administered at a dosage of from about 100 mg to about 1000 mg. In some embodiments, acetazolamide is administered at a dosage of from about 250 mg to about 500 mg.

[0016] In some embodiments, the nonbenzodiazepine sedative-hypnotic is selected from the group consisting of eszopiclone, pagoclone, pazinaclone, suproclone, suriclone, zopiclone. divapion, fasiplon. indiplon, loredipion, ocinaplon, panadiplon. taniplon, zaleplon, alpidem, necopidem, saripidem, and zolpidem, and any combination thereof. In some embodiments, the nonbenzodiazepine sedative-hypnotic is eszopiclone. In some embodiments, eszopiclone is administered at a dosage of from about 0.5 mg to about 8 mg. In some embodiments, eszopiclone is administered at a dosage of about 2 mg.

[0017] In some embodiments, the carbonic anhydrase inhibitor and the nonbenzodiazepine sedative-hypnotic are administered in a single composition or separate compositions. In some embodiments, a single composition or separate compositions are administered daily. In some embodiments, the single composition or separate compositions are orally administered. In some embodiments, the single composition or separate compositions are in a form comprising a syrup, pill, tablet, troche, capsule, or patch.

[0018] In some embodiments, the methods of treating sleep apnea, decreasing sleep disturbances, or increasing total sleep time and / or sleep efficiency, further comprise administering to the subject an effective amount of a serotonin and norepinephrine reuptake inhibitor (SNRI). In some embodiments, the SNRI is selected from the group consisting of venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, and tramadol. In some embodiments, the SNRI is venlafaxine. In some embodiments, venlafaxine is administered at a dosage of from about 10 mg to about 200 mg. In some embodiments, venlafaxine is administered at a dosage of about 50 mg.

[0019] In some embodiments, the carbonic anhydrase inhibitor, the nonbenzodiazepine sedative-hypnotic, and the SNRI are administered in a single or separate compositions. In some embodiments, the single composition or separate compositions are orally administered. In some embodiments, the single composition or separate compositions are in a form comprising a syrup, pill, tablet, troche, capsule, or patch.

[0020] In some embodiments, the methods are effective in reducing the subject’s OSA severity of apnea-hypopnea index during supine, non-rapid eye movement sleep (AHINREM, supine) compared to the subject’s AHINREM, supine prior to the first administration.

[0021] Also provided herein are pharmaceutical compositions comprising a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions further comprise a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0022] In some embodiments, the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sultiame, benzolamide, and any combination thereof. In some embodiments, the nonbenzodiazepine sedativehypnotic is selected from the group consisting of eszopiclone, pagoclone, pazinaclone, suproclone, suriclone, zopiclone. divapion, fasiplon, indiplon, loredipion. ocinaplon, panadiplon. taniplon. zaleplon, alpidem, necopidem. saripidem, and zolpidem, and any combination thereof. In some embodiments, the carbonic anhydrase inhibitor is acetazolamide, and the nonbenzodiazepine sedative-hypnotic is eszopiclone.

[0023] In some embodiments, the SNRI is selected from the group consisting of venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, and tramadol, and any combination thereof. In some embodiments, the SNRI is venlafaxine.

[0024] In some embodiments, acetazolamide is present in a dosage of from about 100 mg to about 1000 mg, and eszopiclone is present in a dosage of from about 0.5 mg to about 8 mg. In some embodiments, acetazolamide is present in a dosage of from about 250 mg to about 500 mg, and eszopiclone is present in a dosage of about 2 mg. In some embodiments, venlafaxine is present in a dosage of from about 10 mg to about 200 mg. In some embodiments, venlafaxine is present in a dosage of about 50 mg.

[0025] In some embodiments, the pharmaceutical compositions are for use in treating a subject having sleep apnea. In some embodiments, the sleep apnea comprises obstructive sleep pharmaceutical composition of apnea (OSA), central sleep apnea (CSA), or complex sleep apnea syndrome. In some embodiments, the sleep apnea is OSA. In some embodiments, the pharmaceutically acceptable carrier comprises water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oils, mineral oils, silicones, gelatin, starches, cellulose derivatives, polymers, sorbitol, sucrose, lactose, mannitol, microcrystalline cellulose, magnesium stearate, calcium phosphate, or sodium chloride.

[0026] DESCRIPTION OF DRAWINGS

[0027] FIG. 1 shows the study design of interventional, randomized, double-blind, placebo-controlled, cross-over trial. There were two experimental arms and three treatment periods (Phase I, Phase II, and Phase III) in this study. In the arm of Dual Drug-Placebo, eligible patients received sequential treatment of Dual Drug (DualRx) for period 1, placebo for period 2, and Single / Triple Drug for period 3. In the arm of Placebo-Dual Drug, eligible patients received sequential treatment of placebo for period 1, DualRx for period 2, and Single / Triple Drug for period 3. The treatment for period 3 was determined based on the response to DualRx.

[0028] FIG. 2 shows the summary of enrollment results. 88 patients were assessed for eligibility, among which 20 were randomized to sequence wi th 68 excluded.

[0029] FIG. 3 shows the absolute changes in parameters including apnea hypopnea index la (“American Academy of Sleep Medicine [AASM] recommended, AHI) during supine non-rapid eye movement (AHlNREM.suPin ) (top) and AHIoveraii (middle) and the AASM-acceptable apnea hypopnea index lb, AHI4overaii (botom) from baseline across the three interventions including placebo (left), DualRx (middle), and TripleRx (right) for each parameter.

[0030] FIGs. 4A-4B show the percent changes in AHlNREM,suPin (FIG. 4A) and AHIoveraii (FIG. 4B) from baseline across the three interventions including placebo (top). DualRx (middle), and TripleRx (botom). A probability density function is overlaid over the histograms to give a visual estimate of the underlying distribution.

[0031] FIG. 5 shows the general characteristics, the evaluation of OSA severity, and the assessment of underlying OSA mechanisms of the 20 enrolled participants randomized into the two arms.

