Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F5/00—Orthopaedic methods or devices for non-surgical treatment of bones or joints; Nursing devices ; Anti-rape devices
  • A61F5/56—Devices for preventing snoring
  • A61F5/566—Intra-oral devices
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/4035—Isoindoles, e.g. phthalimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention provides methods of treating pharyngeal airway collapse (e.g., sleep apnea) by administering a norepinephrine reuptake inhibitor (NRI) in combination with mandibular advancement device (MAD) therapy.
• pharyngeal airway collapse e.g., sleep apnea
• NRI norepinephrine reuptake inhibitor
• MAD mandibular advancement device
• OSA Obstructive Sleep Apnea
• One aspect of the present invention provides a method of treating a subject having a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof an effective amount of a norepinephrine reuptake inhibitor (NRI) in combination with mandibular advancement device (MAD) therapy.
• NRI norepinephrine reuptake inhibitor
• MAD mandibular advancement device
• the NRI is a norepinephrine selective reuptake inhibitor (NSRI).
• the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daledalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof.
• the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of amitriptiline, amoxapine, bupropion, ciclazindol, desipramine, desvenlafaxine, dexmethilphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protryptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharmaceutically acceptable salt thereof.
• NRI norepinephrine non-selective reuptake inhibitor
• the NRI is selected from the group consisting of atomoxetine or a pharmaceutically acceptable salt thereof and reboxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is reboxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering a muscarinic receptor antagonist (MRA) to the subject.
• MRA muscarinic receptor antagonist
• the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, or a pharmaceutically acceptable salt thereof.
• the MRA is selected from the group consisting of anisotropine, benztropine, biperiden, clidinium, cycrimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof.
• the MRA is oxybutynin or a pharmaceutically acceptable salt thereof.
• the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.
• the method further comprises administering a hypnotic to the subject.
• the hypnotic is selected from the group consisting of trazodone, zolpidem, eszopiclone, benzodiazepines, gabapentin, tiagabine, and xyrem.
• the hypnotic is trazodone.
• the hypnotic is zolpidem.
• the atomoxetine or pharmaceutically acceptable salt thereof is administered at a dose of from about 20 to about 150 mg.
• the atomoxetine or pharmaceutically acceptable salt thereof is administered at a dose of from about 25 to about 100 mg. In some embodiments, the oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 1 to about 15 mg. In some embodiments, the oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 2 mg to about 10 mg. In some embodiments, the (R)- oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 0.5 to about 10 mg. In some embodiments, the (R)-oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 5 mg.
• the NRI, MRA and/or hypnotic are administered in a single composition.
• the single composition is an oral administration form.
• the oral administration form is a syrup, pill, tablet, troche, capsule, or patch.
• the single composition is in an immediate release formulation.
• the single composition is in an immediate release formulation and the NRI is administered at a dose of from about 20 to about 150 mg and the MRA is administered at a dose of from about 1 to about 15 mg.
• the single composition is in an immediate release formulation and the NRI is administered at a dose of from about 25 to about 100 mg and the MRA is administered at a dose of from about 2 to about 10 mg.
• the single composition is in an immediate release formulation and the NRI is administered at a dose of from about 20 to about 50 mg and the MRA is administered at a dose of from about 2 to about 10 mg. In some embodiments, the single composition is in an immediate release formulation and the NRI is administered at a dose of from about 40 to about 80 mg and the MRA is administered at a dose of from about 2 to about 10 mg. In some embodiments, the single composition is in a controlled release formulation. In some embodiments, the single composition is in a controlled release formulation and the NRI is administered at a dose of from about 20 to about 150 mg and the MRA is administered at a dose of from about 0.5 to about 10 mg.
