Methods and compositions for treating conditions associated with central hypoventilation

Abstract

Described herein are pharmaceutical compositions comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI), and methods for treating conditions associated with central hypoventilation.

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 278,324, filed November 11, 2021, and No. 63 / 305,305, filed February 1, 2022, the entire contents of each of which are incorporated herein by reference.

[0002] Technical Field The present invention provides pharmaceutical compositions comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor, and methods for treating conditions associated with central hypoventilation. [Background technology]

[0003] background Obesity hypoventilation syndrome (OHS) is an obesity-related condition in which the patient cannot breathe quickly or deeply enough, resulting in low oxygen levels and high blood CO2 levels. Untreated OHS is associated with significant morbidity. Summary of the Invention

[0004] overview One aspect of the invention provides a method of treating a subject having a condition associated with central hypoventilation, the method comprising administering to a subject in need of said treatment effective amounts of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI).

[0005] Embodiments of this aspect of the invention may include any one or more of the following features. In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amidaburin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine and venlafaxine or a pharmaceutically acceptable salt thereof.In some embodiments, the NRI is reboxetine or a pharmaceutically acceptable salt thereof.In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sulthiame, and any combination thereof, such as a pharmaceutically acceptable salt thereof. In some embodiments, the CAI is acetazolamide or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI, such as atomoxetine or a pharmaceutically acceptable salt thereof, is administered at a dose of about 20 to about 200 mg. In some embodiments, the NRI, such as atomoxetine or a pharmaceutically acceptable salt thereof, is administered at a dose of about 25 to about 100 mg. In some embodiments, the CAI, such as acetazolamide, is administered at a dose of about 150 mg to about 750 mg.In some embodiments, the carbonic anhydrase inhibitor, such as acetazolamide, is administered in a dose of about 500 mg. In some embodiments, the carbonic anhydrase inhibitor, such as acetazolamide, is administered in a dose of about 250 mg. In some embodiments, the dose is a daily dose, i.e., administered once a day. In some embodiments, the dose is a twice-daily dose, i.e., administered twice a day (e.g., once in the morning and once before bedtime). In some embodiments, the NRI and CAI are administered as separate compositions. In some embodiments, the NRI and CAI are administered in a single composition. In some embodiments, the separate compositions or the single composition are oral dosage forms. In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, capsule or patch. In some embodiments, the condition associated with central hypoventilation is obesity hypoventilation syndrome (OHS) or obesity-related sleep hypoventilation (ORSH). In some embodiments, the condition associated with central hypoventilation is obesity hypoventilation syndrome (OHS). In some embodiments, the condition associated with central hypoventilation is obesity-related sleep hypoventilation (ORSH).

[0006] Another aspect of the present invention provides a pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI) and (iii) a pharma- ceutically acceptable carrier.

[0007] Embodiments of this aspect of the invention may include any one or more of the following features. In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amidaburin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine and venlafaxine or a pharmaceutically acceptable salt thereof.In some embodiments, the NRI is reboxetine or a pharmaceutically acceptable salt thereof.In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sulthiame, and any combination thereof, such as a pharma- ceutically acceptable salt thereof. In some embodiments, the CAI is acetazolamide or a pharma- ceutically acceptable salt thereof. In some embodiments, the NRI, such as atomoxetine or a pharma- ceutically acceptable salt thereof, is present in an amount of about 20 to about 200 mg. In some embodiments, the NRI, such as atomoxetine or a pharma- ceutically acceptable salt thereof, is present in an amount of about 25 to about 100 mg. In some embodiments, the CAI, such as acetazolamide, is present in an amount of about 150 mg to about 750 mg. In some embodiments, the carbonic anhydrase inhibitor, such as acetazolamide, is present in an amount of about 500 mg.In some embodiments, the carbonic anhydrase inhibitor, e.g., acetazolamide, is present in an amount of about 250 mg. In some embodiments, the NRI and CAI are formulated as separate compositions. In some embodiments, the NRI and CAI are formulated in a single composition. In some embodiments, the separate compositions or the single composition are oral dosage forms. In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, capsule or patch. In some embodiments, the pharmaceutical composition is for use in treating a subject having a condition associated with central hypoventilation. In some embodiments, the condition associated with central hypoventilation is obesity hypoventilation syndrome (OHS) or obesity-related sleep hypoventilation (ORSH). In some embodiments, the condition associated with central hypoventilation is obesity hypoventilation syndrome (OHS). In some embodiments, the condition associated with central hypoventilation is obesity-related sleep hypoventilation (ORSH). In some embodiments, the pharmaceutical composition is administered daily. In some embodiments, the pharmaceutical composition is administered twice daily.

[0008] Also provided herein are norepinephrine reuptake inhibitors (NRIs) and carbonic anhydrase inhibitors (CAIs) for use in treating a subject having a condition associated with central hypoventilation.

[0009] Further provided in the present invention is a therapeutic combination of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI) for use in treating a subject having a condition associated with central hypoventilation.

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Methods and materials are described herein for use in the present invention, and other suitable methods and materials known in the art can also be used.Materials, methods and examples are illustrative only and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety.In case of conflict, the present specification, including definitions, will control.