[0032] FIG. 6 shows result summary DualRx vs. Placebo including the evaluation of OSA severity, sleep parameters, OSA mechanism, and clinical outcomes. The clinical outcomes include blood pressure (BP) and heart rates (HR), self-reported symptoms, and psychomotor vigilance. The absolute changes of each parameter between baseline and DualRx adjusted to Placebo (ADualRxvsBL - APlacebovs BL) is subjected to Wilcoxon signed rank test.

[0033] FIG. 7 shows proportion of responders based on different treatments including Placebo, DualRx, and TripleRx.

[0034] FIG. 8 shows summary of results obtained from comparing TripleRx. DualRx, and Placebo. The parameters for comparison include the evaluation of OSA severity, sleep parameters, OSA mechanism, and clinical outcomes. The clinical outcomes include blood pressure (BP) and heart rates (HR), self-reported symptoms, and psychomotor vigilance. The absolute changes of each parameter between baseline and TripleRx adjusted to Placebo (ATripleRxvs BL - APlacebovs BL) or adjusted to DualRx (ATripleRxvs BL - ADualRxvs BL) is subjected to Wilcoxon signed rank test.

[0035] FIG. 9 shows proportion of adverse events across interventions. The number (%) reflect the number of participants who reported a given adverse event during each intervention. There were no serious adverse events. All events were rated as mild- moderate.

[0036] FIG. 10 shows absolute changes in AHINREM, supine (top), AHIoveraii (middle) and AHI4oveiaii (botom) across the four experimental conditions of baseline, placebo, DualRx, and TripleRx. DETAILED DESCRIPTION

[0037] Provided herein are methods of treating sleep apnea in a subject, the method comprising: identifying a subject as having sleep apnea; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and nonbenzodiazepine sedative-hypnotic.

[0038] Also provided herein are methods of decreasing sleep disturbances in a subject, the method comprising: identifying a subject as having apnea-related sleep disturbances; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

[0039] Provided herein are methods of increasing total sleep time and / or sleep efficiency in a subject, the method comprising: identifying a subject as having apnea- related reduction of total sleep time and / or sleep efficiency; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

[0040] Also provided herein are pharmaceutical compositions comprising a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic in a pharmaceutically acceptable carrier.

[0041] Obstructive sleep apnea (OSA)

[0042] Sleep apnea is a sleep-related breathing disorder in which repetitive pauses in breathing, periods of shallow breathing, or collapse of the upper airway during sleep results in poor ventilation and sleep disruption. Sleep apnea can be categorized as comprises obstructive sleep apnea (OSA), central sleep apnea (CSA), and complex sleep apnea syndrome.

[0043] OSA is a common sleep-related breathing disorder characterized by recurrent episodes of complete or partial obstruction of the upper airway, leading to pauses or reduction in breathing during sleep. These episodes are termed ‘‘apneas” with complete or near-complete cessation of breathing, or “hypopneas” when the reduction in breathing is partial. Either apnea or hypopnea can cause disruptions in sleep patterns and reduce the flow of oxygen to vital organs, resulting in daytime fatigue, impaired cognitive function, and other health complications. OSA is often associated with snoring, gasping, or choking during sleep and is more prevalent in overweight individuals, older adults, and those with anatomical abnormalities of the upper airway. In some embodiments, OSA is associated with general health conditions. In some embodiments, OSA is associated with a wide array of other diseases, including hypertension, diabetes, fatty liver, hypercholesterolemia, coronary artery disease, asthma, HIV (well controlled), insomnia, mood disorder, or nasal congestion.

[0044] OSA severity is ty pically assessed based on the frequency of abnormal breathing events, oxygen desaturation levels, and associated symptoms. Apnea Hypopnea Index (AHI or AHIoveraii) is a major measure of sleep apnea severity and based on the American Academy of Sleep Medicine [AASM] recommended criteria defined as the number of apneas (no breathing for 10+ seconds) and hypopneas (reduced breathing for 10+ seconds associated with a >=3% desaturation or cortical arousal) per hour of sleep; based on the AASM-acceptable criteria Apnea Hypopnea Index (AHI4 or AHI4overaii) is defined as the number of apneas (no breathing for 10+ seconds) and hypopneas (reduced breathing for 10+ seconds associated with a >=4% desaturation) per hour of sleep. Oxygen desaturation levels are monitoring of blood oxygen levels during sleep (oxyhemoglobin saturation) to assess the severity of oxygen desaturation associated with apnea events. Severe OSA is often characterized by frequent drops in oxygen saturation below 90%. Associated symptoms are daytime symptoms such as excessive daytime sleepiness, fatigue, morning headaches, impaired concentration, and irritability , which can indicate the severity of OSA and its impact on daily life. OSA severity is commonly categorized into mild, moderate, and severe using AHI shown in the table below.

[0045] As used herein, overall refers to all sleep. NREM refers to non-rapid eye movement sleep. For example, AHI and AHIoveraii can be used interchangeably. For another example. AHI4 and AHI4overaii can be used interchangeably.

[0046] In some embodiments, assessment of OSA severity typically involves evaluation by a sleep specialist, including, but not limited to, a thorough medical history, physical examination, and / or diagnostic sleep studies, e.g., polysomnography (PSG) or home sleep apnea test. PSG is a comprehensive sleep study conducted in a sleep laboratory, which includes monitoring various physiological parameters such as brain waves (electroencephalogram, EEG), eye movements (electrooculogram, EOG), muscle activity (electromyogram, EMG), heart rate (electrocardiogram, ECG), respiratory effort (thoracic and abdominal movements), airflow (nasal and oral airflow), oxygen saturation (pulse oximetry), snoring sounds, and body position.

[0047] In some embodiments, assessment of OSA includes a home sleep apnea test. Home sleep apnea test is a diagnostic tool that allows individuals to undergo sleep monitoring in the comfort of their own home. The individual receives the home sleep apnea test device and instructions from a sleep clinic. Then, the individual sleeps as they normally would while the home sleep apnea test device records various parameters such as breathing patterns, airflow, blood oxygen levels, and sometimes heart rate. After the sleep study is complete (usually one night), the individual returns the home sleep apnea test device to the sleep clinic. Sleep specialists analyze the collected data to assess the severity of OSA based on the frequency and duration of apneas and hypopneas per hour of sleep (e.g., AHI). Other parameters, such as oxygen desaturation levels, are also evaluated.

