Methods of treating visceral pain syndromes

• US 20030203055A1
• Filed: 03/17/2003
• Published: 10/30/2003
• Est. Priority Date: 03/15/2002
• Status: Abandoned Application

• Current Assignee: Cypress Systems Incorporated (Logisteed Limited)
• Original Assignee: Cypress Systems Incorporated (Logisteed Limited)
• Inventors: Kranzler, Jay D., Rao, Srinivas G.
• Application Number:
  US10/391,110
• Publication Number:
  US 20030203055A1
• Time in Patent Office: Days
• US Class Current: 424/738
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7008 Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• CPC Class Codes: A61K 31/7012 Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid gluconic acid A61K31/191; ascorbic acid A61K31/375
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

The present invention provides a method of treating a visceral pain syndromes in a mammal. The method includes administering to the mammal an effective amount of a selective norepinephrine (NE)-serotonin (5-HT) reuptake inhibitor (NSRI), e.g., milnacipran.

Claims

1. A method of treating a visceral pain syndrome in a mammal, the method comprising administering to the mammal an effective amount of a selective norepinephrine (NE)-serotonin (5-HT) reuptake inhibitor (NSRI) that is not a tricylcic antidepressant (TCA).

2. The method of claim 1 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of at least about 1.

3. The method of claim 1 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of up to about 20.

4. The method of claim 1 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of about 1;

1 to about 20;

1.

5. The method of claim 1 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of about 1;

1 to about 5;

1.

6. The method of claim 1 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of about 1;

1 to about 3;

1.

7. The method of claim 1 wherein the selective NSRI has limited post-synaptic receptor effects, such that the ki at each of adrenergic and cholinergic sites is greater than about 500 nanomolar (nM).

8. The method of claim 1 wherein the selective NSRI is an N-methyl-D-aspartate (NMDA) receptor antagonist.

9. The method of claim 8 wherein the N-methyl-D-aspartate (NMDA) receptor antagonist has a dissociation constant with the NMDA receptor of 50 micromolar (μ

M) or less.

10. The method of claim 8 wherein the N-methyl-D-aspartate (NMDA) receptor antagonist has a dissociation constant with the NMDA receptor of 20 micromolar (μ

M) or less.

11. The method of claim 8 wherein the N-methyl-D-aspartate (NMDA) receptor antagonist is a non-competitive NMDA receptor antagonist, a competitive NMDA receptor antagonist, a glycine-site antagonist, a glutamate-site antagonist, an NR1 subunit antagonist, an antagonist of an NR2 subunit, or an NR3 subunit antagonist.

12. The method of claim 8 wherein the NMDA receptor antagonist is a PCP-site NMDA receptor antagonist.

13. The method of claim 1 wherein the selective NSRI is a selective norepinephrine reuptake inhibitor (NERI).

14. The method of claim 13 wherein the selective norepinephrine reuptake inhibitor (NERI) has an IC₅₀ for inhibition of noradrenaline reuptake into synaptosomes from cerebral cortex of 1 micromolar (μ

M) or less.

15. The method of claim 13 wherein the selective norepinephrine reuptake inhibitor (NERI) has an IC₅₀ for inhibition of noradrenaline reuptake into synaptosomes from cerebral cortex of 100 nanomolar (nM) or less.