[0011] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description Obese subjects have increased ventilator demands and elevated work of breathing, in addition to slight respiratory muscle weakness and reduced respiratory compliance. Obese individuals generally have increased central respiratory drive compared to normal weight patients to compensate for the increased ventilatory needs. Despite this, obese subjects (BMI > 30 kg / m2) evaluated in sleep clinics have increased ventilator demands and elevated work of breathing. 2 In 20% of cases, OSA is accompanied by diurnal hypercapnia (PaCO2 > 45 mm Hg), which defines obesity-hypoventilation syndrome (OHS) (1).

[0013] Compared to isolated OSA, OHS is characterized by increased morbidity and mortality due to cardiovascular and metabolic diseases associated with systemic inflammation, endothelial dysfunction, and insulin resistance, and is often diagnosed only after acute respiratory failure. (2) However, OHS often remains undiagnosed and untreated until patients require admission to intensive care units due to acute decompensation. (2, 3)

[0014] Lack of ventilatory responsiveness to gas changes and insufficient ability to compensate for upper airway obstruction are pathophysiological correlates of OHS. If the balance between obesity-related respiratory load and ventilatory responsiveness to gas changes can be maintained during the day, it may be lost during sleep, and isolated nocturnal hypoventilation is initially determined. Therefore, hypoventilation is most and primarily evident during sleep as a result of sleep-related physiological adaptations, which may or may not be related to sleep apnea. In fact, it has recently been described that isolated sleep hypoventilation (defined as PtcCO2 > 55 mmHg or > 50 mmHg, when transcutaneous carbon dioxide pressure, PtcCO2, increases by more than 10 mmHg during sleep longer than 10 min compared to the awake supine value) progresses to OHS without awakening hypercapnia, similar to that observed in neuromuscular and chest wall diseases (4). This condition was termed obesity-related sleep hypoventilation (ORSH) and is now considered to be an early stage of hypoventilation in patients with obesity (5, 6). Recent evidence indicates that approximately 20% of patients with grade III obesity present with ORSH (7, 8), thus supporting a massive underestimation of the disease.

[0015] The only available treatment option for OHS to date is to address the underlying pathophysiological condition, such as upper airway obstruction, with positive air pressure (PAP). However, adherence to treatment is often very difficult with poor tolerance and consequently reduced compliance to PAP, resulting in an under-treated state of OHS.

[0016] Acetazolamide is a diuretic that inhibits carbonic anhydrase, increases HCO3 excretion, and induces metabolic acidosis, thus stimulating ventilation. By addressing the plant gain, acetazolamide acts as a mild ventilatory stimulant and stabilizes breathing, thereby reducing the shallow breathing and subsequent hyperventilation typical of ORSH patients. Acetazolamide has been shown to improve alveolar ventilation in patients with OHS (9, 10). However, acetazolamide alone does not affect all of the pathogenic contributors to obesity hypoventilation.

[0017] To date, no pharmacologic treatments for OHS or ORSH have been approved.

[0018] Treatment method The methods described herein include methods for the treatment of conditions associated with central hypoventilation. In some embodiments, the condition is obesity hypoventilation syndrome (OHS) or obesity-related sleep hypoventilation (ORSH).

[0019] Generally, the method comprises administering to a subject in need of or determined to be in need of such treatment an effective amount of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor. In some embodiments, the method comprises administering to a subject in need of or determined to be in need of such treatment an effective amount of (i) atomoxetine or a pharma- ceutically acceptable salt thereof and (ii) acetazolamide or a pharma-ceutically acceptable salt thereof.

[0020] In some embodiments, the method further comprises administering a therapeutically effective amount of a hypnotic drug. In certain embodiments, the method comprises administering effective amounts of (i) atomoxetine or a pharma- ceutically acceptable salt thereof, (ii) acetazolamide or a pharma- ceutically acceptable salt thereof, and (iii) trazodone or a pharma- ceutically acceptable salt thereof to a subject in need of or determined to be in need of such treatment.

[0021] In some embodiments, the method further comprises administering (iii) a therapeutically effective amount of an antimuscarinic agent. In some embodiments, the method comprises administering effective amounts of (i) atomoxetine or a pharmaceutically acceptable salt thereof, (ii) acetazolamide or a pharmaceutically acceptable salt thereof, and (iii) oxybutynin or a pharmaceutically acceptable salt thereof to a subject who is in need of, or has been determined to be in need of, such treatment. In some embodiments, the method comprises administering effective amounts of (i) atomoxetine or a pharmaceutically acceptable salt thereof, (ii) acetazolamide or a pharmaceutically acceptable salt thereof, and (iii) (R)-oxybutynin or a pharmaceutically acceptable salt thereof to a subject who is in need of, or has been determined to be in need of, such treatment.

[0022] In this context, "treat" means to improve at least one symptom of the disorder associated with central hypoventilation. In some embodiments, the disorder associated with central hypoventilation is obesity hypoventilation syndrome (OHS). Often, OHS causes sleepiness, lack of energy, shortness of breath, headache and depression during the day. At night, OHS causes loud and frequent snoring and / or breathing stops during sleep. OHS patients may also have right heart failure with swelling of the lower extremities. Therefore, treatment may cause reduction of snoring, apnea, breathing stops, shortness of breath, headache and other symptoms associated with OHS.

