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WO2007047576A1 - Traitements pharmacologiques contre des troubles du sommeil - Google Patents

Traitements pharmacologiques contre des troubles du sommeil Download PDF

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Publication number
WO2007047576A1
WO2007047576A1 PCT/US2006/040363 US2006040363W WO2007047576A1 WO 2007047576 A1 WO2007047576 A1 WO 2007047576A1 US 2006040363 W US2006040363 W US 2006040363W WO 2007047576 A1 WO2007047576 A1 WO 2007047576A1
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Prior art keywords
sleep
agents
antitussive
serotonin
apnea
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David W. Carley
Miodrag Radulovaski
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University of Illinois at Urbana Champaign
University of Illinois System
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University of Illinois at Urbana Champaign
University of Illinois System
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    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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

Definitions

  • the invention generally relates to methods for pharmacological treatment of breathing disorders and, more specifically, to administration of agents or compositions having antitussive activity for the alleviation of sleep apnea (central and obstructive) and other sleep-related breathing disorders.
  • sleep apnea is defined as an intermittent cessation of airflow at the nose and mouth during sleep.
  • apneas of at least 10 seconds in duration have been considered important; however, in most individuals, the apneas are 20-30 seconds in duration and may be as long as 2-3 minutes. While there is some uncertainty as to the minimum number of apneas that should be considered clinically important, by the time most individuals come to a doctor's attention they have at least 10 to 15 events per hour of sleep. Sleep apneas have been classified into three types: central, obstructive (the most common type), and mixed. In central sleep apnea, the neural drive to all respiratory muscles is transiently abolished.
  • obstructive sleep apneas airflow ceases despite continuing respiratory drive because of occlusion of the oropharyngeal airway.
  • Mixed apneas which consist of a central apnea followed by an obstructive component, are a variant of obstructive sleep apnea.
  • Obstructive sleep apnea syndrome has been identified in as many as 24% of working adult men and 9% of similar women, with peak prevalence in the sixth decade. Habitual heavy snoring, which is an almost invariant feature of OSAS, has been described in up to 24% of middle aged men, and 14% of similarly aged women, with even greater prevalence in older subjects.
  • a definitive event of obstructive sleep apnea syndrome is the occlusion of the upper airway, frequently at the level of the oropharynx. The resultant apnea generally leads to a progressive-type asphyxia until the individual is briefly aroused from the sleeping state, thereby restoring airway patency and airflow.
  • the most common manifestations are neuropsychiatric and behavioral disturbances that are thought to arise from the fragmentation of sleep and loss of slow-wave sleep induced by the recurrent arousal responses. Nocturnal cerebral hypoxia also may play an important role.
  • the most pervasive manifestation is excessive daytime sleepiness.
  • OSAS is now recognized as a leading cause of daytime sleepiness and has been implicated as an important risk factor for such problems as motor vehicle accidents.
  • Other related symptoms include, but are not limited to, intellectual impairment, memory loss, personality disturbances, and impotence.
  • the other major manifestations are cardiorespiratory in nature and are thought to arise from the recurrent episodes of nocturnal asphyxia.
  • Central sleep apnea is less prevalent as a syndrome than OSAS 3 but can be identified in a wide spectrum of patients with medical, neurological, and/or neuromuscular disorders associated with diurnal alveolar hypoventilation or periodic breathing.
  • a definitive event in central sleep apnea is transient abolition of central drive to the ventilatory muscles.
  • the resulting apnea leads to a primary sequence of events similar to those of OSAS.
  • Several underlying mechanisms can result in cessation of respiratory drive during sleep. First are defects in the metabolic respiratory control system and respiratory neuromuscular apparatus. Other central sleep apnea disorders arise from transient instabilities in an otherwise intact respiratory control system.
  • PAP positive airway pressure
  • an individual wears a tight- fitting plastic mask over the nose when sleeping.
  • the mask is attached to a compressor, which forces air into the nose creating a positive pressure within the patient's airways.
  • the principle of the method is that pressurizing the airways provides a mechanical "splinting" action that prevents airway collapse and therefore, obstructive sleep apnea.
  • acetazolamide a carbonic anhydrase inhibitor that produced variable improvement in individuals with primarily central apneas, but caused an increase in obstructive apneas
  • medroxyprogesterone a progestin that has demonstrated no consistent benefit in OSAS
  • theophylline a compound usually used for the treatment of asthma that may benefit patients with central apnea, but appears to be of no use in adult patients with obstructive apnea.
  • adenosine a ubiquitous compound within the body that is elevated in individuals with OSAS, has been shown to stimulate respiration and is somewhat effective in reducing apnea in an animal model of sleep apnea.
  • OSAS pharmacological treatment options
  • agents that stimulate brain activity or are opioid antagonists include agents that stimulate brain activity or are opioid antagonists.
  • central stimulants or opioid antagonists were thought to be a helpful treatment of OSAS.
  • doxapram a compound that stimulates the central nervous system and carotid body chemoreceptors, was found to decrease the length of apneas, but did not alter the average arterial oxygen saturation in individuals with obstructive sleep apnea.