16. The method of claim 1 wherein the selective NSRI is a compound of formula (Ia):

17. The method of claim 16 wherein R is hydrogen.

18. The method of claim 16 wherein n is 1.

19. The method of claim 16 wherein R₁ is alkyl.

20. The method of claim 16 wherein R₁ is ethyl.

21. The method of claim 16 wherein R₂ is alkyl.

22. The method of claim 16 wherein R₂ is ethyl.

23. The method of claim 16 wherein R₃ is hydrogen.

24. The method of claim 16 wherein R₄ is hydrogen.

25. The method of claim 16 wherein the compound is milnacipran.

26. The method of claim 25 wherein the milnacipran is administered up to about 400 mg/day.

27. The method of claim 25 wherein the milnacipran is administered in about 25 mg/day to about 250 mg/day.

28. The method of claim 25 wherein the milnacipran is administered one or more times per day.

29. The method of claim 1 wherein the visceral pain syndrome comprises irritable bowel syndrome (IBS), noncardiac chest pain (NCCP), functional dyspepsia, interstitial cystitis, essential vulvodynia, urethral syndrome, orchialgia, sphincter of oddi dysfunction, functional anorectal pain syndromes, abdominal migraine, or symptoms associated thereof.

30. The method of claim 1 wherein the selective NSRI is not administered adjunctively with a neurotransmitter precursor.

31. The method of claim 1 wherein the selective NSRI is not administered adjunctively with a neurotransmitter precursor selected from phenylalanine, tyrosine, tryptophan, or a combination thereof.

32. The method of claim 1 wherein the selective NSRI is administered adjunctively with a therapeutically effective amount of a medicament for the treatment of dysphagia, dyspepsia, aerophagia, irritable bowel syndrome, abdominal bloating, constipation, diarrhea, abdominal pain, abdominal migraine, gallbladder dysfunction, sphincter of Oddi dysfunction, fecal incontinence, anorectal pain, proctalgia fugax, dyssynergia, dyschezia, vulvodynia, orchialgia, urethral syndrome, penile pain, prostatodynia, coccygodynia, perineal pain, rectal pain,or a combination thereof.

33. The method of claim 32, wherein the anorectal pain includes ischemia, inflammatory bowel disease, cryptitis, intramuscular abscess, fissure, hemorrhoids, prostatitis, solitary rectal ulcer, or a combination thereof.

34. The method of claim 32, wherein the vulvodynia includes vulvar dermatoses, cyclic vulvovaginitis, vulvar vestibulitis, vulvar papillomatosis, dysesthetic vulvodynia, or a combination thereof.

35. The method of claim 1 wherein the selective NSRI is administered adjunctively with an antidepressant, an antidiarrheal, an analgesic, an antispasmodic, an antifatigue agent, an anorectic, a stimulant, an antiepileptic drug, a sedative/hypnotic, a laxative, a 5-HT₁ agonist, an alpha adrenergic agonist, or a combination thereof.

36. The method of claim 1 wherein the selective NSRI is administered adjunctively with a serotonin reuptake inhibitor, a heterocyclic antidepressant, a monoamine oxidase inhibitor, serotonergicnoradrenergic, a 5-HT₂ antagonist, catecholaminergic, an anticholinergic, a 5-HT₃ receptor antagonist, paregoric, glucose-electrolyte solution, an opiate, an opioid agonist, a NSAID, an indole, a naphthylalkanone, oxicam, a para-aminophenol derivative, propionic acid, salicylate, fenamate, a pyrazole, a salicylate, a gut analgesic, a belladonna alkaloid, nitroglycerin, an anticholinergic, a calcium channel blocker, a corticosteroid, a glucocorticoid, acetazolamide, carbamazepine, clonazepam, ethosuximide, fosphenytoin, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, topiramate, valproate, a barbiturate, benzodiazepine, imidazopyridine, nondepolarizing neuromuscular blocking agent, a stool softener, a bulk forming agent, alosetron, amphetamine, atropine, buprenorphine, buspirone, carbamazepine, clonidine, codeine, dicyclomine, 1-DOPA, hyoscyamine, lactose, lidocaine, loperamide, mineral oil, modafinil, morphine, neurotonin, octreotide, opiates, phenolpthyaline, pramipexole, pregabalin, psyllium, sibutramine, tegaserod, tizanidine, tramadol, trazodone, tropisetron, valium, zolpidem, zopiclone, or a combination thereof.

37. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective anti-visceral pain syndrome amount of a selective norepinephrine (NE)-serotonin (5-HT) reuptake inhibitor (NSRI) that is not a tricylcic antidepressant (TCA).

38. The pharmaceutical composition of claim 37 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of at least about 1.

39. The pharmaceutical composition of claim 37 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of up to about 20.

40. The pharmaceutical composition of claim 37 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of about 1;

1 to about 20;

1.

41. The pharmaceutical composition of claim 37 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of about 1;

1 to about 5;

1.

42. The pharmaceutical composition of claim 37 wherein the selective NSRI has an NE:

5-HT reuptake inhibition ratio of about 1;

1 to about 3;

1.

43. The pharmaceutical composition of claim 37 wherein the selective NSRI has limited post-synaptic receptor effects, such that the ki at each of adrenergic and cholinergic sites is greater than about 500 nanomolar (nM).

44. The pharmaceutical composition of claim 37 wherein the selective NSRI is an N-methyl-D-aspartate (NMDA) receptor antagonist.

45. The pharmaceutical composition of claim 44 wherein the N-methyl-D-aspartate (NMDA) receptor antagonist has a dissociation constant with the NMDA receptor of 50 micromolar (μ

M) or less.

46. The pharmaceutical composition of claim 44 wherein the N-methyl-D-aspartate (NMDA) receptor antagonist has a dissociation constant with the NMDA receptor of 20 micromolar (μ

M) or less.

47. The pharmaceutical composition of claim 44 wherein the N-methyl-D-aspartate (NMDA) receptor antagonist is a non-competitive NMDA receptor antagonist, a competitive NMDA receptor antagonist, a glycine-site antagonist, a glutamate-site antagonist, an NR1 subunit antagonist, an antagonist of an NR2 subunit, or an NR3 subunit antagonist.

48. The pharmaceutical composition of claim 44 wherein the NMDA receptor antagonist is a PCP-site NMDA receptor antagonist.

49. The pharmaceutical composition of claim 37 wherein the selective NSRI is a selective norepinephrine reuptake inhibitor (NERI).

50. The pharmaceutical composition of claim 49 wherein the selective norepinephrine reuptake inhibitor (NERI) has an IC₅₀ for inhibition of noradrenaline reuptake into synaptosomes from cerebral cortex of 1 micromolar (μ

M) or less.

51. The pharmaceutical composition of claim 49 wherein the selective norepinephrine reuptake inhibitor (NERI) has an IC₅₀ for inhibition of noradrenaline reuptake into synaptosomes from cerebral cortex of 100 nanomolar (nM) or less.

52. The pharmaceutical composition of claim 37 wherein the selective NSRI is a compound of formula (Ia):

53. The pharmaceutical composition of claim 52 wherein R is hydrogen.

54. The pharmaceutical composition of claim 52 wherein n is 1.

55. The pharmaceutical composition of claim 52 wherein R₁ is alkyl.

56. The pharmaceutical composition of claim 52 wherein R₁ is ethyl.

57. The pharmaceutical composition of claim 52 wherein R₂ is alkyl.

58. The pharmaceutical composition of claim 52 wherein R₂ is ethyl.

59. The pharmaceutical composition of claim 52 wherein R₃ is hydrogen.

60. The pharmaceutical composition of claim 52 wherein R₄ is hydrogen.

61. The pharmaceutical composition of claim 52 wherein the selective NSRI is milnacipran.

62. The pharmaceutical composition of claim 61 wherein the milnacipran is administered up to about 400 mg/day.

63. The pharmaceutical composition of claim 61 wherein the milnacipran is administered in about 25 mg/day to about 250 mg/day.

64. The pharmaceutical composition of claim 61 wherein the milnacipran is administered one or more times per day.

65. The pharmaceutical composition of claim 37 wherein the visceral pain syndrome comprises irritable bowel syndrome (IBS), noncardiac chest pain (NCCP), functional dyspepsia, interstitial cystitis, essential vulvodynia, urethral syndrome, orchialgia, sphincter of oddi dysfunction, functional anorectal pain syndromes, abdominal migraine, or symptoms associated thereof.