[0023] In some embodiments, the disorder associated with central hypoventilation is obesity-related sleep hypoventilation (ORSH).ORSH can be described as a condition that has isolated sleep hypoventilation (defined as PtcCO2>55mmHg or >50mmHg when transcutaneous carbon dioxide pressure, PtcCO2, increases by more than 10mmHg during sleep longer than 10 minutes compared to the awake supine value) without waking hypercapnia, and progresses to OHS, similar to that observed in neuromuscular and chest wall diseases.

[0024] In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, e.g., to treat a condition associated with central hypoventilation, e.g., to treat Obesity Hypoventilation Syndrome (OHS) or Obesity Related Sleep Hypoventilation (ORSH).

[0025] Patients with "hypoventilation syndrome" typically have mild hypercapnia or elevated serum bicarbonate levels upon awakening, which often worsens during sleep. Hypoventilation syndrome includes, but is not limited to, Obesity Hypoventilation Syndrome (OHS).

[0026] "Hypoventilation" is defined as an elevated level of arterial carbon dioxide (pCO2), e.g., at least 10 mm Hg above the upper normal limit. Treatment of hypoventilation syndrome generally aims to correct or improve waking pCO2.

[0027] Effective amount can be administered in one or more administrations, applications or doses.The composition can be administered from once or more per day to once or more per week; for example, once every other day.In some embodiments, the composition is administered daily.Those skilled in the art will understand that certain factors, including but not limited to, the severity of disease or disorder, previous treatment, the general health and / or age of the subject, and other diseases present, can affect the dosage and timing required to effectively treat the subject.Furthermore, treatment of a subject with a therapeutically effective amount of the therapeutic compound described herein can include a single treatment or a series of treatments.

[0028] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.A therapeutically effective amount of a compound refers to the amount of a therapeutic agent alone or in combination with other treatments that provides a therapeutic benefit in the treatment of a disease, disorder or condition.The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.In some embodiments, a therapeutically effective amount includes an amount that normalizes or improves wakefulness pCO2 levels.

[0029] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), specifically "mammals" such as non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more specifically humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., horses, cows, pigs, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a human.

[0030] As used herein, "pharmaceutical acceptable" means approved or approvable by a regulatory agency of the Federal or State government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0031] "Pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts". "Pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc., which retain the biological effectiveness of the free base and are not biologically or otherwise undesirable.

[0032] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference.)

[0033] As used herein, the term "unit dosage form" is defined as the form in which a compound is administered to a subject.Specifically, the unit dosage form can be, for example, a pill, a capsule or a tablet.In some embodiments, the unit dosage form is a capsule.

[0034] As used herein, "solid dosage form" means a solid pharmaceutical dose or doses, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[0035] For the compounds disclosed herein, single stereochemical isomers as well as enantiomers, diastereomers, cis / trans conformational isomers, and rotamers, as well as racemic and non-racemic mixtures thereof, are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0036] Atomoxetine is the generic name of the pharmaceutical agent having the chemical name (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine and its pharmaceutical salts. Atomoxetine is the R(-)-isomer as determined by X-ray diffraction. In some embodiments, atomoxetine can be atomoxetine hydrochloride.

[0037] Acetazolamide is the generic name for the pharmaceutical substance with the chemical name N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide and its pharmaceutical salts. Acetazolamide is available as a generic drug and is sold under the trade names Diamox, Dacarb, and others.

[0038] In some embodiments, the method includes administering a dose of about 20 mg to about 200 mg of atomoxetine or a pharma- ceutically acceptable salt thereof (or the dose equivalent of another NRI). In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 25 mg to about 100 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 40 mg to about 80 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 20 mg to about 50 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 50 mg to about 100 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 25 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 40 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 50 mg. In some embodiments, the dose of atomoxetine or its pharmaceutically acceptable salt is about 80mg. In some embodiments, the dose of atomoxetine or its pharmaceutically acceptable salt is about 100mg. In some embodiments, the dose is a daily dose, i.e., administered once a day. In some embodiments, the dose is a two-times-a-day dose, i.e., administered in two separate doses a day, for example, one in the morning and one at bedtime. In some embodiments, the dose of atomoxetine or its pharmaceutically acceptable salt is about 25mg daily. In some embodiments, the dose of atomoxetine or its pharmaceutically acceptable salt is about 50mg daily. In some embodiments, the dose of atomoxetine or its pharmaceutically acceptable salt is about 100mg daily. In some embodiments, the dose of atomoxetine or its pharmaceutically acceptable salt is a total daily dose of 25mg administered in two separate doses. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is a total daily dose of about 50 mg administered in two separate administrations.In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is a total daily dose of about 100 mg administered in two separate doses. In some embodiments, the two separate doses are a morning dose and a bedtime dose. In some embodiments, the two separate doses are a morning dose and an evening dose.