[0048] In some embodiments, OSA severity is measured by parameters including AHI ( / hour), fraction of hypopneas (%), SpO2 nadir (%), Hypoxic burden (% minute / hour), and T90 (% Total Sleep Time (TST)). In some embodiments, to avoid confounding by sleep stages and positions across study nights, the primary focus was on the AHI during supine non rapid eye movement (NREM) sleep (AHINREM, supine). In some embodiments, the AHI during supine rapid eye movement (REM) sleep (AHIREM. supine) is measured.

[0049] As used herein, fraction of hypopneas refers to the proportion of hypopneas among all respiratory events (including both apneas and hypopneas) detected during sleep monitoring. As used herein, SpO2 nadir refers to the lowest measured blood oxygen saturation during the overnight sleep study measured in percent.

[0050] Sleep disturbance

[0051] Sleep disturbance refers to any condition or factor, e.g., OSA, that disrupts the normal pattern or quality of sleep. This can include difficulty falling asleep, frequent awakenings during the night, waking up too early and being unable to return to sleep, experiencing non-restorative sleep, or excessive daytime sleepiness.

[0052] Generally, sleep disturbance can be measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Scale. The PROMIS Sleep Disturbance Scale is a patient-reported measure designed to assess sleep quality and sleep-related impairment. The PROMIS Sleep Disturbance Scale consists of several questions that evaluate various aspects of sleep, including difficulty falling asleep, difficulty staying asleep, sleep quality, sleep depth, restoration associated with sleep, difficulties with sleep disturbance, difficulties with sleep-related impairment. The scores are then converted into standardized T-scores, which can be compared to the general population or specific patient groups.

[0053] Total sleep time and sleep efficiency

[0054] Total sleep time refers to the overall duration of sleep achieved during a specified period, either during the nocturnal sleep episode or across the 24-hour period, typically measured in hours. It represents the total amount of time spent asleep, including both rapid eye movement (REM) sleep and non-REM sleep stages.

[0055] Sleep efficiency refers to the percentage of time spent asleep while in bed, calculated by dividing the total time spent asleep by the total time spent in bed and then multiplying by 100. It reflects how effectively an individual is using their time in bed for sleep. Eligher sleep efficiency percentages indicate better sleep consolidation and quality.

[0056] Total sleep time and sleep efficiency can be measured using various methods, including questionnaire, sleep diary, actigraphy, polysomnography (PSG), home sleep apnea test or consumer sleep trackers. For an example, single-item questionnaire or self-report measures of sleep duration have often been utilized (e.g., How many hours of sleep do you obtain on a typical night?) in population-based epidemiologic studies. For another example, sleep diaries, actigraphy, polysomnography, and / or home sleep apnea test provide assessments of sleep duration in clinical and research settings.

[0057] Stanford Sleepiness Scale (SSS) is a one-item self-report questionnaire measuring levels of sleepiness (e.g., subjective sleepiness) throughout the day. In some embodiments, the subjective sleepiness is assessed using SSS in the mornings following the overnight sleep study. The score ranges from 1 to 7, with greater values indicating more sleepiness. Pharmaceutical composition

[0058] The standard of care for OSA is continuous positive airway pressure therapy (CPAP), but many patients are unable to tolerate CPAP therapy with long-term discontinuation rates between 40-60%. Thus, many patients with OSA remain untreated. Single-drug therapies have shown promising results in treating sleep apnea, but on average patients have only experienced partial relief.

[0059] The prospect of a potential drug therapy for OSA is based on the fact that non- anatomical traits, also known as '‘endotypes’’, play a direct role in OSA pathogenesis for the majority of patients. Three key traits have been identified: unstable ventilatory control ("high loop gain"’), a low arousal threshold (e.g., waking up too easily), and poor upper airway dilator muscle compensation. Importantly, these traits can be targeted pharmacologically. Acetazolamide, for instance, stabilizes ventilation, while eszopiclone increases the arousal threshold. Additionally, noradrenergic drugs such as venlafaxine may increase upper airw ay dilator muscle compensation. Thus, acetazolamide, eszopiclone, and venlafaxine can target different underlying mechanism of OSA. Acetazolamide, eszopiclone. and venlafaxine have been tested separately for OSA treatment, but any of combination thereof has not been disclosed.

[0060] Provided herein are pharmaceutical compositions including carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic. In some embodiments, the pharmaceutical compositions further include a serotonin and norepinephrine reuptake inhibitor (SNRI). In some embodiments, the pharmaceutical composition do not include an SNRI. As used herein, the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide. brinzolamide, methazolamide. zonisamide, ethoxzolamide, topiramate, sultiame, benzolamide, and any combination thereof. In some embodiments, the carbonic anhydrase inhibitor is acetazolamide. As used herein, the nonbenzodiazepine sedative-hypnotic is selected from the group consisting of eszopiclone, pagoclone, pazinaclone, suproclone, suriclone, zopiclone. divapion, fasiplon, indiplon, loredipion. ocinaplon, panadiplon. taniplon. zaleplon, alpidem, necopidem. saripidem, and zolpidem, and any combination thereof. In some embodiments, the nonbenzodiazepine sedative-hypnotic is eszopiclone. As used herein, the SNRI is selected from the group comprises consisting of venlafaxine, desvenlafaxine, duloxetine. levomilnacipran. milnacipran, sibutramine, and tramadol. In some embodiments, the SNRI is venlafaxine.

[0061] In some embodiments, the combination of a carbonic anhydrase inhibitor (e.g., acetazolamide) and a nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) can be administered in a single composition or separate compositions. In some embodiments, the carbonic anhydrase inhibitor (e.g., acetazolamide) and a nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) can be administered in a single composition and the SNRI is administered as a separate composition.

[0062] Provided herein are pharmaceutical compositions including a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic, optionally combined with an SNRI, in a pharmaceutically acceptable carrier. As used here, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The term “pharmaceutically-acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material. In some embodiments, the pharmaceutically acceptable carrier comprises water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oils, mineral oils, silicones, gelatin, starches, cellulose derivatives, polymers, sorbitol, sucrose, lactose, mannitol, microcrystalline cellulose, magnesium stearate, calcium phosphate, or sodium chloride.