  • the opioid antagonist naloxone which is known to stimulate ventilation, was only slightly helpful in individuals with obstructive sleep apnea.
  • agents such as angiotensin-converting enzyme (ACE) inhibitors may be of benefit in treating OSAS individuals with hypertension, but this may not be a viable treatment for OSAS itself.
  • ACE angiotensin-converting enzyme
  • Buspirone a specific serotonin subtype 1 receptor agonist that stimulates respiration (Mendelson et ah, 1990, Am. Rev. Respir. Dis., vol. 141, no. 6, pp. 1527-1530), has been shown to reduce apnea index in 4 of 5 patients with sleep apnea syndrome (Mendelson et al. (1991) J Clin. Psychopharmacol., vol. 11, no. 1, pp. 71-72) and to eliminate post-surgical apneustic breathing in one child (Wilken, B. et al. (1997) J Pediatr., vol. 130, no. 1, pp. 89-94).
  • serotonin antagonists also have been examined as drug treatments for sleep apnea in humans and in animal models of sleep related breathing disorders.
  • the serotonin antagonists ondansetron, R-zacopride, and mirtazapine all have been shown to reduce apnea frequency.
  • Mirtazapine was able to reduce apnea frequency by 50% in one study of OSAS patients, whereas ondansetron failed to demonstrate any effect in another study.
  • several patents have been issued describing the use of serotonin antagonists to treat OSAS (U.S. Patent Nos.
  • the invention is directed generally to providing pharmacological treatments for prevention or amelioration of sleep-related breathing disorders, such as sleep apnea syndrome.
  • the invention is specifically directed to methods for preventing or ameliorating sleep-related breathing disorders, methods comprising the step of administering an effective dose of an antitussive agent to a patient in need of a therapy for preventing or ameliorating sleep-related breathing disorders.
  • the present invention is also specifically directed to methods comprising the step of administering to a patient in need thereof a combination of antitussive agents for preventing or ameliorating sleep-related breathing disorders.
  • the combination of antitussive agents may be directed to a single receptor subtype or to more than one receptor subtype.
  • the invention is further directed to methods comprising the step of administering to a patient in need thereof an antitussive agent or a combination of antitussive agents in conjunction with a one or more serotonin receptor agonists for preventing or ameliorating sleep-related breathing disorders.
  • the antitussive agent or combination of antitussive agents may be directed to a single receptor subtype or to more than one receptor subtype and the combination of serotonin receptor agonists may be directed to a single serotonin receptor subtype or to more than one serotonin receptor subtype.
  • the invention is further directed to methods comprising the step of administering to a patient in need thereof an antitussive agent or a combination of antitussive agents in conjunction with a one or more cannabimimetic agents including cannabinoid receptor agonists, endocannabinoid breakdown inhibitors, or endocannabinoid transporter inhibitors for preventing or ameliorating sleep-related breathing disorders.
  • an antitussive agent or a combination of antitussive agents in conjunction with a one or more cannabimimetic agents including cannabinoid receptor agonists, endocannabinoid breakdown inhibitors, or endocannabinoid transporter inhibitors for preventing or ameliorating sleep-related breathing disorders.
  • the antitussive agent or combination of antitussive agents may be directed to a single receptor subtype or to more than one receptor subtype and the combination of cannabimimetic agents including cannabinoid receptor agonists, endocannabinoid breakdown inhibitors, or endocannabinoid transporter inhibitors may be directed to a single cannabinoid receptor subtype or to more than one cannabinoid receptor subtype.
  • the invention is also directed to methods comprising the step of administering to a patient in need thereof an antitussive agent or a combination of antitussive agents in conjunction with a serotonin reuptake inhibitor for preventing or ameliorating sleep- related breathing disorders.
  • the antitussive agent or combination of antitussive agents may be directed to a single receptor subtype or to more than one receptor subtype.
  • the invention is also directed to methods comprising the step of administering to a patient in need thereof an antitussive agent or a combination of antitussive agents in conjunction with a noradrenalin reuptake inhibitor for preventing or ameliorating sleep- related breathing disorders.
  • the antitussive agent or combination of antitussive agents may be directed to a single receptor subtype or to more than one receptor subtype.
  • the invention is also directed to methods comprising the step of administering to a patient in need thereof an antitussive agent or a combination of antitussive agents in conjunction with a combination of serotonin or noradrenalin reuptake inhibitors for preventing or ameliorating sleep-related breathing disorders.
  • the antitussive agent or combination of antitussive agents may be directed to a single receptor subtype or to more than one receptor subtype and the combination of serotonin or noradrenalin reuptake inhibitors may directed to either serotonin reuptake or to noradrenalin reuptake inhibitors, or to both serotonin and noradrenalin reuptake inhibitors.
  • Figure 1 shows the apnea-hypopnea index (AHI) ratio of four test subjects (D4, D12, D24, and D28) receiving capsazepine as compared to placebo.
  • AHI apnea-hypopnea index
  • the invention provides methods for preventing or suppressing sleep-related breathing disorders, and in particular central and obstructive sleep apneas, by administering one or a combination of antitussive agents.