• the single composition is in a controlled release formulation and the NRI is administered at a dose of from about 25 to about 100 mg and the MRA is administered at a dose of from about 2 to about 6 mg. In some embodiments, the single composition is in a controlled release formulation and the NRI is administered at a dose of from about 20 to about 50 mg and the MRA is administered at a dose of from about 2 to about 6 mg. In some embodiments, the single composition is in a controlled release formulation and the NRI is administered at a dose of from about 40 to about 80 mg and the MRA is administered at a dose of from about 2 to about 6 mg. In some embodiments, the single composition further comprises a pharmaceutically acceptable carrier.
• the single composition is administered prior to the start of the mandibular advancement device (MAD) therapy. In some embodiments, the single composition is administered concurrently with the mandibular advancement device (MAD) therapy.
• the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway collapse is snoring. In some embodiments, the condition associated with pharyngeal airway collapse is simple snoring. In some embodiments, the subject is in a non- fully conscious state. In some embodiments, the non- fully conscious state is sleep.
• Another aspect of the invention provides a norepinephrine reuptake inhibitor (NRI) and a mandibular advancement device (MAD), for use in treating a subject having a condition associated with pharyngeal airway collapse.
• Some embodiments further comprise a muscarinic receptor antagonist (MRA) and/or a hypnotic.
• MRA muscarinic receptor antagonist
• Another aspect of the invention provides a therapeutic combination comprising (a) a pharmaceutical composition comprising a norepinephrine reuptake inhibitor (NRI) and a pharmaceutically acceptable carrier, and (b) a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway collapse.
• the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA) and/or a hypnotic.
• MRA muscarinic receptor antagonist
• Another aspect of the invention provides atomoxetine or a pharmaceutically acceptable salt thereof, oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof, and a mandibular advancement device (MAD), for use in treating a subject having a condition associated with pharyngeal airway collapse.
• oxybutynin e.g., (R)-oxybutynin
• MAD mandibular advancement device
• Another aspect of the invention provides atomoxetine or a pharmaceutically acceptable salt thereof, a hypnotic (e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof), and a mandibular advancement device (MAD), for use in treating a subject having a condition associated with pharyngeal airway collapse.
• a hypnotic e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof
• MAD mandibular advancement device
• Another aspect of the invention provides atomoxetine or a pharmaceutically acceptable salt thereof, oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof, and a mandibular advancement device (MAD), for use in treating sleep apnea.
• oxybutynin e.g., (R)-oxybutynin
• MAD mandibular advancement device
• Another aspect of the invention provides atomoxetine or a pharmaceutically acceptable salt thereof, oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof, and a mandibular advancement device (MAD), for use in treating snoring.
• oxybutynin e.g., (R)-oxybutynin
• MAD mandibular advancement device
• Another aspect of the invention provides atomoxetine or a pharmaceutically acceptable salt thereof, a hypnotic (e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof), and a mandibular advancement device (MAD), for use in treating sleep apnea.
• a hypnotic e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof
• MAD mandibular advancement device
• Another aspect of the invention provides atomoxetine or a pharmaceutically acceptable salt thereof, a hypnotic (e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof), and a mandibular advancement device (MAD), for use in treating snoring.
• a hypnotic e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof
• MAD mandibular advancement device
• FIG. 1 is a graphic illustration of an obstructive apnea.
• the top channel shows the electroencephalogram (EEG) pattern of sleep.
• the next channel represents airflow.
• the next three channels show ventilator effort by movements of the rib cage and abdomen and changes in esophageal pressure, all of which reflect a respiratory effort against an occluded upper airway.
• the last channel indicates oxyhemoglobin saturation.
• FIG. 2 is an overview of the MandADO study design described herein.
• the pharyngeal airway region has no bone or cartilage support, and it is held open by muscles. When these muscles relax during sleep, the pharynx can collapse resulting in cessation of airflow. As shown in Fig. 1, ventilatory effort continues and increases in an attempt to overcome the obstruction, shown by an increase in esophageal pressure change. Rib cage and abdominal movements are in the opposite direction as a result of the diaphragm contracting against an occluded airway, forcing the abdominal wall to distend out and the chest wall to cave inward.
• Fig. 1 is a graphic illustration of an obstructive apnea.