[0063] Additional examples of carriers are synthetic or natural polymers in the form of macromolecular complexes, nanocapsules, microspheres, or beads, and lipid-based formulations including oil-in-water emulsions, micelles, mixed micelles, synthetic membrane vesicles, and resealed erythrocytes. Optionally, the pharmaceutically acceptable carrier comprises a polymeric matrix.

[0064] Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g.. Remington: The Science and Practice of Pharmacy, 21sted., 2005; and the books in the series Drugs arid the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). The pharmaceutical composition may be administered orally in various forms, including tablets, capsules, powders, granules, solutions, suspensions, emulsions, or chewable dosage forms. In some embodiments, pharmaceutical compositions of multiple medications are a single composition or separate compositions. In some embodiments, the pharmaceutical compositions are in a form including a syrup, pill, tablet, troche, capsule, and patch. In some embodiments, the pharmaceutical compositions are administered daily. The dosage form and formulation may be optimized based on factors such as the physicochemical properties of the active ingredient, desired release profile, and patient preferences.

[0065] In one embodiment, 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. 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 (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0066] Method of treatment

[0067] The methods described herein include methods for the treatment of disorders associated with sleep apnea (e.g., OSA) in a subject by administering the pharmaceutical compositions described herein. A subject can be an individual (e.g., a mammal such as a human) having or suspected of having OSA. In some embodiments, the subject is indicated to have OSA based on a self-assessment, in other embodiments the OSA is determined by laboratory PSG or home sleep apnea test. In some embodiments, the subject has moderate or severe untreated OSA, or wherein the OSA is not sufficiently resolved with other interventions. In some embodiments, the subject has an apnea hypopnea index of about 15 / h or more. In some embodiments, the subject has a body mass index (BMI) less than about 40 kg / m2, less than about 39 kg / m2, less than about 38 kg / m2, less than about 37 kg / m2, less than about 36 kg / m2, less than about 35 kg / m2, less than about 34 kg / m2, less than about 33 kg / m2, less than about 32 kg / m2, less than about 31 kg / m2, less than about 30 kg / m2, less than about 29 kg / m2, less than about 28 kg / m2, less than about 27 kg / m2, less than about 26 kg / m2, less than about 25 kg / m2, less than about 24 kg / m2, less than about 23 kg / m2, less than about 22 kg / m2, less than about 21 kg / m2, less than about 20 kg / m2, less than about 19 kg / m2. In some embodiments, the subject has partial obstruction, for example at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the sleep obstructive events a subject may have in a given night may be hypopneas.

[0068] The methods also described herein include methods for decreasing apnea- related sleep disturbances in a subject by administering a pharmaceutical composition described herein. A subject can be an individual (e.g., a mammal such as a human) having or suspected of having apnea-related sleep disturbances. In some embodiments, the apnea-related sleep disturbance is OSA associated sleep disturbance.

[0069] Further included herein are methods for increasing total sleep time and / or sleep efficiency in a subject by administering a pharmaceutical composition described herein. A subject can be an individual (e.g., a mammal such as a human) having or suspected of having reduced total sleep time or sleep efficiency. In some embodiments, the total sleep time and / or sleep efficiency is measured during sleeping in a subject having OSA.

[0070] As used in this context, to “treat” means to ameliorate at least one symptom of the disorders associated with OSA, sleep disturbances, or decreased total sleep time and / or sleep efficiency. Thus, a treatment can result in a reduction in OSA severity and sleep disturbances, or an increase in total sleep time and / or sleep efficiency. Generally, the methods include administering a combination of pharmaceutical therapies as described herein to a subject who is in need of, or who has been determined to be in need of, such treatment. In some embodiments, the methods include administering a therapeutically effective amount of a treatment comprising a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic. In some embodiments, the methods include administering a therapeutically effective amount of a treatment further comprising a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0071] As used herein, the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide. methazolamide, zonisamide, ethoxzolamide, topiramate, sultiame, benzolamide, and any combination thereof. In some embodiments, the carbonic anhydrase inhibitor is acetazolamide. In some embodiments, acetazolamide is administered at a dosage of about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 700, about 800, about 900, or about 1000 mg. For example, acetazolamide is administered at a dosage of about 250 or about 500 mg daily. In some embodiments, a subject is administered the same dosage of the carbonic anhydrase inhibitor each day, in other embodiments, the subject is administered a different dosage of the carbonic anhydrase inhibitor from a previous or subsequent day. In some embodiments, the dosage of carbonic anhydrase inhibitor administered to the subject is based on the subjects weight. In some embodiments, the dosage of carbonic anhydrase inhibitor administered to the subject independent of the subject’s weight.

[0072] As used herein, the nonbenzodiazepine sedative-hypnotic is selected from the group consisting of eszopiclone, pagoclone, pazinaclone, suproclone. suriclone, zopiclone, divapion, fasiplon, indiplon, loredipion, ocinaplon. panadiplon, tampion, zaleplon, alpidem, necopidem, saripidem, and zolpidem, and any combination thereof. In some embodiments, the nonbenzodiazepine sedative-hypnotic is eszopiclone. In some examples, eszopiclone is administered at a dosage of about 0.5, about 1, about 1.5. about 2, about 2.5. about 3, about 4. about 5, about 6. about 7, or about 8 mg. For example, eszopiclone is administered at a dosage of about 2 mg daily. In some embodiments, a subject is administered the same dosage of the nonbenzodiazepine sedative-hypnotic each day, in other embodiments, the subject is administered a different dosage of the nonbenzodiazepine sedative-hypnotic from a previous or subsequent day. In some embodiments, the dosage of nonbenzodiazepine sedativehypnotic administered to the subject is based on the subject’s weight. In some embodiments, the dosage of nonbenzodiazepine sedative-hypnotic administered to the subject independent of the subject's weight.