  • the antitussive agents are administered according to the inventive methods either per se or in combination with other agents, including, but not limited to, serotonin receptor agonists, serotonin reuptake inhibitors, noradrenaline reuptake inhibitors, combined serotonin/noradrenalin reuptake inhibitors and cannabimimetic agents including cannabinoid receptor agonists and endocannabinoids, endocannabinoid breakdown inhibitors and endocannabinoid membrane transport inhibitors.
  • Effective treatments for preventing or suppressing sleep-related breathing disorders include systemic administration of an antitussive agent either alone or in combination.
  • the antitussive agent exhibits activity only in the peripheral nervous system and/or does not cross the blood-brain barrier.
  • Effective treatments for the prevention or suppression of sleep-related breathing disorders include, but are not limited to, systemic administration of antitussive agents, either alone or in combination with other agents.
  • buspirone acts systemically, serotonin subtype 1 receptors in the peripheral nervous system have not been shown to play a role in apnea genesis.
  • the modest apnea suppression induced by buspirone is a central nervous system effect that goes unopposed by serotonergic effects in the peripheral nervous system.
  • noradrenaline may also play a role in promoting hypoglossal motor neuron outputs to upper airway muscles (Fenik et al. (2004) Arch. Ital. Biol. 142: 237- 249).
  • This observation provides a rationale for inhibiting reuptake of both serotonin and noradrenalin, either using an SNRI or a combination of agents.
  • the key to efficacy of this approach against apnea is to combine the SNRI with at least one additional agent that will control the apnea-genic properties of serotonin in the peripheral nervous system.
  • Pharmacological treatments other than antitussive agents may also be combined with antitussive agents to enhance the therapeutic effects of the antitussive agent or agents activity.
  • antagonism of presynaptic ⁇ 2 adrenergic receptors located on brain stem serotonergic neurons (heteroreceptors) enhances serotonin release.
  • Selective receptor antagonists have been shown to block presynaptic and postsynaptic receptors (See e.g., de Boer, 1996, J. Clin. Psychiatry 57: 19-25; Devane, 1998, J. Clin. Psychiatry 59: 85-93; Puzantian, 1998, Am. J. Health Syst. Pharm. 55: 44-49).
  • Central serotonin release is increased with minimal adrenergic side effects, such as hypertension, if the affinity of such agents for central ⁇ 2 receptors is about 10 times higher than for peripheral ⁇ 2 receptors.
  • An individual diagnosed with a sleep related breathing disorder can be administered a compound, composition, or agent having any of the pharmacological activities disclosed herein, namely antitussive agents either alone or in combination with other agents as set forth herein, in an amount effective to prevent or suppress such sleep related breathing disorders.
  • the specific dose can be calculated as disclosed herein according to body weight or body surface. Further refinement of the calculations necessary to determine the appropriate dosage for treatment of sleep related breathing disorders is routinely made by those skilled in the appropriate arts without undue experimentation, again as disclosed herein.
  • Appropriate dosages can be determined through the use of established assays for setting dosages.
  • Routes of administration for the treatments disclosed herein can be any systemic or local means including, but not necessarily limited to, oral, inhalation, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, and the like.
  • Other forms of administration can also be employed, including, but not limited to, osmotic pumps, osmotic release dosage forms, timed release dosage forms, extended release dosage forms, slow release dosage forms, other depot forms of administration, and the like.
  • the pharmacological treatment can be administered to the person, patient, or subject in need of such treatment immediately before sleep or at any time prior to sleep with the appropriate slow release or delayed release dosage forms as required for the circumstances.
  • the effect of such pharmacological treatment will be the alleviation, amelioration, suspension, and/or cessation of the sleep related breathing disorder(s) of the person, patient, or subject.
  • serotonin receptor agonists such as, but not limited to, 8-OH-DPAT, almotriptan, sumatriptan, L694247 (2-[5-[3-(4- methylsulphonylamino)benzyl-l,2,4-oxadiazol-5-yl]- 33 lH-indol-3yl]ethanamine), tegaserod, buspirone, ainitidan, zaiospirone, ipsapirone, gepirone, zolmitriptan, elitriptan, naratriptan, frovatriptan, rizatriptan, 311C90, a-Me-5-HT, BW723C86 (l-[5(2- thienyhnethoxy)-lH-3-indolyl[propan-2-amine hydrochloride), MCPP (m- chlorophenylpiperazine), MK-212, buf
  • cannabimimetic agents such as, but not limited to, the cannabinoid CBl agonists arachidonyl-2'-chloroethylamide, arachidonylcyclopropylamide, and methanandamide; the cannabinoid CB2 agonists L- 759633, L-759656, JWH-133, HU-308 and palmitoylethanolamide; the endocannibinoids oleamide, linoleoylethanolamide, and oleoylethanolamide; the inhibitors of cannabinoid metabolism phenylmethylsulphonyl fluoride, palmitylsulphonyl fluoride, stearylsulphonyl fluoride, methyl arachidonyl fluorophosphonate, and 0-1887; the inhibitors of endocannibinoid membrane transport AM404, VDMIl and arvanil; the precursors or prodrags N-arachidon
  • serotonin and/or noradrenalin release promoters such, but not limited to phenoxybenzamine, phentolamine, tolazoline, terazosine, doxazosin, trimazosin, yohimbine, indoramin, ARC239, and prazosin, as well as others may be used in conjunction with antitussive agents to prevent or ameliorate sleep-related breathing disorders.