[0039] In some embodiments, the method includes administering a dose of about 50 mg to about 1000 mg of acetazolamide (or its dose equivalent of another CAI), about 100 mg to about 800 mg of acetazolamide, about 150 mg to about 750 mg of acetazolamide, about 250 mg to about 750 mg, about 500 mg to about 750 mg of acetazolamide, or about 450 mg to about 650 mg of acetazolamide. In some embodiments, the dose of acetazolamide is about 250 mg. In some embodiments, the dose of acetazolamide is about 500 mg. In some embodiments, the dose is a daily dose, i.e., administered once a day. In some embodiments, the dose is a two-daily dose, i.e., administered in two separate doses a day, e.g., one in the morning and one at bedtime. In some embodiments, the dose of acetazolamide is about 250mg daily. In some embodiments, the dose of acetazolamide is about 500mg daily. In some embodiments, the dose of acetazolamide is about 250mg total daily dose administered in two separate doses. In some embodiments, the dose of acetazolamide is about 500mg total daily dose administered in two separate doses. In some embodiments, the two separate doses are a morning dose and a bedtime dose. In some embodiments, the two separate doses are a morning dose and an evening dose.

[0040] In some embodiments, the NRI and CAI are administered in the absence of antimuscarinic therapy. In some embodiments, the NRI and CAI are administered in the absence of other active agents.

[0041] Pharmaceutical Compositions Also provided herein is a pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI) as active ingredients. The active ingredients can be in a single composition or in separate compositions. In some embodiments, the pharmaceutical composition comprises (i) atomoxetine or a pharma- ceutically acceptable salt thereof and (ii) acetazolamide or a pharma- ceutically acceptable salt thereof as active ingredients. In some embodiments, the pharmaceutical composition does not include an antimuscarinic agent. In some embodiments, the NRI and the CAI are the only active ingredients in the pharmaceutical composition.

[0042] Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs such as amidaburin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daredalin (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 non-selective NRIs such as amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone) and venlafaxine; and pharmaceutically acceptable salts thereof.

[0043] In some embodiments, the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof.In some embodiments, the NRI is reboxetine or a pharma- ceutically acceptable salt thereof.

[0044] Exemplary carbonic anhydrase inhibitors (CAIs) include acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sulthiame, and any combination thereof, including pharma- ceutically acceptable salts thereof.

[0045] In some embodiments, the carbonic anhydrase inhibitor is acetazolamide or a pharma- ceutically acceptable salt thereof.

[0046] Pharmaceutical compositions typically include a pharma- ceutically acceptable carrier. As used herein, the term "pharma- ceutically acceptable carrier" includes saline, solvents, dispersion media, diluents, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.

[0047] Supplementary active compounds, such as muscarinic receptor antagonists (MRA), such as oxybutynin or its pharmaceutically acceptable salt or hypnotic drug, can also be integrated into the composition.In some embodiments, the pharmaceutical composition further comprises muscarinic receptor antagonists (MRA).Exemplary muscarinic receptor antagonists (MRA) include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium and oxybutynin, which have activity on M2 receptor, and its pharmaceutically acceptable salt. Other exemplary antimuscarinics include anisotropine, benztropine, biperiden, clidinium, cycrimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixe ne, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, and pharmaceutically acceptable salts thereof.

[0048] In some embodiments, the muscarinic receptor antagonist is oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof.As used herein, (R)-oxybutynin refers to the (R)-oxybutynin stereoisomer that is substantially free of other stereoisomers of oxybutynin.

[0049] In some embodiments, the pharmaceutical composition further comprises a hypnotic. Exemplary hypnotic agents include zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine and xyrem or a pharmaceutically acceptable salt thereof. In some embodiments, the hypnotic agent is trazodone or a pharmaceutically acceptable salt thereof.

[0050] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration, which includes systemic oral, transdermal and parenteral administration.

[0051] Methods for formulating suitable pharmaceutical compositions using pharmaceutically acceptable carriers are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and series of books Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally contain an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, active compound(s) can be combined with excipients and used in the form of pills, tablets, lozenges or capsules, such as gelatin capsules. Oral compositions can also be prepared using fluid carriers. In some embodiments, the composition of the present invention can be in unit dosage form. In some embodiments, the composition of the present invention can be in solid dosage form, such as tablets or capsules.

[0052] Pharmaceutically compatible binder and / or adjuvant material can be included as part of composition.Tablet, pill, capsule, lozenge etc. can contain any of the following ingredients or compounds with similar properties: binder such as microcrystalline cellulose, tragacanth or gelatin; excipient such as starch or lactose, disintegrant such as alginic acid, primogel or corn starch; lubricant such as magnesium stearate or sterotes; glidant such as colloidal silicon dioxide; sweetener such as sucrose or saccharin; or flavoring agent such as peppermint, methyl salicylate or orange flavoring.

[0053] Systemic administration of the compounds described herein can also be by transdermal means, for example, using a patch, gel or lotion applied to the skin. For transdermal administration, a penetrant suitable for penetrating the epithelial barrier can be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal administration, the active compound can be formulated into an ointment, salve, gel or cream, as generally known in the art. Gels and / or lotions can be provided in individual sachets or via a metered pump that is applied daily; see, for example, Cohn et al., Ther Adv Urol. 2016, Apr; 8(2): 83-90.