[0073] As used herein, the SNRI is selected from the group comprises consisting of venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, and tramadol. In some embodiments, the SNRI is venlafaxine. In some embodiments, venlafaxine is administered at a dosage of about 10, about 20. about 40, about 60, about 80. about 100, about 120, about 140, about 160. about 180, or about 200 mg. For example, venlafaxine is administered at a dosage of about 50 mg daily. In some embodiments, a subject is administered the same dosage of the SNRI each day. in other embodiments, the subject is administered a different dosage of the SNRI from a previous or subsequent day. In some embodiments, the dosage of SNRI administered to the subject is based on the subject’s weight. In some embodiments, the dosage of SNRI administered to the subject independent of the subject’s weight.

[0074] In some embodiments, acetazolamide, eszopiclone, or venlafaxine can be administered individually. In some embodiments, each of acetazolamide, eszopiclone, and venlafaxine is administered daily. In some embodiments, each of acetazolamide, eszopiclone, and venlafaxine is administered once a day. In some embodiments, the combination of acetazolamide, eszopiclone, and venlafaxine can be administered on the same day. In some embodiments, any combination of acetazolamide, eszopiclone, and venlafaxine can be administered sequentially. In some embodiments, venlafaxine can be administered about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days before the combination of acetazolamide and eszopiclone. In some embodiment, venlafaxine can be added at any time to the combination of acetazolamide and eszopiclone. In some embodiments, venlafaxine can be administered about 1, about 2, about 3, about 4, about 5, about 6, about 7 days after the combination of acetazolamide and eszopiclone.

[0075] In some embodiments, each of the carbonic anhydrase inhibitor (e.g., acetazolamide) and a nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) is administered daily. In some embodiments, each of the carbonic anhydrase inhibitor (e.g., acetazolamide) and a nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) is administered once a day. twice a day, or in split doses. In some embodiments, the combination of the carbonic anhydrase inhibitor (e.g., acetazolamide) and a nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) can be administered concurrently or sequentially. In some embodiments, the carbonic anhydrase inhibitor (e.g., acetazolamide) can be administered about 1. about 2, about 3. about 4, about 5, about 6, or about 7 days before eszopiclone. In some embodiments, the carbonic anhydrase inhibitor (e.g., acetazolamide) can be administered about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days after eszopiclone. The carbonic anhydrase inhibitor (e.g., acetazolamide) can be administered every day, and the nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) can be administered less than every day (e.g., every two days, even' three days, twice a week, once a week). The nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) can be administered every day, and the carbonic anhydrase inhibitor (e.g., acetazolamide) can be administered less than every day (e.g., every two days, every three days, twice a week, once a week).

[0076] The SNRI can be administered every day the carbonic anhydrase inhibitor (e.g.. acetazolamide) and a nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) combination is administered, or the SNRI can be administered can be administered less than every day (e.g., every' two days, every three days, twice a week, once a week) the carbonic anhydrase inhibitor (e.g., acetazolamide) and a nonbenzodiazepine sedative-hypnotic (e.g., eszopiclone) combination is administered.

[0077] The disclosed methods of administering the combination of acetazolamide and eszopiclone in a subject can be effective in reducing AHINREM, supine, AHIoveraii, hypoxic burden compared to those parameters prior to the first administration (baseline). In some embodiments, the combination of acetazolamide and eszopiclone can be effective in improving sleep architecture. In some embodiments, the combination of acetazolamide and eszopiclone can be effective in reducing hypopneas and / or central apneas. Also disclosed herein, the combination of acetazolamide and eszopiclone can be effective in increasing total sleep time and / or sleep efficiency, as well as reducing respiratory-related arousals.

[0078] The disclosed methods of administering the combination of acetazolamide, eszopiclone, and venlafaxine in a subject can be effective in improving some parameters of OSA-related hypoxemia including, but not limited to, AHI4overaii, Fhypopneas, hypoxic burden, Mean SpCh, and T90.

[0079] EXAMPLES

[0080] The materials and methods described here have been used to generate the examples described herein.

[0081] Methods

[0082] Study Design

[0083] A mechanistic, randomized, double-blind, placebo-controlled crossover trial (NCT04639193, IRB #191990) was conducted. The study design is outlined in FIG. 1: interested research candidates who were screened positive based on a phone interview underwent an in-laboratory polysomnography to verify full eligibility (e.g., sufficient OSA severity and fraction of hypopneas) and to assess outcomes at baseline. Eligible participants underwent a dual drug therapy (“DualRx’’; acetazolamide 250-500 mg x 3 days + eszopiclone 2 mg on the third day) and a placebo (matching capsules x 3 days) phase in random order. On the third day of the DualRx and placebo regimens, participants underwent another overnight polysomnography to repeat the outcome measures. After completion of the DualRx and Placebo phases, participants were invited to complete a final open-label phase depending on their response to DualRx: to assess the relative importance of eszopiclone in the DualRx phase, the plan was to offer the participants whose OSA fully was resolved clinically (defined as an apnea hypopnea index (AHI) reduction by > 50% to < 10 / hour) single drug therapy with acetazolamide x 3days; conversely, for participants whose OSA was not fully resolved with DualRx, a trial of triple drug therapy (“TripleRx”; DualRx + venlafaxine 50 mg on the third day) was offered to test whether addition of venlafaxine may augment the effect of DualRx.

[0084] The washout period between each phase was set at 4-10 days (e.g., at least 7 days between polysomnography tests) to prevent carryover effects. Study drugs were administered within 30 min before bedtime.

[0085] Power calculation

[0086] A sample size of 20 subjects was estimated to provide > 0.8 power to detect a 50% (±75%) reduction of the placebo-adjusted AHINREM, supine on DualRx vs baseline with an alpha level of 0.05.

[0087] Participants

[0088] Patients were eligible for the study if they w ere 18-65 years of age, w ere medically stable and had moderate / severe untreated OSA (AHI > 15 / h). To enrich for patients with mild upper airway collapsibility (e.g., OSA more likely due to non- anatomical traits) and a low arousal threshold, while ensuring feasibility and including patients with high loop gain, a body mass index (BMI) <40kg / m2and a fraction of hypopneas (Fhypopneas) >25% was required. Polysomnograms

[0089] A registered polysomnographic technologist scored the AHI for primary analyses according to American Academy of Sleep Medicine (AASM) recommended criteria (e.g., hypopneas defined as a > 30% decrease in airflow for 10+ seconds associated with an oxygen desaturation of > 3% or arousal). For secondary analyses, an AASM-acceptable “AHI4” (e.g., hypopneas defined as a >30% decrease in airflow for 10+ seconds associated with an oxygen desaturation of >4%) was calculated as well.