• the top channel shows the electroencephalogram (EEG) pattern of sleep.
• the next channel represents airflow.
• the next three channels show ventilatory effort by movements of the rib cage and abdomen and changes in esophageal pressure, all of which reflect a respiratory effort against an occluded upper airway.
• the last channel indicates oxyhemoglobin saturation.
• OSA When a stringent definition of OSA is used (an AHI of >15 events per hour or AHI >5 events per hour with daytime sleepiness), the estimated prevalence is approximately 15 percent in males and 5 percent in females. An estimated 30 million individuals in the United States have OSA, of which approximately 6 million have been diagnosed. The prevalence of OSA in the United States appears to be increasing due to aging and increasing rates of obesity. OSA is associated with major comorbidities and economic costs, including: hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue/lost productivity. (Young, T. et al., WMJ 2009; 108:246; Peppard, PE. et al., Am J Epidemiol 2013; 177:1006.)
• CPAP continuous positive airway pressure
• the methods described herein include the treatment of disorders associated with pharyngeal airway muscle collapse during sleep.
• the disorder is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring).
• the methods include administering a therapeutically effective amount of a norepinephrine reuptake inhibitor (NRI) in combination with mandibular advancement device (MAD) therapy, to a subject who is in need of, or who has been determined to be in need of, such treatment.
• NRI norepinephrine reuptake inhibitor
• MAD mandibular advancement device
• the treatment further comprises administering a muscarinic receptor antagonist (MRA) and/or a hypnotic.
• MRA muscarinic receptor antagonist
• the methods include administering a therapeutically effective amount of (i) atomoxetine or a pharmaceutically acceptable salt thereof and (ii) oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof, in combination with mandibular advancement device (MAD) therapy, to a subject who is in need of, or who has been determined to be in need of, such treatment.
• MRA muscarinic receptor antagonist
• the methods include administering a therapeutically effective amount of (i) atomoxetine or a pharmaceutically acceptable salt thereof and (ii) a hypnotic (e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof), in combination with mandibular advancement device (MAD) therapy, to a subject who is in need of, or who has been determined to be in need of, such treatment.
• a therapeutically effective amount of i) atomoxetine or a pharmaceutically acceptable salt thereof and (ii) a hypnotic (e.g., trazodone or zolpidem or a pharmaceutically acceptable salt thereof), in combination with mandibular advancement device (MAD) therapy, to a subject who is in need of, or who has been determined to be in need of, such treatment.
• MAD mandibular advancement device
• pharyngeal airway collapse during sleep results in snoring and/or an interruption in breathing (apnea or hypopnea), arousal from sleep, and reduced oxygenation (hypoxemia); thus, a treatment can result in a reduction in snoring, apneas/hypopneas, sleep fragmentation, and hypoxemia.
• Administration of a therapeutically effective amount of a compound described herein for the treatment of a subject with OSA may result in decreased AHI.
• Measurement of OSA disease and symptoms may be, for example, by polysomnography (PSG).
• an “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a condition associated with pharyngeal airway collapse, e.g., to treat sleep apnea or snoring.
• the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
• An effective amount encompasses therapeutic and prophylactic treatment.
• An effective amount can be administered in one or more administrations, applications or dosages.
• the the NRI, MRA and/or hypnotic can be administered from one or more times per day to one or more times per week; including once every other day.
• the the NRI, MRA and/or hypnotic are administered daily.
• the the NRI, MRA and/or hypnotic are administered daily before sleep time, e.g., immediately before sleep time or 15-60 minutes before sleep time.
• the the NRI, MRA and/or hypnotic are administered daily before placing the MAD in the subject, e.g., immediately before placing the MAD or 15-60 minutes before placing the MAD.
• the NRI, MRA and/or hypnotic are administered daily concurrently with the MAD already placed in the subject.
• the NRI, MRA and/or hypnotic are administered as a single composition.
• the compositions are administered orally.
• treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments.