  • serotonin and/or noradrenalin reuptake inhibitors such, but not limited to fluoxetine, norfluoxetine, R(+)-fluoxetine, S(- )-fluoxetine, paroxetine, zimelidine, pirandarnine, fluvoxamine, citalopram escitalopram, ORG6582, p-bromo EXP561, LM5008, sertraline and other serotonin reuptake inhibitors; desipramine, nortriptyline, reboxetine, nisoxetine, atomoxetine, LYl 39603 (tomoxetine) and other noradrenalin reuptake inhibitors; venlafaxine, milnacipran, duloxetine, pregabalin, LY248686, strattera and other SNRIs, as well as others may be used in conjunction with antitussive agents to prevent or ameliorate sleep-related breathing disorders.
  • An individual diagnosed with a sleep-related breathing disorder is administered either a composition or agent having any of the foregoing pharmacological profiles in an amount effective to prevent or suppress such disorders.
  • the specific dose may be calculated according to such factors as body weight or body surface. Further refinement of the calculations necessary to determine the appropriate dosage for treatment of sleep- related breathing disorders is routinely made by those of ordinary skill in the art without undue experimentation. Appropriate dosages may be ascertained through use of established assays for determining dosages.
  • Routes of administration for the foregoing methods may be by any systemic means including oral, intraperitoneal, subcutaneous, intravenous, intramuscular, transdermal, or by other routes of administration.
  • Osmotic mini-pumps and timed-released pellets or other depot forms of administration may also be used.
  • compounds discussed above may contain a center of chirality.
  • agents may exist as different enantiomers of enantiomeric mixtures.
  • Use of any one enantiomer alone or contained within an enantiomeric mixture with one or more stereoisomers is contemplated by the present invention.
  • Routes of administration for the foregoing methods may be by any systemic means including oral, intraperitoneal, subcutaneous, intravenous, intramuscular, transdermal, inhaled, or by other routes of administration.
  • Osmotic mini-pumps and timed-released pellets or other depot forms of administration may also be used. The only limitation being that the route of administration results in the ultimate delivery of the pharmacological agent to the appropriate receptor.
  • antitussive agents include, but are not limited to RSD931, FK888, CP99994, SR48968, codeine, SRl 42801, SB235375, nociceptin/orphanin FQ, 15-HPETE, NADA, anandamide, lidocaine, benzonatate, mexiletine, NS 1619, furosemide, zafirlukast, HOE140, dihydrocodone, oxycodone, BW443C noscapine, dextromethorphan, SKF10047, baclofen, diphenhydramine, caramiphen, glaucine, cilomilast, RO-64-6198, NKP608, levchromkalim, BRL55834, icatibant, suplatast tosilate, epinastine, levodropropizine, and other antitussive agents ⁇ Trends in Pharm Sci 25: 569-576, 2004; Br J Pharmacol 117
  • Exemplary serotonin reuptake inhibitors include but are not limited to fluoxetine, norfluoxetine, R(+)- fluoxetine, S(-)-fluoxetine, paroxetine, zimelidine, pirandamine, fluvoxamine, citalopram escitalopram, ORG6582, p-bromo EXP561, LM5008, sertraline, and other serotonin reuptake inhibitors.
  • Exemplary noradrenalin reuptake inhibitors include but are not limited to desipramine, nortriptyline, reboxetine, nisoxetine, atomoxetine, LYl 39603 (tomoxetine), and other noradrenalin reuptake inhibitors.
  • Exemplary combined serotonin/noradrenalin reuptake inhibitors include but are not limited to venlafaxine, milnacipran, duloxetine, pregabalin, LY248686, strattera, and other combined serotonin/noradrenalin reuptake inhibitors.
  • cannabimimetic agents include, but are not limited to: cannabinoid receptor agonists including, but not limited to, arachidonyl-2'-chloroethylamide, arachidonylcyclopropylamide, and methanandamide L-759633, L-759656, JWH-133, HU- 308, and palmitoylethanolamide 9-tetrahydrocannabinol, 8-tetrahydrocannabinol, HU-210, CP55940, WTN55,212-2, O-1057, 2-arachidonoyl glycerol, anandamide, dexanabinol, nabilone, levonantradol, and N-(2-hydroxyethyl)hexadecanoamide; endocannabinoids including but not limited to oleamide, linoleoylethanolamide, and oleoylethanolamide; endocannabinoid breakdown inhibitors including but not limited to pheny
  • Intravenous administration of serotonin, 2-methyl-5-hydroxytryptamine or a high dose of ⁇ -methyl-5-hydroxytryptamine (a 5-hydroxytryptamine 2 receptor agonist) to anesthetized rats produced immediate apnea with a duration determined by the drug dose - an effect that was blocked by bilateral transection of the vagus nerves above the nodose ganglia (Yoshioka et at., 1992, J. Pharmacol. Exp. Ther. 260: 917-924).