[0090] Endotype Measurements

[0091] To explore potential predictors and mechanisms underlying changes in OSA severity in response to DualRx and TripleRx, endotypical traits were estimated from raw signals obtained during NREM-sleep portions of the in-laboratory polysomnography. The parameters that were quantified include passive upper airway collapsibility (Vpassive, higher is better), responsiveness of upper airway dilator muscles (V active, Vcomp; higher is better), ventilatory instability (loop gain, high is worse), the arousal threshold (lower is worse), ventilatory response to arousal (higher may be worse), and circulatory delay.

[0092] Outcome Measurements

[0093] To avoid confounding by sleep stage and position effects, a priori the AHI during supine non-rapid eye movement (NREM) sleep (AHINREM, supine) was selected as the primary' outcome measure. In addition, participants were successfully encouraged to sleep supine across all nights (median (interquartile, IQR) percent of total sleep time spent supine was 100 (100 to 100)% with a range of 67.5 to 100% across all nights). Secondary7outcomes included other measures of OSA severity^ (e.g., overall AHI, SpO2 nadir, sleep-apnea specific hypoxic burden), responder status (e.g., AHI reduction by >50%), measures of sleep architecture, adverse events (actively queried during each visit), morning blood pressure, psychomotor vigilance (PVT; with a focus on the response speed and lapses), subjective morning sleepiness based on the Stanford sleepiness scale (higher is worse), and the PROMIS sleep disturbance 8b instrument t-score (mean [standard deviation] is 50

[0010] for the general US population, with higher scores reflecting more sleep disturbance). Statistical Analysis

[0094] Data were summarized as median (IQR) or number (percent). The primary comparison was the change in AHINREM, supine from baseline to DualRx vs the change from baseline to placebo (e.g., placebo-adjusted 4DualRxvs BL = 1DualRxvs BL - ZlPlacebovs BL), which was assessed using Wilcoxon signed-rank test based on the intention-to-treat principle (which coincided with a per-protocol analyses since all participants received their assigned therapy and there were no dropouts). Secondary outcomes and responses to TripleRx were assessed similarly, using McNemar test for categorical outcomes. To explore potential predictors and mechanisms of AHI changes, the characteristics across responders (defined as reduction of AHINREM, supine by >50%) and non-responders were compared using Wilcoxon rank sum and Fisher exact tests, and regressed AHI changes on potential predictors and mechanisms. Furthermore, the correlations between changes in clinical outcomes and changes in OSA severity metrics (e.g., AHI, hypoxic burden) were explored.

[0095] Example 1. Patient enrollment review

[0096] Out of 88 patients screened, 20 were enrolled and completed the DualRx / placebo phases according to their randomly assigned sequence (FIG. 2). Subsequently, two patients were excluded (1 lost to follow up, 1 developed a rash during the final polysomnography of the DualRx / Placebo phase), thus 18 patients proceeded to the open label phase, all of whom were assigned to — and received — triple drug therapy (note: 1 patient met a priori responder criteria and was erroneously assigned to TripleRx). There was no evidence of period or cany' over effects (P > 0.4).

[0097] The 20 enrolled participants were on average middle-aged, overweight, generally healthy with mildly elevated systolic blood pressure and had severe, hypopnea-predominant OSA (FIG. 5). 20% of the cohort were female. 60% nonWhite, 25% Hispanic, with most participants exhibiting normal levels of psychomotor vigilance and reporting only mild sleep disturbance at baseline. OSA was primarily driven by a severe upper airway collapsibility (low Vpassive in 90%), low arousal threshold (60%), and poor pharyngeal muscle compensation (low Vactive / Vcomp in 40-60%), with only 15% of patients having high loop gain. Example 2. The effect of DualRx

[0098] With DualRx there was a placebo-adjusted median (interquartile, IQR) reduction in AHlNREM,suPine by -13.8 [24.1 to -5.2] events / hour or -45 [-77 to -14] %, P = 0.003 (FIGs. 3, 6 and 10). Results were slightly attenuated for the overall AHI (- 11.9 [-22 to -4.6] events / hour or -33 [-66 to -13] %, P = 0.001) as there was no significant placebo-adjusted change in the AHI during REM sleep (P = 0.15).

[0099] Improvements were primarily driven by a reduction of hypopneas and central apneas as well as a slight increase in event duration (P < 0.05). SpCh nadir and T90 did not significantly change, but hypoxic burden improved by -11.7 [-24.2 to - 2.6] %min / h, P = 0.03.

[0100] In terms of sleep parameters. DualRx significantly increased total sleep time and sleep efficiency, with a shift from non-rapid eye movement (NREM) stage NREM1 to NREM2 sleep and a reduction of (respiratory-related) arousals (P < 0.02).

[0101] While there was a clinically and statistically significant decrease in systolic blood pressure with DualRx from baseline (-7 [-14 to 1.2] mmHg, P = 0.04), this change became non-significant once adjusted for placebo (-1.5 [-10.2, 3.2] mmHg. P = 0.22). There were no significant changes in heart rate, self-reported symptoms or psychomotor vigilance.

[0102] Predictors of Response

[0103] FIG. 7 summarizes responder frequencies using varying definitions. Using the typical definition of a reduction of the overall AHI > 50% from baseline there were 7 (35%) responders on DualRx vs 2 (10%) on placebo (FIG. 4B). When defining responders as participants with a reduction of AHlNREM-supine by >50% from baseline, then there were 9 (45%) on DualRx vs 3 (15%) on placebo (FIG. 4A). Using the latter definition, there were no meaningful differences in baseline characteristics in responders vs non-responders, although a higher AHI at baseline was associated with greater reductions in AHlNREM-supine on DualRx (beta standardized = -0.53, 95%-CI: - 0.95 to -0. 11. P=0.02).