• 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 means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
• the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
• the terms “subject” and “patient” are used interchangeably.
• the terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), specifically a "mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more specifically a human.
• a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
• a primate e.g., a monkey, chimpanzee and a human
• the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.
• a farm animal e.g., a horse, cow, pig or sheep
• a pet e.g., a dog, cat, guinea pig or rabbit.
• the subject is a human.
• “pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
• “Pharmaceutically acceptable salts” includes “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts.” “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malic 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, and the like.
• inorganic acids such as hydrochloric
• “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 the ammonium, potassium, sodium, calcium, and magnesium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including 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, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
• basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, triprop
• organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
• isopropylamine diethylamine
• ethanolamine trimethylamine
• dicyclohexylamine choline
• caffeine a compound that has a wide range of properties that has a wide range of properties that has a wide range of properties that has a wide range of properties of organic bases.
• exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
• unit dosage form is defined to refer to the form in which the compound is administered to a subject.
• the unit dosage form can be, for example, a pill, capsule, or tablet.
• the unit dosage form is a capsule.
• the unit dosage form is a tablet.
• solid dosage form means a pharmaceutical dose(s) in solid form, e.g. tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.
• NRIs Norepinephrine Reuptake Inhibitors
• MRAs Muscarinic Receptor Antagonists
• NRIs norepinephrine reuptake inhibitors
• exemplary norepinephrine reuptake inhibitors include the selective NRIs, e.g., amedalin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daledalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), talsupram (Lu 5-005), tandamine (AY- 23,946), viloxazine (Vivalan); and the non-selective NRIs, e.g., amitriptiline, amoxapine, bupropion, ciclazindol, desipramine, desvenlafaxine, dexmethilphenidate,
• the NRI is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is reboxetine or a pharmaceutically acceptable salt thereof.
• Atomoxetine is the generic name of the pharmaceutical substance with the chemical name (-)-A-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 may be atomoxetine hydrochloride.
• the methods include administering a dose of from about 20 mg to about 150 mg of atomoxetine or a pharmaceutically acceptable salt thereof (or a dose equivalent of another NRI).
• the dose of atomoxetine or a pharmaceutically acceptable salt thereof is from about 25 mg to about 100 mg.
• the dose of atomoxetine or pharmaceutically acceptable salt thereof is from about 40 mg to about 80 mg.
• the dose of atomoxetine or pharmaceutically acceptable salt thereof is from about 20 mg to about 50 mg.
• the dose of atomoxetine or a pharmaceutically acceptable salt thereof is from about 50 mg to about 100 mg.
• the dose of atomoxetine or pharmaceutically acceptable salt thereof is about 40 mg.
• the dose of atomoxetine or pharmaceutically acceptable salt thereof is about 80 mg.
• exemplary muscarinic receptor antagonists include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, and pharmaceutically acceptable salts thereof, which have activity on the M2 receptor.
• exemplary antimuscarinics include anisotropine, benztropine, biperiden, clidinium, cycrimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, and pharmaceutically acceptable salts thereof.
• the muscarinic receptor antagonist is oxybutynin or (R)- oxybutynin, or a pharmaceutically acceptable salt thereof.
• (R)-oxybutynin refers to the (R)-oxybutynin stereoisomer substantially free of other stereoisomers of oxybutynin.
• the muscarinic receptor antagonist is fesoterodine.
• Oxybutynin is the generic name for the pharmaceutical substance with the chemical name 4-diethylamino-2-butynylphenylcyclohexylglycolate or 4-(diethylamino)but-2-ynyl 2- cyclohexyl-2 -hydroxy-2 -phenylacetate, and its pharmaceutically acceptable salts.
• oxybutynin may be a racemic mixture of R- and S- enantiomers, or an isolated enantiomer, e.g., the R-enantiomer.
• oxybutynin may be oxybutynin chloride or (R)-oxybutynin chloride.
• the dose of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof may be from about 0.5 mg to about 25 mg (or a dose equivalent thereof of another MRA), or in some embodiments, from about 2 mg to about 15 mg.