  • Vagus sensory neurons with their cell bodies in the nodose ganglia, carry information to the brain from many receptors distributed throughout the lungs and chest wall.
  • Several antagonists have been shown to reduce the severity of chemoreflex apnea, but the primary neurotransmitters responsible for mediating the reflex remain unclear.
  • the antitussive agent levodropropizine has been shown to reduce the response of pulmonary vagal afferent fibers to chemoreflex stimulation by intravenous phenylbiguanide (Shams et al., 1996, Br. J Pharmacol. 117: 853-858). In concert, the duration of chemoreflex apnea was shortened by 50%.
  • the findings may account for blockade of vagus nerve-dependent reflexive apnea by antitussive agents.
  • vagus-nerve reflex apnea and sleep apnea are actually quite different.
  • Reflex apnea occurs because of an external stimulus ⁇ e.g., fluid or foreign body aspiration, irritant inhalation, or excessive lung inflation), both in awake and sleeping individuals, whereas sleep apnea occurs spontaneously and specifically during sleep.
  • An agent useful to block one of these forms of apnea is not necessarily capable nor would be expected to be capable of blocking the other form of apnea. Indeed, in some instances, a treatment for one form of apnea actually worsens the other form of apnea.
  • anti-histamines can effectively reduce reflexive apnea (Downs et al., 1995, Laryngoscope 105: 857-861), but they worsen sleep apnea (Ponsonby et ah, 1997, J. Paediatr. Child. Health 33: 317-323).
  • application of positive airway pressure produces immediate reflex apnea (Coon, 1994, J. Appl. Physiol. 76: 2546-2551), but treats sleep apnea (Haniffa et al., 2004, Cochrane Database Syst. Rev. 4: CD003531).
  • the presumptive mechanism for this effect is interference with the activation of vagus sensory neurons by endogenous stimuli.
  • a possible site of action for the apnea-inhibiting effects of antitussive agents is thought to be the nodose ganglia of the vagus nerve. More specifically, several studies have concluded that the apnea component of the Bezold-Jarisch reflex results from the activation of nodose ganglion afferent neurons (Jacobs & Comroe, 1971, Circ. Res. 29: 45-155; Yoshioka et al, 1992, Id, McQueen et al, 1998, J. Physiol.
  • antitussive agents singly and in combination, in freely moving animals in order to assess whether interfering with vagal reflexes by administration of antitussive agents can overcome exacerbation of spontaneous sleep-related apneas induced by apnea promoting agents such as serotonin.
  • the following Examples illustrate this testing of the effects of antitussive agent administration, and in particular the ability of these agents to cause suppression of spontaneous apneas during NREM and especially during REM sleep.
  • the following Examples also illustrate testing the effects of serotonin administration to induce spontaneous apnea expression, and the ability of antitussive agents to block this effect.
  • the following Examples further describe the pharmacological profiles best suited for single agents or combinations of agents to successfully prevent or ameliorate sleep-related breathing disorders, including: (a) a single agent or combination of agents having antitussive activity;
  • a single agent or combination of agents having antitussive activity in conjunction with an endocannabinoid breakdown inhibitor e.g. a fatty acid amide hydrolase inhibitor
  • a single agent or combination of agents having antitussive activity in conjunction with an endocannabinoid e.g. a fatty acid amide
  • sleep related breathing disorders can be effectively prevented or suppressed via systemic administration of:
  • agents that exhibit both the proper antagonistic and agonistic pharmacological profile i.e., an agent that is both an antitussive and an agonist/mimetic at the receptor subtypes set forth above.
  • an agent or combination of agents wherein the cannabimimetic agent is an inhibitor of cannabinoid breakdown; (i) an agent or combination of agents wherein the cannabimimetic agent is an inhibitor of endocannabinoid membrane transport; (j) an agent or combination of agents wherein the cannabimimetic agent is a cannabinoid precursor or prodrug or both; (k) an agent or combination of agents that have the ability to induce central nervous system serotonin and/or noradrenalin release and that exhibit antitussive activity; or (1) an agent or combination of agents that have the ability to induce central nervous system serotonin and/or noradrenalin release and exhibit only peripheral antitussive activity; or (m) an agent or combination of agents that have the ability to inhibit reuptake of serotonin and/or noradrenalin and that exhibit antitussive activity; or (n) an agent or combination of agents that have the ability to inhibit reuptake of serotonin and/or noradrenalin and
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount, or dose, of a compound that treats sleep- related breathing disorders.
  • a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant can be prepared together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant.
  • agent denotes a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.
  • composition refers to a composition comprising a pharmaceutically acceptable carrier, excipient, or diluent and a chemical compound, peptide, or composition as described herein that is capable of inducing a desired therapeutic effect when properly administered to a patient.
  • the term "therapeutically effective amount” refers to the amount of a pharmaceutical composition of the invention or a compound identified in a screening method of the invention determined to produce a therapeutic response in a mammal. Such therapeutically effective amounts are readily ascertained by one of ordinary skill in the art and using methods as described herein.
  • substantially pure means an object species that is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition).
  • a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent
  • a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in the composition.