[0054] In one embodiment, the therapeutic compound is prepared with a carrier that protects the therapeutic compound against rapid elimination from the body, for example, a controlled release formulation, such as implants and microencapsulated delivery systems.Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used.Such formulations can be prepared using standard techniques or can be commercially obtained, for example, from Alza Corporation and Nova Pharmaceuticals, Inc.Liposomal suspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to the methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0055] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0056] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0057] In some embodiments, the pharmaceutical composition is for use in treating a condition associated with central hypoventilation. In some embodiments, the condition is obesity hypoventilation syndrome (OHS). In some embodiments, the condition associated with central hypoventilation is obesity-related sleep hypoventilation (ORSH). In some embodiments, the condition is obesity-related sleep hypoventilation (ORSH).

[0058] combination The present invention also provides a norepinephrine reuptake inhibitor (NRI) and a carbonic anhydrase inhibitor (CAI) for use in treating a subject with a condition associated with central hypoventilation.The present invention further provides a therapeutic combination of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI) for use in treating a subject with a condition associated with central hypoventilation.In some embodiments, the condition is obesity hypoventilation syndrome (OHS).In some embodiments, the condition associated with central hypoventilation is obesity-related sleep hypoventilation (ORSH). EXAMPLES

[0059] Working Example The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0060] Example 1. Pharmaceutical Treatment for Obesity Hypoventilation Syndrome introduction Obese subjects have increased ventilator demands and elevated work of breathing, in addition to slight respiratory muscle weakness and reduced respiratory compliance. Thus, in addition to the increased prevalence of obstructive sleep apnea (OSA), which increases in proportion to body mass index (BMI), obese individuals also generally have an increased central respiratory drive compared to normal weight patients to compensate for the increased ventilatory needs. Despite this, obese subjects (BMI > 30 kg / m2) evaluated in sleep clinics have 2 In 20% of cases, OSA is accompanied by diurnal hypercapnia (PaCO2 > 45 mm Hg), which defines obesity-hypoventilation syndrome (OHS) (1).

[0061] Compared to isolated OSA, OHS is characterized by increased morbidity and mortality due to cardiovascular and metabolic diseases associated with systemic inflammation, endothelial dysfunction, and insulin resistance, and diagnosis is often made only after acute respiratory failure (2). However, OHS often remains undiagnosed and untreated until patients require admission to intensive care units due to acute decompensation (2, 3). Therefore, timely identification and management of OHS at an earlier stage may improve patient prognosis.

[0062] Lack of ventilatory responsiveness to gas changes and insufficient ability to compensate for upper airway obstruction are pathophysiological correlates of OHS. If the balance between obesity-related respiratory load and ventilatory responsiveness to gas changes can be maintained during the day, it may be lost during sleep, and isolated nocturnal hypoventilation is initially determined. Hypoventilation is therefore most and mainly evident during sleep as a result of sleep-related physiological adaptations, which may or may not be related to sleep apnea. In fact, it has recently been described that isolated sleep hypoventilation (defined as PtcCO2 > 55 mmHg or transcutaneous carbon dioxide pressure > 50 mmHg when PtcCO2 increases by more than 10 mmHg during sleep longer than 10 min compared to the awake supine value) progresses to OHS without awakening hypercapnia, similar to what is observed in neuromuscular and chest wall diseases (4). This condition was termed obesity-related sleep hypoventilation (ORSH) and is now considered to be an early stage of hypoventilation in patients with obesity (5, 6). Recent evidence indicates that approximately 20% of patients with grade III obesity present with ORSH (7, 8), thus supporting a massive underestimation of the disease.

[0063] To date, the only available treatment option for OHS is to address the underlying pathophysiological condition, such as upper airway obstruction, with positive air pressure (PAP). However, adherence to treatment is often very difficult with poor tolerance to PAP and consequently reduced compliance, resulting in an under-treated state of OHS.

[0064] Acetazolamide is a diuretic that inhibits carbonic anhydrase, increases HCO3 excretion, causes metabolic acidosis, and therefore stimulates ventilation. By addressing the increase in capacity, acetazolamide acts as a mild ventilatory stimulant and stabilizes breathing, thus reducing the shallow breathing and subsequent hyperventilation typical of ORSH patients. Previously, acetazolamide has been shown to improve alveolar ventilation in patients with OHS (9, 10). However, acetazolamide alone does not affect all of the pathogenic contributors to obesity hypoventilation. We decided to investigate atomoxetine in combination with acetazolamide. Atomoxetine is a noradrenergic drug that reactivates upper airway muscles during sleep, reducing their collapsibility (11).

[0065] Our objective was to test the efficacy of the combination of atomoxetine and acetazolamide in obese adults with hypoventilation.

[0066] Test Design This is a randomized, double-blind, placebo-controlled, crossover, single-center efficacy study of the combination of atomoxetine and acetazolamide in adults with ORSH.

[0067] Twelve participants will be equally randomized to receive a combination of atomoxetine 80 mg and acetazolamide 500 mg or a matching placebo. Administration of study treatment will occur immediately prior to bedtime.

[0068] Of the 12 subjects with ORSH (early stage of OHS), we estimate that at least 2 of them also present with diurnal hypercapnia (advanced OHS).