• the dose of oxybutynin or pharmaceutically acceptable salt thereof is from about 2.5 mg to about 10 mg, e.g., 5 mg.
• the dose of (R)- oxybutynin or pharmaceutically acceptable salt thereof is from about 0.5 mg to about 5 mg, e.g., 2.5 mg.
• the dose of oxybutynin or (R) -oxybutynin or pharmaceutically acceptable salt thereof is from about 1 mg to about 5 mg.
• Exemplary hypnotics include benzodiazepines, e.g., temazepam, brotizolam, flurazepam, nitrazepam, and triazolam; cyclopyrrolone hypnotics, e.g., zolpidem, zopiclone, and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; and tiagabin and pharmaceutically acceptable salts thereof.
• benzodiazepines e.g., temazepam, brotizolam, flurazepam, nitrazepam, and triazolam
• cyclopyrrolone hypnotics e.g., zolpidem, zopiclone, and eszopic
• the hypnotic is trazodone or a pharmaceutically acceptable salt thereof. In some embodiments, the hypnotic is zolpidem or a pharmaceutically acceptable salt thereof.
• Mandibular Advancement Devices including mandibular advancement splints (MAS) or mandibular repositioning appliances (MRA), prevent upper airway collapse by protruding the mandible forward, thus altering the jaw and tongue position.
• MAS mandibular advancement splints
• MRA mandibular repositioning appliances
• Both video endoscopy and magnetic resonance imaging (MRI)-guided studies have determined that these devices predominantly increase the volume of the airway at the level of the velopharynx. The airway space is mostly enlarged laterally, thought to be due to traction on soft tissue connections between the pharynx and the mandibular ramus.
• MADs also improve the strength and rigidity of the airway by increasing the muscle activity of the tongue and other muscles of the airway.
• the MAD is a boil and bite MAD, a one-piece custom MAD, or a two-piece custom MAD.
• the MAD is a boil and bite MAD.
• Non-adjustable, “boil and bite” MADs can be obtained from pharmacies and on various websites. They are constructed of a thermoplastic material that becomes moldable when warmed by immersion in hot water. The user takes a mold of their teeth by biting into the softened material that then sets on cooling.
• the MAD is a custom made MAD.
• Custom made MADs are constructed in a lab using dental impressions.
• Custom made MADs can be a one-piece or an adjustable two-piece device.
• the MAD is a one-piece custom MAD.
• Upper and lower dental splints are fused in the one-piece device (monobloc).
• most of these appliances are a bespoke dentally produced device, “semi-bespoke” MAD, which require no specialist dental input, exist.
• the MAD is a two-piece custom MAD. Adjustable two-piece devices come in separate upper and lower plates. Construction requires additional specialist jaw articulation and is more expensive. Serially titrated mandibular protrusion is thought to increase treatment success by allowing gradual adaptation to optimal protrusion. The ability to titrate protrusion according to efficacy and tolerance is an advantage of adjustable MAD (aMAD).
• aMAD adjustable MAD
• fMAD fixed MAD
• fMAD fixed MAD
• the MAD to be used in the methods of the present invention can vary depending on the subject’s needs and body/mouth/teeth structure.
• compositions comprising a norepinephrine reuptake inhibitor (NRI) and a muscarinic receptor antagonist (MRA) and/or a hypnotic, as active ingredients.
• the active ingredients can be in a single composition or in separate compositions.
• the pharmaceutical compositions include (i) atomoxetine or a pharmaceutically acceptable salt thereof and (ii) oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof, as active ingredients.
• compositions typically include a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
• oxybutynin is oxybutynin chloride.
• (R)-oxybutynin is (R)-oxybutynin chloride.
• atomoxetine is atomoxetine hydrochloride.
• compositions are typically formulated to be compatible with its intended route of administration.
• routes of administration include systemic oral or transdermal administration, as well as sublingual administration, e.g., via tablet or spray.