[0104] Mechanisms of Response

[0105] Except for a slight increase in circulatory delay, there were no significant changes in pathophysiological traits on the group level relative to placebo. Improvements in AHlNREM-supine on DualRx correlated moderately with improvements in passive and active upper airway collapsibility, and pharyngeal dilator muscle function (r ~0.5, P < 0.02)

[0106] Clinical Consequences of Improved OSA severity

[0107] There was a moderate but non-significant correlation between improvements in AHI and improvements in self-reported sleep disturbance (r = 0.4, P=0.08).

[0108] Example 3. The effect of TripleRx

[0109] With TripleRx the placebo-adjusted changes in AHINREM, supine and total AHI were less pronounced than with DualRx and did not quite reach statistical significance (FIGs. 3, 4, and 8). But of note, compared to placebo there was a large, borderline significant reduction in AHIREM, supine (-23.4 [-27.2 to -0.9] events / hour or -35 [-55 to 4] %, n=l 1, P=0.054), a more pronounced reduction in AHI4 (FIGs. 3 and 10), a significant reduction in hypopneas and (obstructive) apneas with an overall shift towards hypopneas, and a large reduction in hypoxic burden (-30.6 [-48. 1 to -6. 1], P = 0.01). In terms of sleep parameters, with TripleRx there was a shift towards lighter sleep with substantially more Nl, less REM sleep and more spontaneous arousals compared to both placebo and DualRx. Compared to placebo and DualRx, the heart rate during sleep and the number of lapses during the PVT task were significantly increased from baseline (P < 0.05). Otherwise, there were no significant changes in other PVT metrics or self-reported symptoms.

[0110] Predictors of Response

[0111] Overall, the percentage of responders with TripleRx was similar as with DualRx (FIG. 7), although numerically there were more participants on TripleRx who achieved full OSA resolution (e.g., reduction of the overall AHI by >50% to <10 events / hour; 4 [22%] vs 1 [5%], P = 0.25). Responders had similar baseline characteristics as non-responders, and there were no meaningful correlations between candidate predictors and changes in AHINREM , supine.

[0112] Mechanisms of Response

[0113] Compared with placebo, TripleRx significantly reduced loop gain and arousal threshold. Improvements in AHlNREM-supine on TripleRx were moderately associated with improvements in passive upper airway col lapsibil i ty , and increases in circulatory delay (P < 0.05). Paradoxically, increases in pharyngeal muscle compensation (Vcomp) from baseline were associated with increases in AHlNREM-supine.

[0114] Clinical Consequences of Improved OSA severity

[0115] Based on effect sizes, improvements in AHI and hypoxic burden were moderately correlated with improvements in systolic blood pressure (r ~ 0.4, P<0.1).

[0116] Example 4. Adverse Events

[0117] Events were all rated as mild-moderate and there were no serious adverse events. DualRx was generally well tolerated with most reported events typical for the administered study drugs (paresthesia, polyuria, fatigue) and a similar number of participants who experienced at least one adverse event (that was at least possibly related to their study participation) as on placebo (55% vs 50%, P = 1; FIG. 9). With TripleRx most participants (89%) experienced at least one adverse event, most frequently GI upset, sleepiness, and headache.

[0118] References

[0119] 1. Taranto-Montemurro L, Messineo L, Wellman A. Targeting Endotypic Traits with Medications for the Pharmacological Treatment of Obstructive Sleep Apnea. A Review of the Current Literature. Journal of clinical medicine 2019; 8.

[0120] 2. Eckert DJ. White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. American journal of respiratory and critical care medicine 2013; 188: 996- 1004.

[0121] 3. Schmickl CN, Owens RL, Edwards BA, Malhotra A. OSA Endotypes: What Are They and What Are Their Potential Clinical Implications? (available online at https: / / rdcu.be / 2nNf). Current Sleep Medicine Reports 2018; 4: 231-242.

[0122] 4. Eckert DJ, Owens RL, Kehlmann GB. Wellman A, Rahangdale S, Yim-Yeh S, White DP. Malhotra A. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea / hypopnoea index in obstructive sleep apnoea patients with a low7arousal threshold. Respirology (Carlton, Vic) 2011; 120: 505-514.

[0123] 5. Schmickl C, Landry S, Orr J, Nokes B, Edw ards B, Malhotra A, Owens R. Effects of Acetazolamide on Control of Breathing in Sleep Apnea Patients: Mechanistic Insights using Meta-Analyses and Physiological Model Simulations. Physiological reports 2021; 9(20): el5071.

[0124] 6. Taranto-Montemurro L, Sands SA, Edwards BA, Azarbarzin A, Marques M, de Melo C, Eckert DJ, White DP, Wellman A. Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation. The European respiratory journal 2016; 48: 1340-1350.

[0125] 7. Schmickl CN, Li Y, Orr JE, Jen R, Sands SA, Edwards BA, DeYoung P, Owens RL, Malhotra A. The Effect of Venlafaxine on Apnea Hypopnea Index in Patients with Sleep Apnea - a Randomized, Double-Blind Crossover Study. Chest 2020; 158: 765-775.

[0126] 8. Taranto-Montemurro L, Messineo L, Azarbarzin A, Vena D, Hess LB, Calianese NA, White DP, Wellman A, Sands SA. Effects of the Combination of Atomoxetine and Oxybutynin on OSA Endotypic Traits. Chest 2020; 157: 1626-1636.

[0127] OTHER EMBODIMENTS

[0128] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:1 . A method of treating sleep apnea in a subject, the method comprising: identifying a subject as having sleep apnea; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

2. A method of decreasing sleep disturbances in a subject, the method comprising: identifying a subject as having breathing-related sleep disturbances; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

3. A method of increasing total sleep time and / or sleep efficiency in a subject, the method comprising: identifying a subject as having sleep apnea-related reduction of total sleep time and / or sleep efficiency; and administering to the subject an effective amount of a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic.

4. The method of any of claims 1-3, wherein the sleep apnea and / or breathing- related sleep disturbances comprises obstructive sleep apnea (OSA), central sleep apnea (CSA), or complex sleep apnea syndrome.