[0069] Study participants will undergo eligibility screening, which may include an overnight inpatient PSG study with PtcCO2 monitoring. In the morning, blood gas analysis will also be performed.

[0070] One week later, on the last night of dosing, participants return to the study site for an inpatient PSG. Participants have a 7-10 day washout and switch to the other arm of the study. Five days later, on the last night of dosing, participants return to the study site for an inpatient PSG.

[0071] The primary efficacy endpoint is mean nocturnal PtCO2 from screening / baseline to the last night of treatment with study treatment.

[0072] Secondary outcomes include apnea / hypopnea index (AHI) and nocturnal saturation (hypoxia load and mean SpO2).

[0073] Include criteria Male or female participants aged 18-70 BMI > 35 kg / m at previous PSG visit 2 , comprehensive Nocturnal hypoventilation defined as PtcCO2 >55mmHg or >50mmHg if PtcCO2 increased by >10mmHg during sleep longer than 10 minutes compared to the awake supine value Previous surgical treatment for OSA was permitted if ≥1 year prior to enrollment.

[0074] Exclusion criteria History of narcolepsy. Clinically significant craniofacial anomalies. Clinically significant heart or lung disease (heart failure, COPD, ILD) disease or hypertension requiring more than three medications for control. History of schizophrenia, schizoaffective disorder, or bipolar disorder according to the Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) or International Classification of Disease, 10th edition criteria. History of suicide attempt or suicidal ideation within 1 year prior to screening, or current suicidal ideation. a positive screen for DSM-V-defined drugs of abuse or substance use disorder within the 12 months prior to the screening visit. Significant illness or infection requiring medical treatment within the past 30 days. Clinically significant cognitive impairment. Untreated narrow-angle glaucoma. Pregnant or breastfeeding women. History of oxygen therapy Treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or monoamine oxidase inhibitor (MAOI) or linezolid within 14 days of initiating treatment or concomitantly with treatment. Central apnea index > 5 / hour

[0075] intervention There are two treatment groups: [Table 1]

[0076] References [Table 2-1] [Table 2-2]

[0077] Example 2. A crossover, double-blind, phase 2 study of a fixed-dose combination of atomoxetine and acetazolamide versus placebo in obesity-hypoventilation syndrome. This is a randomized, double-blind, placebo-controlled crossover study of the combination of atomoxetine 100 mg + acetazolamide 500 mg (Ato / Actz) in adults with OHS documented by PSG with PtcCO2 monitoring. The dose will be gradually increased: 7 days of atomoxetine 50 mg and acetazolamide 500 mg, followed by an additional 7 days of atomoxetine 100 mg + acetazolamide 500 mg, to allow better treatment tolerance. Approximately 15 participants will be randomized to receive the Ato / Actz combination or a matching placebo. After 14 days of treatment and a 3-14 day washout period, patients will receive the alternative treatment for 14 days. Alternatively, participants may experience a treatment period of 30 days or more.

[0078] Study participants will undergo a screening visit prior to the performance of any study-specific procedures to confirm enrollment eligibility. Participants who otherwise meet all enrollment criteria will undergo one night of inpatient PSG with PtcCO2 monitoring. Arterial blood gas testing will be performed if not available in the previous 6 months. For participants who are eligible and enrolled in the study, the screening PSG night will serve as the baseline reference for PtcCO2 as well as other PSG efficacy and safety endpoints. Participants will also receive a pulse oximetry device worn overnight at home for all nights of PSG. On the last night of study product administration, participants will return for a second inpatient PSG with PtcCO2 (Visit 1) and blood gas testing the morning after PSG. After a washout period, participants will continue to wear the pulse oximeter nightly at home across the other arm of the study (Visit 2). After 14 days (or alternatively 30 days or more) of treatment, participants undergo an inpatient PSG with PtcCO2 (Visit 3) and an arterial blood gas test the morning after the PSG.

[0079] The primary outcome was arterial PaCO2.

[0080] intervention There are two treatment groups: [Table 3]

[0081] The overall duration is up to 9 weeks, as follows: screening and baseline PSG until day 28; randomized home study treatment for 14 days; laboratory PSG night with PtcCO2 monitoring; washout for 3-16 days (until day 16 if required for planning); crossover to the other treatment arm for 14 days; and final laboratory PSG night with PtcCO2 monitoring. Alternatively, a 30-day (or longer) treatment period may be used instead of the 14-day treatment period.

[0082] Criteria including 1. Participants must be able to understand the nature of the study and must have the opportunity to answer any questions. Participants will voluntarily agree to participate in this study and will sign an ethical committee approved informed consent form before carrying out any of the screening visit procedures. 2. Male or female participants aged 18-75 years 3. BMI > 35 kg / m at previous PSG visit 2 , comprehensive 4. Presence of nocturnal hypoventilation defined as a mean PtcCO2 >55mmHg or >50mmHg when PtcCO2 increases by >10mmHg during sleep longer than 10 minutes compared to the awake supine value 5. Previous surgical treatment for OSA is permitted if ≥1 year prior to enrollment. 6. Participants with known OHS and treatment are eligible for screening / baseline PSG if they report CPAP or mandibular advancement device or positional therapy intolerance or poor compliance (compliance defined as use of CPAP or other treatments for 4 hours per night during 70% of the nights; participant self-report); participants who used CPAP for at least 4 hours per night during at least 70% of the nights are eligible for further screening and baseline PSG for this study only if CPAP or other treatments are not used for 2 weeks prior to screening / baseline PSG for this study.