  • the object species is purified to essential homogeneity (wherein contaminating species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
  • the term "patient” includes human and animal subjects. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
  • An individual diagnosed with a sleep-related breathing disorder is administered either a composition or agent having any of the foregoing pharmacological profiles in an amount effective to prevent or suppress such disorders.
  • the specific dose may be calculated according to such factors as body weight or body surface. Further refinement of the calculations necessary to determine the appropriate dosage for treatment of sleep- related breathing disorders is routinely made by those of ordinary skill in the art without undue experimentation. Appropriate dosages may be ascertained through use of established assays for determining dosages.
  • Routes of administration for the foregoing methods may be by any systemic means including oral, intraperitoneal, subcutaneous, intravenous, intramuscular, transdermal, or by other routes of administration.
  • Osmotic mini-pumps and timed-released pellets or other depot forms of administration may also be used.
  • Acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.
  • the pharmaceutical composition can contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic
  • compositions may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antibodies of the invention.
  • the primary vehicle or carrier in a pharmaceutical composition may be either aqueous or non-aqueous in nature.
  • a suitable vehicle or carrier may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • compositions can comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which may further include sorbitol or a suitable substitute therefor.
  • Pharmaceutical compositions of the invention can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (REMINGTON'S PHARMACEUTICAL SCIENCES, Id.) in the form of a lyophilized cake or an aqueous solution. Further, the compositions can be formulated as a lyophilizate using appropriate excipients such as sucrose.
  • Formulation components are present in concentrations that are acceptable to the site of administration. Buffers are advantageously used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.
  • compositions of the invention can be delivered parenterally.
  • the therapeutic compositions for use in this invention may be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the desired compound identified in a screening method of the invention in a pharmaceutically acceptable vehicle.
  • a particularly suitable vehicle for parenteral injection is sterile distilled water in which the compound identified in a screening method of the invention is formulated as a sterile, isotonic solution, appropriately preserved.
  • Preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that may provide controlled or sustained release of the product which may then be delivered via a depot injection.
  • an agent such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that may provide controlled or sustained release of the product which may then be delivered via a depot injection.
  • Formulation with hyaluronic acid has the effect of promoting sustained duration in the circulation.
  • Implantable drug delivery devices may be used to introduce the desired molecule.
  • compositions may be formulated for inhalation.
  • an antagonist or agonist as disclosed herein can be formulated as a dry powder for inhalation, or inhalation solutions may also be formulated with a propellant for aerosol delivery, such as by nebulization.
  • Pulmonary administration is further described in PCT Application No. PCT/US94/001875, which describes pulmonary delivery and is incorporated by reference.
  • compositions of the invention can be delivered through the digestive tract, such as orally.
  • the preparation of such pharmaceutically acceptable compositions is within the skill of the art.
  • An antagonist or agonist as disclosed herein that are to be administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized.
  • Additional agents can be included to facilitate absorption of the antagonist or agonist as disclosed herein. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.
  • a pharmaceutical composition can involve an effective quantity of an antagonist or agonist as disclosed herein in a mixture with non-toxic excipients that are suitable for the manufacture of tablets.
  • excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
  • sustained- or controlled-delivery formulations including formulations involving an antagonist or agonist as disclosed herein in sustained- or controlled-delivery formulations.
  • Techniques for formulating a variety of other sustained- or controlled-delivery means such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. See, for example, PCT Application No. PCT/US93/00829, which describes the controlled release of porous polymeric microparticles for the delivery of pharmaceutical compositions.
  • Sustained-release preparations may include semipermeable polymer matrices in the form of shaped articles, e.g.
  • Sustained release compositions may also include liposomes, which can be prepared by any of several methods known in the art. See e.g., Eppstein et ah, 1985, Proc. Natl. Acad. Sd. USA, vol. 82, pp. 3688-3692; European Patent No. 036,676; European Patent No. 088,046, and European Patent No. 143,949.
  • the pharmaceutical composition to be used for in vivo administration typically is sterile. In certain embodiments, this may be accomplished by filtration through sterile filtration membranes. In certain embodiments, where the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. Li certain embodiments, the composition for parenteral administration may be stored in lyophilized form or in a solution. In certain embodiments, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • composition of the invention may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder.
  • Such formulations may be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration.
  • kits for producing a single-dose administration unit can each contain both a first container having a dried antagonist or agonist compound as disclosed herein and a second container having an aqueous formulation, including for example single and multi-chambered pre- filled syringes (e.g., liquid syringes, lyosyringes or needle-free syringes).
  • aqueous formulation including for example single and multi-chambered pre- filled syringes (e.g., liquid syringes, lyosyringes or needle-free syringes).
  • the effective amount of a pharmaceutical composition of the invention to be employed therapeutically will depend, for example, upon the therapeutic context and objectives.
  • One skilled in the art will appreciate that the appropriate dosage levels for treatment, according to certain embodiments, will thus vary depending, in part, upon the antagonist or agonist delivered, the indication for which the pharmaceutical composition is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient.
  • a clinician may titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.
  • Typical dosages range from about 0.1 ⁇ g/kg to up to about 100 mg/kg or more, depending on the factors mentioned above.