5. The method of any one o claims 1-4, wherein the sleep apnea is OSA.

6. The method of any one of claims 1-5, wherein the OSA is moderate or severe untreated OSA.

7. The method of any one of claims 1-6, wherein the subject has an apnea hypopnea index of about 15 / h or more.

8. The method of any one of claims 1-7, wherein the subject has a body massindex (BMI) less than about 40 kg / m2and a fraction of hypopneas more than about 25%.

9. The method of any one of claims 1-8, wherein the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide. topiramate, sultiame, benzolamide, and any combination thereof.

10. The method of any one of claims 1-9, wherein the nonbenzodiazepine sedative-hypnotic is selected from the group consisting of eszopiclone, pagoclone, pazinaclone, suproclone, suriclone, zopiclone, divapion, fasiplon, indiplon, loredipion, ocinaplon, panadiplon, taniplon, zaleplon, alpidem, necopidem, saripidem, and zolpidem, and any combination thereof.

11. The method of any one of claims 1-10. wherein the carbonic anhydrase inhibitor is acetazolamide.

12. The method of any one of claims 1-11. wherein acetazolamide is administered at a dosage of from about 100 mg to about 1000 mg.

13. The method of any one of claims 1-12. wherein acetazolamide is administered at a dosage of from about 250 mg to about 500 mg.

14. The method of any one of claims 1-13. wherein the nonbenzodiazepine sedative-hypnotic is eszopiclone.

15. The method of any one of claims 1-14, wherein eszopiclone is administered at a dosage of from about 0.5 mg to about 8 mg.

16. The method of any one of claims 1-15, wherein eszopiclone is administered at a dosage of about 2 mg.

17. The method of any one of claims 1-16. wherein the carbonic anhydraseinhibitor and the nonbenzodiazepine sedative-hypnotic are administered in a single composition or separate compositions.

18. The method of any one of claims 1-17. wherein a single composition or separate compositions are administered daily.

19. The method of any one of claims 1-18. wherein the single composition or separate compositions are orally administered.

20. The method of any one of claims 1-19. wherein the single composition or separate compositions are in a form comprising a syrup, pill, tablet, troche, capsule, or patch.

21. The method of any one of claims 1-20, further comprises administering to the subject an effective amount of a serotonin and norepinephrine reuptake inhibitor (SNRI).

22. The method of claim 21, wherein the SNRI is selected from the group consisting of venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, and tramadol.

23. The method of claim 21 or 22, wherein the SNRI is venlafaxine.

24. The method of any one of claims 21-23, wherein venlafaxine is administered at a dosage of from about 10 mg to about 200 mg.

25. The method of any one of claims 21-24, wherein venlafaxine is administered at a dosage of about 50 mg.

26. The method of any one of claims 21-25, wherein the carbonic anhydrase inhibitor, the nonbenzodiazepine sedative-hypnotic, and the SNRI are administered in a single or separate compositions.

27. The method of claim 26, wherein the single composition or separate compositions are orally administered.

28. The method of any one of claims 21-27, wherein the single composition or separate compositions are in a form comprising a syrup, pill, tablet, troche, capsule, or patch.

29. The method of any one of claims 1-28, wherein the method is effective in reducing the subject’s OSA severity as measured by metrics comprising apnea-hypopnea index during supine, non-rapid eye movement sleepoverall AHI (AHIoveraii), or AHI4, hypoxic burden, compared to the subject’s OSA severity prior to the first administration.

30. A pharmaceutical composition comprising a carbonic anhydrase inhibitor and a nonbenzodiazepine sedative-hypnotic in a pharmaceutically acceptable carrier.

31. The pharmaceutical composition of claim 30, further comprising a serotonin and norepinephrine reuptake inhibitor (SNRI).

32. The pharmaceutical composition of claim 30 or 31, wherein the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sultiame, benzolamide, and any combination thereof.

33. The pharmaceutical composition of claim 30 or 31, wherein the nonbenzodiazepine sedative-hypnotic is selected from the group consisting of eszopiclone, pagoclone, pazinaclone, suproclone, suriclone, zopiclone, divapion, fasiplon, indiplon, loredipion, ocinaplon, panadiplon, taniplon, zaleplon, alpidem, necopidem. saripidem, and zolpidem, and any combination thereof.

34. The pharmaceutical composition of claim 30 or 31, wherein the SNRI isselected from the group consisting of venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, and tramadol, and any combination thereof.

35. The pharmaceutical composition of any one of claims 30-34, wherein the carbonic anhydrase inhibitor is acetazolamide, and the nonbenzodiazepine sedative-hypnotic is eszopiclone.

36. The pharmaceutical composition of any one of claims 30-35, wherein the SNRI is venlafaxine.

37. The pharmaceutical composition of any one of claims 30-36, wherein acetazolamide is present in a dosage of from about 100 mg to about 1000 mg, and eszopiclone is present in a dosage of from about 0.5 mg to about 8 mg.

38. The pharmaceutical composition of any one of claims 30-37, wherein acetazolamide is present in a dosage of from about 250 mg to about 500 mg, and eszopiclone is present in a dosage of about 2 mg.

39. The pharmaceutical composition of any one of claims 30-38, wherein venlafaxine is present in a dosage of from about 10 mg to about 200 mg.

40. The pharmaceutical composition of any one of claims 30-39, wherein venlafaxine is present in a dosage of about 50 mg.

41. The pharmaceutical composition of any one of claims 30-40, for use in treating a subject having sleep apnea.

42. The pharmaceutical composition of any one of claims 30-41, wherein the sleep apnea comprises obstructive sleep pharmaceutical composition of apnea (OSA), central sleep apnea (CSA). or complex sleep apnea syndrome.

43. The pharmaceutical composition of claim 41 or 42, wherein the sleep apnea is OSA.

4. The pharmaceutical composition of claim 30, wherein the pharmaceutically acceptable carrier comprises water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oils, mineral oils, silicones, gelatin, starches, cellulose derivatives, polymers, sorbitol, sucrose, lactose, mannitol, microcrystalline cellulose, magnesium stearate, calcium phosphate, or sodium chloride.

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