Pharmacological treatment for sleep apnea

• US 20020086870A1
• Filed: 12/14/2001
• Published: 07/04/2002
• Est. Priority Date: 02/27/1998
• Status: Active Grant

• Current Assignee: N.V. Organon (Merck & Co., Inc.)
• Original Assignee: Board of Trustees of The University of Illinois
• Inventors: Radulovacki, Miodrag, Carley, David W.
• Granted Patent: US 6,727,242 B2
• Time in Patent Office: Days
• US Class Current: 514/259.41
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 : Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/16 : Central respiratory analeptics
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates generally to pharmacological methods for the prevention of amelioration of sleep-related breathing disorders via administration of agents or combinations of agents that possess serotonin-related pharmacological activity.

Claims

1. A method of preventing or ameliorating sleep-related breathing disorder the method comprising administering to a patient in need thereof an effective amount of a serotonin receptor antagonist.

2. The method of claim 1 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.

3. The method of claim 1 or claim 2 wherein the serotonin receptor antagonist is selected from the group consisting of ketanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, 3-tropanyl-indole-3-carboxylate methiodide, methysergide, risperidone, cyproheptadine, clozapine, mianserin, ritanserin, and granisetron.

4. The method of claim 1 or claim 2 wherein the serotonin receptor antagonist is a 5-hydroxytryptamine₂ receptor subtype antagonist.

5. The method of claim 1 or claim 2 wherein the serotonin receptor antagonist is a 5-hydroxytryptamine₃ receptor subtype antagonist.

6. The method of claim 1 or claim 2 wherein the serotonin receptor antagonist is both a 5-hydroxytryptamine₂ receptor subtype antagonist and a 5-hydroxytryptamine₃ receptor subtype antagonist.

7. A method of preventing or ameliorating sleep-related breathing disorders the method comprising administering to a patient in need thereof an effective amount of an agent or combination of agents having both 5-hydroxytryptamine₂ subtype receptor antagonistic activity and 5-hydroxytryptamine₃ subtype receptor antagonistic activity.

8. The method of claim 7 wherein the sleep-related breathing disorder is S selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.

9. The method of claim 7 or claim 8 wherein the effects of the agent or combination of agents are exerted only in the peripheral nervous system.

10. A method of preventing or ameliorating sleep-related breathing disorders the method comprising administering to a patient in need thereof an effective amount of a composition comprising a serotonin receptor antagonist and a serotonin receptor agonist.

11. The method of claim 10 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.

12. The method of claim 10 or claim 11 wherein the serotonin receptor antagonist is selected from the group consisting of ketanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, 3-tropanyl-indole-3-carboxylate methiodide, methysergide, risperidone, cyproheptadine, clozapine, mianserin, ritanserin, and granisetron.

13. The method of claim 10 or claim 11 wherein the serotonin receptor agonist is selected from the group consisting of 8-OH-DPAT, sumatriptan, L694247, buspirone, alnitidan, zalospirone, ipsapirone, gepirone, zolmitriptan, risatriptan, 311C90, α

-Me-5-HT, BW723C86, and MCPP.

14. The method of claim 10 or claim 11 wherein the serotonin receptor antagonist is a 5-hydroxytryptamine₂ receptor subtype antagonist.

15. The method of claim 10 or claim 11 wherein the serotonin receptor antagonist is a 5-hydroxytryptamine₃ receptor subtype antagonist.

16. The method of claim 10 or claim 11 wherein the serotonin receptor agonist is a 5-hydroxytryptamine₁ receptor subtype agonist.

17. The method of claim 10 or claim 11 wherein the serotonin receptor agonist is a S-hydroxytryptamine₂ receptor subtype agonist.

18. The method of claim 10 or claim 11 wherein the effects of the serotonin receptor agonist are exerted in the central nervous system.

19. The method of claim 10 or claim 11 wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system.

20. The method of claim 10 or claim 11 wherein the effects of the serotonin receptor agonist are exerted in the central nervous system and wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system.

21. The method of claim 10 or claim 11 wherein the serotonin receptor antagonist exhibits both 5-hydroxytryptamine₂ and 5-hydroxytryptamine₃ receptor subtype antagonistic activity.

24. The method of claim 21 or claim 22 wherein the agent or combination of agents demonstrate the serotonin receptor antagonistic activity only in the peripheral nervous system.

22. A method of preventing or ameliorating sleep-related breathing disorders the method comprising administering to a patient in need thereof an effective amount of an agent or combination of agents exhibiting both 5-hydroxytryptamine₂ and 5-hydroxytryptamine₃ receptor subtype antagonistic activity and wherein the agent or combination of agents further exhibits the ability to induce serotonin release within the central nervous system.

23. The method of claim 22 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.

26. The method of claim 25 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.

27. The method of claim 25 or claim 26 wherein the serotonin receptor antagonist is selected from the group consisting of ketanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205 ,557, 3-tropanyl-indole-3-carboxylate, 3-tropanyl-indole-3-carboxylate methiodide, methysergide, risperidone, cyproheptadine, clozapine, mianserin, ritanserin, and granisetron.

28. The method of claim 25 or claim 26 wherein the α

₂ adrenergic receptor subtype antagonist is selected from the group consisting of phenoxybenzamine, phentolamine, tolazoline, terazosine, doxazosin, trimazosin, yohimbine, indoramin, ARC239, and prazosin.

29. The method of claim 25 or claim 26 wherein the α

₂ adrenergic antagonist effects are exerted within the central nervous system.

30. The method of claim 25 or claim 26 wherein the serotonin antagonist effects are exerted in the peripheral nervous system.

31. The method of claim 25 or claim 26 wherein the α

₂ adrenergic antagonist effects are exerted in the central nervous system and the serotonin antagonist effects are exerted in the peripheral nervous system.

32. The method of claim 29 wherein the α

₂ adrenergic antagonist effect is exerted presynaptically.

33. The method of claim 30 wherein the α

₂ adrenergic antagonist effect is exerted presynaptically.

34. The method of claim 31 wherein the α

₂ adrenergic antagonist effect is exerted presynaptically.

35. The method of claim 29 wherein the wherein the α

₂ adrenergic antagonist effects are exerted selectively at presynaptic heteroreceptors located on serotonergic neurons.

36. The method of claim 30 wherein the wherein the α

₂ adrenergic antagonist effects are exerted selectively at presynaptic heteroreceptors located on serotonergic neurons.

37. The method of claim 31 wherein the wherein the α

₂ adrenergic antagonist effects are exerted selectively at presynaptic heteroreceptors located on serotonergic neurons.

25. A method of preventing or ameliorating sleep-related breathing disorders the method comprising administering to a patient in need thereof an effective amount of an agent or composition exhibiting a2 adrenergic receptor subtype antagonism and either 5-hydroxytryptamine₂ or 5-hydroxytryptamine₃ receptor subtype antagonism or both.