  • the dosage may range from 0.1 ⁇ g/kg up to about 100 mg/kg; or 1 ⁇ g/kg up to about 100 mg/kg; or 5 ⁇ g/kg up to about 100 mg/kg.
  • the dosing frequency will depend upon the pharmacokinetic parameters of an antagonist or agonist as disclosed herein in the formulation. For example, a clinician administers the composition until a dosage is reached that achieves the desired effect.
  • the composition may therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate dose-response data.
  • Administration routes for the pharmaceutical compositions of the invention include orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, or intralesional routes; by sustained release systems or by implantation devices.
  • the pharmaceutical compositions may be administered by bolus injection or continuously by infusion, or by implantation device.
  • the pharmaceutical composition also can be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device may be implanted into any suitable tissue or organ, and delivery of the desired molecule may be via diffusion, timed-release bolus, or continuous administration.
  • Pharmaceutical compositions of the invention can be administered alone or in combination with other therapeutic agents, in particular, in combination with other sleep disorder agents.
  • Example 1 describes how animals are prepared for treatment with antitussive agents, alone or in combination with other agents, and subsequent physiological recording and testing.
  • Example 2 describes physiological recording methods used in treated and control animals and interpretation of results that can be obtained from administration of one or more antitussive agents.
  • Example 3 describes interpretation of results that can be obtained from animals first treated with one or more apnea-promoting agents (e.g., serotonin) followed by one or more antitussive agents.
  • Example 4 describes physiological recording methods useful for treated and control animals and interpretation of results that can be obtained from administration of one or more antitussive agents in combination with one or more other agents.
  • Example 5 describes agents or compositions that possess a specific antitussive and other pharmacological activity that is used to effectively suppress or prevent sleep-related breathing disorders.
  • Acclimatized animals are anesthetized using a mixture of ketamine (80 mg/mg) and xylazine (5 mg/kg) at a volume of 1 ml/kg body weight for the implantation of cortical electrodes for electroencephalogram (EEG) recording and neck muscle electrodes for electromyogram (EMG) recording.
  • EEG electroencephalogram
  • EMG electromyogram
  • the surface of the skull is exposed surgically and cleaned with a 20% solution of hydrogen peroxide followed by a solution of 95% isopropyl alcohol.
  • a dental preparation of sodium fluoride (Flura-GEL®, Saslow Dental, Mt. Prospect, IL) is applied to harden the skull above the parietal cortex and allowed to remain in place for 5 minutes.
  • the fluoride mixture is then removed from the skull above the parietal cortex.
  • the EEG electrodes consisting of four stainless steel machine screws, having leads attached thereto, are threaded into the skull to rest on the dura over the parietal cortex.
  • a thin layer of Justi® resin cement (Saslow Dental, Mt. Prospect, IL) is applied to cover the screw heads (of screws implanted in the skull) and surrounding skull to further promote the adhesion of the implant.
  • EMG electrodes consisting of two ball-shaped wires are inserted into the bilateral neck musculature.
  • AU leads i.e., EEG and EMG leads
  • 39F1401 Newark Electronics, Schaumburg, IL
  • Physiological parameters from each animal prepared as set forth in Example 1 are recorded on 2 occasions in random order, with recordings for an individual animal separated by at least 3 days. Fifteen minutes prior to each recording an animal receives a systemic injection (1 ml/kg intraperitoneal bolus) of either saline (control) or an active dose of a drug treatment (as above).
  • Respiration is recorded by placing each animal, unrestrained, inside a single chamber plethysmograph (PLYUN1R/U; Buxco Electronics, Sharon, CT; dimension 6 in. x 10 in. x 6 in.) ventilated with a bias flow of fresh room air at a rate of 2 L/min.
  • a cable plugged onto the animal's connector and passed through a sealed port is used to collect the bioelectrical activity from the head implant.
  • Respiration, EEG activity, and EMG activity are displayed on a video monitor and simultaneously digitized 100 times per second and stored on computer disk (Experimenter's Workbench; Datawave Technologies, Longmont, CO). Sleep and waking states are assessed using software developed by Benington et al.
  • the events detected represent central apneas because decreased ventilation associated with obstructed or occluded airways would generate an increased plethysmographic signal, rather than a pause.
  • Apnea indexes (Al) defined as apneas per hour in a stage are separately determined for NREM and REM sleep.
  • the effects of sleep stage (NREM vs. REM) and injection (control vs. dose of active test drug) are tested using ANOVA with repeated measures. Multiple comparisons are controlled using Fisher's protected least significant difference (PLSD) test.
  • PLSD Fisher's protected least significant difference
  • the timing and volume of each breath are scored by automatic analysis (Experimenter's Workbench; Datawave Technologies, Longmont, CO).
  • RR mean respiratory rate
  • MV minute ventilation
  • One-way ANOVA is also performed by non-parametric (Friedman) analysis. Conclusions using parametric and non-parametric ANOVA are compared in all cases. Results of the administration of the one or more antitussive agents on the rate of apneas per hour of NREM and REM sleep during the 6 hours of polygraphic recording that demonstrate a significant suppression (p ⁇ 0.05) are indicative of efficacy against sleep apnea and other sleep-related breathing disorders.