[0083] Exclusion criteria 1. History of narcolepsy. 2. Clinically significant craniofacial anomalies. 3. Clinically significant respiratory (COPD, ILD) or cardiac (heart failure, atrial fibrillation, established severe peripheral arterial disease) disease or hypertension requiring more than three medications for control. 4. History of schizophrenia, schizoaffective disorder, or bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) or International Classification of Diseases, 10th edition criteria. 5. History of suicide attempt or suicidal ideation within 1 year prior to screening, or current suicidal ideation. 6. A positive screen for DSM-V defined drugs of abuse or substance use disorder within 12 months prior to the screening visit. 7. Significant illness or infection requiring medical treatment within the past 30 days. 8. Clinically significant cognitive impairment or significant neurological impairment, e.g. epilepsy / convulsions 9. Untreated narrow angle glaucoma. 10. Pregnant or breastfeeding women. 11. History of oxygen therapy 12. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or monoamine oxidase inhibitor (MAOI) or linezolid within 14 days of initiating treatment or concomitantly with treatment. 13. History of pheochromocytoma 14. History of diabetes mellitus with unstable glucose control for the past 15 days 15. Chronic use of aspirin greater than 500 mg / day and very high doses of aspirin (acetylsalicylic acid, a salicylate drug) due to the potential for acetazolamide interactions. 16. Allergy to sulfonamides- e.g. hydrochlorothiazide, furosemide, sulfasalazine, celecoxib, sumatriptan and zonisamide. 17. History of adrenal insufficiency 18. History of low sodium or potassium or evidence of low sodium or potassium on blood test within the last year (if available) 19. History of hyperchloremic acidosis 20. Any condition which, in the opinion of the investigator, presents an unreasonable risk to the participant or which may interfere with participation in the study or confound interpretation of the study. 21. Participant who, for any reason, is deemed by the investigator to be an inappropriate candidate to receive Ato / Acz treatment or unable or likely to not understand or satisfy the dosing schedule or study assessments. 22. History of use of oral or nasal devices for the treatment of OSA may be enrolled as long as no device is used at the time of study entry for at least 2 weeks prior to study initiation. 23. History of use of devices for the treatment of OSA that affect the participant's sleep position, e.g., preventing a supine sleep position, may be registered as long as the device is not used during participation in the study. 24. Use of another investigational agent within 30 days or 5 half-lives prior to dosing, whichever is longer. 25. Use of medications from the list of disallowed concomitant medications set out below.

[0084] Atomoxetine Contraindications Atomoxetine is contraindicated in patients with narrow-angle glaucoma, concurrent MAOI use, and in patients with hypersensitivity to atomoxetine or any of its excipients. Atomoxetine is also contraindicated in patients with current pheochromocytoma, or a history of severe cardiac or vascular disease whose condition would be expected to worsen with a clinically significant increase in blood pressure (15-20 mmHg) or heart rate (20 bpm).

[0085] Acetazolamide contraindications Acetazolamide is contraindicated in patients with significant hepatic disease or insufficiency; depressed sodium and / or potassium levels; adrenal cortical insufficiency; cirrhosis; hyperchloremic acidosis; or severe renal disease or insufficiency.

[0086] Concomitant therapy Concomitant therapy with the following medicines is not permitted: MAOIs or other drugs that affect monoamine concentrations (e.g. rasagiline) [MAOIs are contraindicated for use with reboxetine] Serotonin and norepinephrine reuptake inhibitors (e.g. duloxetine, venlafaxine, mirtazapine) Norepinephrine reuptake inhibitors (e.g. reboxetine) ·lithium Tricyclic antidepressants (e.g. desipramine, imipramine) Strong CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, quinidine, terbinafine) and other strong inhibitors of cytochrome P450 (ketoconazole) Drugs that determine electrolyte changes (thiazide diuretics) Benzodiazepines Opioids Drugs with clinically significant cardiac QT-interval prolongation effects (e.g., moxifloxacin, methadone, mefloquine, Drugs known to lower the seizure threshold (e.g., chloroquine, phenothiazines, butyrophenones, mefloquine, bupropion, tramadol) ·amphetamine Anticonvulsants Modafinil or Armodafinil -Beta-2 agonists (e.g. albuterol) if used more than 3 times per week Antipsychotics Pseudoephedrine, phenylephrine, oxymetazoline Most drugs for Parkinson's, Alzheimer's (memantine), Huntington's, amyotrophic lateral sclerosis or other neurodegenerative diseases Chronic use of aspirin or salicylates greater than 500 mg / day and very high doses of aspirin (acetylsalicylic acid, salicylate drugs) due to the potential for acetazolamide interactions Sodium phosphate: Diuretics may potentiate the nephrotoxic effects of sodium phosphate. Specifically, the risk of acute phosphate nephropathy may be increased.