66. The pharmaceutical composition of claim 37 that does not comprise a neurotransmitter precursor.

67. The pharmaceutical composition of claim 37 that does not comprise a neurotransmitter precursor selected from phenylalanine, tyrosine, tryptophan, or a combination thereof.

68. The pharmaceutical composition of claim 37 further comprising a therapeutically effective amount of a medicament for the treatment of dysphagia, dyspepsia, aerophagia, irritable bowel syndrome, abdominal bloating, constipation, diarrhea, abdominal pain, abdominal migraine, gallbladder dysfunction, sphincter of Oddi dysfunction, fecal incontinence, anorectal pain, proctalgia fugax, dyssynergia, dyschezia, vulvodynia, orchialgia, urethral syndrome, penile pain, prostatodynia, coccygodynia, perineal pain, rectal pain,or a combination thereof.

69. The pharmaceutical composition of claim 68, wherein the anorectal pain includes ischemia, inflammatory bowel disease, cryptitis, intramuscular abscess, fissure, hemorrhoids, prostatitis, solitary rectal ulcer, or a combination thereof.

70. The pharmaceutical composition of claim 68, wherein the vulvodynia includes vulvar dermatoses, cyclic vulvovaginitis, vulvar vestibulitis, vulvar papillomatosis, dysesthetic vulvodynia, or a combination thereof.

71. The pharmaceutical composition of claim 37 further comprising an antidepressant, an antidiarrheal, an analgesic, an antispasmodic, an antifatigue agent, an anorectic, a stimulant, an antiepileptic drug, a sedative/hypnotic, a laxative, a 5-HT₁ agonist, an alpha adrenergic agonist, or a combination thereof.

72. The pharmaceutical composition of claim 37 further comprising a serotonin reuptake inhibitor, a heterocyclic antidepressant, a monoamine oxidase inhibitor, serotonergicnoradrenergic, a 5-HT₂ antagonist, catecholaminergic, an anticholinergic, a 5-HT₃ receptor antagonist, paregoric, glucose-electrolyte solution, an opiate, an opioid agonist, a NSAID, an indole, a naphthylalkanone, oxicam, a para-aminophenol derivative, propionic acid, salicylate, fenamate, a pyrazole, a salicylate, a gut analgesic, a belladonna alkaloid, nitroglycerin, an anticholinergic, a calcium channel blocker, a corticosteroid, a glucocorticoid, acetazolamide, carbamazepine, clonazepam, ethosuximide, fosphenytoin, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, topiramate, valproate, a barbiturate, benzodiazepine, imidazopyridine, nondepolarizing neuromuscular blocking agent, a stool softener, a bulk forming agent, alosetron, amphetamine, atropine, buprenorphine, buspirone, carbamazepine, clonidine, codeine, dicyclomine, 1-DOPA, hyoscyamine, lactose, lidocaine, loperamide, mineral oil, modafinil, morphine, neurotonin, octreotide, opiates, phenolpthyaline, pramipexole, pregabalin, psyllium, sibutramine, tegaserod, tizanidine, tramadol, trazodone, tropisetron, valium, zolpidem, zopiclone, or a combination thereof.

73. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective anti-visceral pain syndrome amount of a selective norepinephrine (NE)-serotonin (5-HT) reuptake inhibitor (NSRI) that is not a tricylcic antidepressant (TCA).

74. A kit comprising an effective anti-visceral pain syndrome amount of a selective norepinephrine (NE)-serotonin (5-HT) reuptake inhibitor (NSRI) that is not a tricylcic antidepressant (TCA), and instructions or indicia.

75. A kit comprising an effective anti-visceral pain syndrome amount of milnacipran, and instructions or indicia.