  • antitussive agents include, but are not limited to RSD931, FK888, CP99994, SR48968, codeine, SR142801, SB235375, nociceptin/orphanin FQ, 15-HPETE, NADA, anandamide, lidocaine, benzonatate, mexiletine, NS 1619, furosemide, zafirlukast, HOE 140, dihydrocodone, oxycodone, BW443C noscapine, dextromethorphan, SKFl 0047, baclofen, diphenhydramine, caramiphen, glaucine, cilomilast, RO-64-6198, NKP608, levchromkalim, BRL55834, icatibant, suplatast tosilate, epinastine, levodropropizine; and other antitussive agents may be used to prevent or ameliorate sleep-related breathing disorders. Further,
  • apnea-promoting agents alone and in combination to produce respiratory responses in anesthetized animals is performed as set forth above in Example 2.
  • An increased rate of sleep apneas after an apnea promoting agent (e.g,. serotonin) and a blockade of this effect by treatment with an antitussive agent is indicative of the therapeutic efficacy of the antitussive agent to treat sleep apnea and other sleep-related breathing disorders.
  • exacerbation of spontaneous apnea during sleep produced by peripherally administered apnea-promoting agents e.g., serotonin
  • apnea-promoting agents e.g., serotonin
  • antitussive agents e.g., serotonin
  • antitussive agents alone and in combination with other agents (e.g., including, but not limited to, serotonin agonists, cannabimimetics, SSRIs, or SNRIs) to produce respiratory responses in anesthetized animals is performed as shown above in Example 2.
  • Isobolographic analysis is an accepted “gold standard” for detecting and characterizing drag interactions (Luszczki & Czuczwar, 2003, Epilepsy Res. 56: 27-42).
  • an "interaction index” has been proposed (Tallarida, 2002, Pain 98: 163-168) to quantify drug synergism, and this index is also useful to characterize synergism when one of the two compounds lacks independent efficacy (e.g., an SSRI; Kraiczi et ah, 1999, Sleep 22: 61-66). Isobolographic analysis and the interaction index rely on statistical estimation of the ED 50 . Thus, it is important to have adequate power in the preclinical tests to confidently measure a 50% reduction in apnea expression. For this form of efficacy determination, dose-dependent changes in sleep apnea expression are determined each agent (i.e., the antitussive agent and the second agent) alone and combined in various ratios.
  • each agent i.e., the antitussive agent and the second agent
  • a decreased rate of sleep apneas after administration of any formulation as above is indicative of the therapeutic efficacy of the formulation to treat sleep apnea and other sleep-related breathing disorders.
  • a preferred combination of agents exhibits greater suppression of apneas than either agent alone, or equivalent suppression of apneas at lower doses than either agent alone.
  • vagal neurons that can participate in reflexive cough and apnea can play an important role in sleep-apnea genesis. More specifically, the nodose ganglia of the vagus nerves appear to be a crucial source of these neurons, which synapse centrally in the nucleus of the solitary tract.
  • Capsazepine a synthetic analog of capsaicin (Brevan et ah, 1992, Br. J. Pharmacol. 107:544) is an antitussive agent that reduces sensitivity to experimental cough induced by citric acid, hydrochloric acid and capsaicin (Lallo et ah, 1995, J. Appl. Physiol. 79:1082; Mazzoneet et ah, 2005, J Physiol. 569:559; Trevisani et ah, 2004, Thorax 59:769).

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Abstract

L'invention concerne des méthodes pour prévenir ou améliorer des troubles de la respiration associés au sommeil. La méthode consiste à administrer à un patient une dose efficace d'un ou de plusieurs agents antitussifs. L'agent antitussif ou la combinaison d'agents antitussifs peuvent être administrés en conjonction avec un ou plusieurs agonistes du récepteur de sérotonine, un ou plusieurs agonistes du récepteur cannabinoïde, un ou plusieurs inhibiteurs de recaptage de sérotonine, une combinaison d'inhibiteurs de recaptage, d'autres agents ou une combinaison quelconque de ces substances.
PCT/US2006/040363 2005-10-14 2006-10-13 Traitements pharmacologiques contre des troubles du sommeil Ceased WO2007047576A1 (fr)

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WO2008017753A3 (fr) * 2006-07-31 2009-02-19 Sanofi Aventis Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
FR2912057A1 (fr) * 2007-02-07 2008-08-08 Sanofi Aventis Sa Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
WO2013154347A1 (fr) * 2012-04-10 2013-10-17 Hanmi Pharm. Co., Ltd. Formulation liquide destinée à une administration orale comprenant de l'ambroxol, de la lévodropropizine et un agent tampon, et son procédé de préparation
KR101915056B1 (ko) 2012-04-10 2018-11-07 한미약품 주식회사 암브록솔, 레보드로프로피진 및 완충제를 포함하는 경구용 액상 제제 및 이의 제조방법
CN115944641A (zh) * 2023-02-10 2023-04-11 军事科学院军事医学研究院环境医学与作业医学研究所 一种硫代酰胺类化合物在调节昼夜节律中的应用

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