• oral compositions generally include an inert diluent or an edible carrier.
• the active compound(s) can be incorporated with excipients and used in the form of pills, tablets, troches, or capsules, e.g., gelatin capsules.
• Oral compositions can also be prepared using a fluid carrier.
• a composition according to the present invention may be a unit dosage form.
• a composition according to the present invention may be a solid dosage form, e.g., a tablet or capsule.
• compositions can be included as part of the composition.
• the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
• a lubricant such as magnesium stearate or Sterotes
• a glidant
• Systemic administration of the compounds as described herein can also be by transdermal means, e.g., using a patch, gel, or lotion, to be applied to the skin.
• transdermal administration penetrants appropriate to the permeation of the epidermal barrier can be used in the formulation. Such penetrants are generally known in the art.
• the active compounds can formulated into ointments, salves, gels, or creams as generally known in the art.
• the gel and/or lotion can be provided in individual sachets, or via a metered-dose pump that is applied daily; see, e.g., Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.
• the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• a controlled release formulation including implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
• Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc.
• Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
• compositions can be included in a container, pack, or dispenser together with instructions for administration or use in a method described herein.
• the pharmaceutical composition is for use in treating a condition associated with pharyngeal airway collapse.
• the condition is sleep apnea (e.g., OSA) or snoring (e.g., simple snoring).
• a pharmaceutical composition comprising atomoxetine or a pharmaceutically acceptable salt thereof and cannabidiol or a pharmaceutically acceptable salt thereof, and optionally oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof for use in treating sleep apnea (e.g., OSA) or snoring (e.g., simple snoring).
• sleep apnea e.g., OSA
• snoring e.g., simple snoring
• a norepinephrine reuptake inhibitor (NRI) and a mandibular advancement device (MAD), for use in treating a subject having a condition associated with pharyngeal airway collapse
• the combination for use further comprises a muscarinic receptor antagonist (MRA).
• MRA muscarinic receptor antagonist
• the combination for use further comprises a hypnotic.
• a therapeutic combination comprising (a) a pharmaceutical composition comprising a norepinephrine reuptake inhibitor (NRI) and a pharmaceutically acceptable carrier, and (b) a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway collapse.
• the combination for use further comprises a muscarinic receptor antagonist (MRA).
• MRA muscarinic receptor antagonist
• the combination for use further comprises a hypnotic.
• NRI is atomoxetine or a pharmaceutically acceptable salt thereof
• MRA is oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof.
• Example 1 Randomized, Double-Blind, Multiple-Dose 2-Period Crossover Study to Evaluate the Efficacy and Safety of AD036 (Atomoxetine+Oxybutynin) plus Mandibular Advancement Device vs. AD036 Alone in OSA patients with Suboptimal Response to Mandibular Advancement Device. (MandADO) [0074] Rationale
• AD036 a combination of atomoxetine and oxybutynin, is a drug combination under development for the treatment of obstructive sleep apnea (OSA).
• OSA obstructive sleep apnea
• the primary mechanism of action of AD036 is thought to be increased pharyngeal muscle stiffness and responsiveness.
• MAD Mandibular advancement device
• MandADO study is designed to assess the safety and efficacy for OSA of combination treatment with AD036 and MAD in patients with inadequate response to MAD alone.
• OSA sleep disorders as a major public health burden.
• OSA is the most common and serious of these sleep disorders and affects approximately 20 million people in the United States (US), with approximately 13% of men and 6% of women affected (1).
• OSA is characterized by repetitive collapse or ‘obstruction’ of the pharyngeal airway during sleep, manifestingas repetitive episodes of hypopnea (i.e., shallow breathing) or apnea (i.e., paused breathing). These episodes of hypopnea or apnea may lead to arousal from sleep, sleep fragmentation, excessive daytime sleepiness, and/or neuropsychological impairment.
• OSA Long-term, OSA is associated with increased mortality and a number of adverse cardiovascular, neurocognitive, metabolic, and daytime functioning consequences (6-15).