[0087] Medications that have no substantial effect on the central nervous system (CNS), respiratory, or muscular activity, including but not necessarily limited to the following drugs and drug classes, are generally permitted according to the investigator's opinion, provided that the dose and frequency are stable for the 3 months prior to enrollment and over the course of the study: Antihypertensives (angiotensin-converting enzyme / angiotensin II receptor blockers, calcium channel blockers, spironolactone, hydrochlorothiazide, etc.) Statins Alpha-1 antagonists (e.g. tamsulosin) Chronic use of sedatives other than non-benzodiazepine "Z drugs" (zolpidem, zaleplon, eszopiclone) Muscle relaxants Antiemetics Proton pump inhibitors and histamine h2 receptor blockers Over-the-counter (OTC) antacids Non-sedating antihistamines (e.g. cetirizine, loratadine) Chronic use of eszopiclone, zolpidem or zaleplon Melatonin Nonsteroidal anti-inflammatory drugs and acetaminophen ·Spasmodic Erectile dysfunction medication Inhaled corticosteroids (e.g. fluticasone) Antidiabetic drugs Ocular hypotensives and other eye medications (e.g. timolol) Hormonal therapy (e.g. estrogen replacement or anti-estrogens) and hormonal contraceptives Thyroid medicine Anticoagulants OTC topicals (e.g. topical pain relievers) Osteoporosis medication

[0088] result Consider the following results:

[0089] Primary outcome: Change in mean nocturnal transcutaneous CO2 pressure (PtcCO2) with Ato / Actz vs. placebo

[0090] Secondary outcomes Proportion of participants without nocturnal hypoventilation in Ato / Actz vs. placebo Change in AHI in Ato / Actz vs. placebo

[0091] Preliminary results Change in total time with oxygen saturation (SaO2) <90% Change in mean SaO2 - Change in minimum SaO2 Changes in AHI4% and hypoxia load -Changes in PaCO2 during wakefulness in arterial blood gas analysis. Changes in ESS and SAQLI Changes in heart rate variability assessed by electrocardiogram (EKG) during PSG Change in Patient Global Impression of OSA Severity (PGI-S) Changes in Psychomotor Vigilance Test (PVT)

[0092] Measuring Results Participant's Global Impression of Severity (PGI-S) is a global index that can be used to assess the severity of a particular condition (i.e., it is a single-state scale).The scale is composed of a one-item questionnaire designed to assess the participant's impression of disease severity.The scale is considered to have clinical relevance for participants, since it allows participants to respond based on the factors that they judge to be most important in their health status.

[0093] The Psychomotor Vigilance Test (PVT) is a sustained attention, reaction time task that measures the speed at which a subject responds to visual stimuli.

[0094] Other Aspects Although the present invention will be described in conjunction with its detailed description, it is understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI) and (iii) a pharmaceutically acceptable carrier for use in treating a subject having a condition associated with central hypoventilation.

2. The pharmaceutical composition of claim 1, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI).

3. The pharmaceutical composition of claim 2, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine and viloxazine or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 1, wherein the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxin, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 1, wherein the NRI is reboxetine or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 1, wherein the NRI is atomoxetine or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 1, wherein the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, sulthiame or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of claim 7, wherein the CAI is acetazolamide or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 6, wherein atomoxetine or a pharmaceutically acceptable salt thereof is present in an amount of about 20 to about 200 mg.

10. The pharmaceutical composition of claim 9, wherein atomoxetine or a pharmaceutically acceptable salt thereof is present in an amount of about 25 to about 100 mg.

11. The pharmaceutical composition of claim 8, wherein acetazolamide is present in an amount of about 150 mg to about 750 mg.

12. The pharmaceutical composition of claim 11, wherein acetazolamide is present in an amount of about 500 mg.

13. The pharmaceutical composition of claim 11, wherein the acetazolamide or a pharmaceutically acceptable salt thereof is present in an amount of about 250 mg.

14. The pharmaceutical composition of claim 1, wherein the NRI and CAI are formulated in separate compositions.

15. The pharmaceutical composition of claim 1, wherein the NRI and CAI are formulated in a single composition.

16. The pharmaceutical composition of claim 15, wherein the single composition is an oral dosage form.

17. The pharmaceutical composition of claim 16, wherein the oral administration form is a syrup, pill, tablet, lozenge, capsule or patch.

18. A pharmaceutical composition described in any one of claims 1 to 17, wherein the condition associated with central hypoventilation is obesity hypoventilation syndrome (OHS) or obesity-related sleep hypoventilation (ORSH).

19. The pharmaceutical composition of claim 18, wherein the condition associated with central hypoventilation is obesity hypoventilation syndrome (OHS).

20. The pharmaceutical composition of claim 18, wherein the condition associated with central hypoventilation is obesity-related sleep hypoventilation (ORSH).

21. The pharmaceutical composition of claim 1, which is administered daily.

22. The pharmaceutical composition of claim 21, administered twice daily.

23. A norepinephrine reuptake inhibitor (NRI) and a carbonic anhydrase inhibitor (CAI) for use in treating a subject having a condition associated with central hypoventilation.

24. A therapeutic combination of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a carbonic anhydrase inhibitor (CAI) for use in treating a subject having a condition associated with central hypoventilation.