• CPAP continuous positive airway pressure
• CPAP continuous positive airway pressure
• CPAP continuous positive airway pressure
• a device that mechanically maintains an open airway.
• efficacy of CPAP is often satisfactory when the device is used, many, perhaps most, patients find these devices uncomfortable or intolerable, and most estimates indicate that fewer than 50% of patients prescribed CPAP use it more than 4 hours per night, if at all (16).
• Mandibular advancement devices are an alternative to CPAP, but patients may have a suboptimal treatment response.
• Current pharmacologic therapies are limited to treatment of excessive daytime sleepiness from OSA.
• Figure 2 provides an overview of the study design.
• the MandADO study is a randomized, double-blind, placebo-controlled, 2-period crossover study in patients with inadequate response to MAD alone. Patients with elevated residual AHI or subjective reports of EDS or snoring on current custom-made MAD therapy provided by a dental or maxillofacial specialist are eligible for screening if there is clinical suspicion or evidence of elevated residual AHI. Participants will undergo initial pre-screening to determine potential study eligibility or exclusionary factors, followed by screening Visit 1 for patients who remain eligible. Only participants who subsequently meet all non-PSG enrollment criteria at Visit 1 are eligible for a screening PSG at Visit 2. The screening PSG is conducted with the MAD in place. Patients are eligible for enrollment in the study if the residual AHI (4%) with the MAD is >10 and all other enrollment criteria are met. [0089] Enrolled patients will be randomized for 1-week periods each the following two study treatments:
• Period 1 MAD use nightly on all nights, combined with a low-dose run-in period of AD036 on Days 1-3 consisting of 40 mg atomoxetine and 5 mg oxybutynin, followed by a full dose period of AD036 on Days 4-7 consisting of 80 mg atomoxetine and 5 mg oxybutynin (all doses over-encapsulated).
• Period 2 MAD used nightly on all nights, combined with 2 matching placebo capsules.
• Study drug for Period 1 is dispensed at Visit 2 prior to patient discharge.
• the study drug consists of two different tablets, one of each of which is taken each night at the patient’s usual bedtime. Following 6 (up to 8) days of at-home dosing, patients return with the remaining dispensed study drug for PSG at Visit 3, with dosing at lights out from that drug supply. The morning after each PSG the symptom questionnaires are administered, and study drug for the second crossover period is dispensed. Patients are instructed not to begin taking the study drug for the second period until after the 1-week washout period.
• the site contacts that patient by phone to initiate dosing of the second crossover period. Similar to Period 1, following 6 (up to 8) days of at-home dosing, patients return with the remaining dispensed study drug for PSG at Visit 4, with dosing of study drug at Visit 4 from the patient’s Period 2 supply.
• Adverse event and concomitant medication information is collected at each study site visit and two weeks after Visit 4 during the End-of-Study call. The End-of-Study call with the patient will take place 2 weeks following the end of study drug dosing.
• AHI(4%) is 8-9 on initial PSG, can be repeated and average AHI(4%) used
• BMI between 18.5 and 40.0 kg/m 2 , inclusive, at the pre-PSG screening visit 6. If male and sexually active with female partner(s) of childbearing potential, participant must agree, from Study Day 1 through 1 week after the last dose of study drug, to practice the protocol specified contraception.
• WOCBP childbearing potential
• the participant must be either postmenopausal (defined as age > 55 years with no menses for 12 or more months without an alternative medical cause) or permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Participant must be able to understand the nature of the study and must have the opportunity to have any questions answered.
• Clinically significant cardiac disease e.g., rhythm disturbances, coronary artery disease or cardiac failure
• hypertension requiring more than 2 medications for control (combination medications are considered as 1 medication for this purpose).
• CYP3A4 cytochrome P450 3A4
• CYP2D6 strong cytochrome P450 2D6
• MAOI monoamine oxidase inhibitors
• Hepatic transaminases >2X the upper limit of normal (ULN), total bilirubin >1.5X ULN (unless confirmed Gilbert syndrome), estimated glomerular filtration rate ⁇ 60 ml/min.
• Participants should refrain from consumption of any nutrients known to modulate CYP enzyme activity (e.g., grapefruit or grapefruit juice, pomelo juice, star fruit, pomegranate, and Seville or Moro [blood] orange products) within 72 hours before the first dose of study drug and during the study.
• nutrients known to modulate CYP enzyme activity e.g., grapefruit or grapefruit juice, pomelo juice, star fruit, pomegranate, and Seville or Moro [blood] orange products
• Diet should be generally stable during the study, e.g., new diet programs should not be initiated.
• AD036 or placebo is taken in each crossover period, in combination with MAD.
• AD036 consists of one over-encapsulated atomoxetine (40 mg days 1-3, 80 mg days 4-7) and one over-encapsulated oxybutynin 5 mg. Table 2 shows the dosage formulation and routes of administration. [0097] Table 2.
• Concomitant therapy with the following medications listed below is disallowed.
• medication that is typically used as-needed for symptomatic conditions e.g., occasional use of a sleep aid
• the medication should not be used for at least one week prior to the first study PSG and for the duration of the study.
• Medications not allowed include, MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline) [MAOIs are contraindicated for use with Atomoxetine; Lithium; Cannabinoids; Selective Serotonin Reuptake Inhibitors (e.g., paroxetine); Selective Norepinephrine Reuptake Inhibitors (e.g., duloxetine); Norepinephrine Reuptake Inhibitors (e.g., reboxetine); Alpha-1 antagonists (e.g., tamsulosin); Tricyclic antidepressants (e.g., desipramine); CYP2D6 inhibitors; Strong CYP3A4 inhibitors (e.g., ketoconazole); Benzodiazepines and other anxiolytics; Opioids; Sedatives and sedative-hypnotics, including nonbenzodiazepine “Z-drugs” (zolpi
• Medications that do not have substantial effects on the central nervous system (CNS), respiration, or muscle activity are generally allowed including, but not necessarily limited to, the following drugs and drug classes: Antihypertensives (angiotensin-converting-enzyme [ACE] /angiotensin II receptor blocker [ARB] inhibitors, calcium channel blockers, hydrochlorothiazide, etc.); Statins; Proton pump inhibitors and histamine I12 receptor blockers; Over-the-counter (OTC) antacids; Non-sedating antihistamines (e.g., cetirizine, loratadine); Acetaminophen; Laxatives; Erectile dysfunction drugs; Inhaled corticosteroids (e.g., fluticasone); Anti-diabetics; Ocular hypotensives and other ophthalmics (e.g., timolol);
• Antihypertensives angiotensin-converting-enzyme [ACE]
• Hormonal therapy e.g., estrogen replacement or anti-estrogens
• hormonal contraceptives e.g., Thyroid medications; Anticoagulants; Osteoporosis drugs.
• Standard overnight PSG recording and data interpretation will be performed in accordance with the American Academy of Sleep Medicine (AASM) scoring manual. Participants will be instrumented with standard PSG electrodes. Time of lights out will be established according to the participants’ habitual schedule and kept constant across the PSG study nights. The participants will be given 8 hours of time-in bed.
• AASM American Academy of Sleep Medicine
• Participants should be actively encouraged to spend at least 1/3 of the night in the supine position and at least 1/3 of the night in the lateral position on each night of study.
• Safety monitoring will be guided by the established safety profiles of atomoxetine and oxybutynin, and MADs. Safety assessments will include physical examinations, measurement of vital signs, monitoring and recording of AEs, SAEs, and pregnancies, recording of study or treatment discontinuations. Effects on OSA and sleep parameters (e.g., sleep time and sleep stages) will also be monitored by PSG. Table 3. Schedule of Activities.
• Vital signs include the following: seated blood pressure, pulse, respiratory rate; vital signs on PSG nights taken evening of admission to PSG lab

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