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Last Updated: March 28, 2024

Details for Patent: 7,074,833


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Title:Use of the (1S,2R) enantiomer of milnacipran for the preparation of a drug
Abstract: A method for treating or preventing a disorder or a condition by double inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake in a subject in need thereof, while limiting the risks of cardiovascular disturbances and/or organ and/or tissue toxicity, comprising the step of administering to said subject a mixture of enantiomers of milnacipran enriched in the (1S,2R) enantiomer of milnacipran and/or of at least one of its metabolites, as well as their pharmaceutically-acceptable salts.
Inventor(s): Deregnaucourt; Jean (Paris, FR), Grosse; Richard (Gidy, FR)
Assignee: Pierre Fabre Medicament (Boulogne-Billancourt, FR)
Filing Date:Mar 22, 2004
Application Number:10/805,940
Claims:1. A method for limiting the risk of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity in the treatment of a living animal body afflicted with disorders which may be treated by double inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake, said method comprising administering to the living animal body an effective amount of a mixture of enantiomers of milnacipran (Z(.+-.)-2-(amino methyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide), as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, such mixture being substantially pure in the (1S,2R) enantiomer, wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran.

2. The method of claim 1, wherein the cardiovascular disturbance corresponds to an increase in blood pressure and/or an increase in heart rate.

3. The method of claim 2, wherein the increase in blood pressure corresponds to an increase in diastolic blood pressure.

4. The method according to claim 1, wherein the organ toxicity is cardiac toxicity and the tissue toxicity is hepatic and/or renal toxicity.

5. The method according to claim 1, wherein mass/mass ratio between the (1S,2R) enantiomer and (1R,2S) enantiomer in the mixture is greater than 95:5 ((1S,2R):(1R,2S)).

6. The method according to claim 1, wherein mass/mass ratio between the (1S,2R) enantiomer and (1R,2S) enantiomer in the mixture is greater than 99:1 ((1S,2R):(1R,2S)).

7. The method according to claim 1, wherein mass/mass ratio between the (1S,2R) enantiomer and (1R,2S) enantiomer in the mixture is greater than 99.5:0.5 ((1S,2R):(1R,2S)).

8. The method according to claim 1, wherein the disorder or condition is selected from depression, bi-polar disease, schizophrenia, generalised anxiety, morose and marasmic states, stress-related diseases, panic attacks, phobias, obsessive-compulsive disorders, behavioural disorders, oppositional disorders, post-traumatic stress disorder, depression of the immune system, fatigue and the associated pain syndromes, chronic fatigue syndrome, fibromyalgia, and other functional somatic disorders, autism, disorders characterised by attention deficit due to general health status, attention disorders due to hyperactivity, eating disorders, neurotic bulimia, neurotic anorexia, obesity, psychotic disorders, apathy, migraine, pain, irritable bowel syndrome, cardiovascular diseases, neuro-degenerative diseases and the associated anxiety-depressive syndromes (Alzheimer's disease, Huntington's chorea, Parkinson's disease), urinary incontinence, drug addiction.

9. The method of claim 8, wherein depression is selected from deep depression, resistant depression, depression in the elderly, psychotic depression, depression induced by treatments with interferon, depressive state, manic-depressive syndrome, seasonal depressive episodes, depressive episodes related to general health status, depression rotated to mood-altering substances.

10. The method of claim 8, wherein the phobia is agoraphobia.

11. The method of claim 8, wherein the pain is chronic pain.

12. The method of claim 8, wherein the cardiovascular disease is selected from anxiety-depressive syndrome in myocardial infarct or in hypertension.

13. The method of claim 8, wherein the urinary incontinence is selected from urinary incontinence related to stress and enuresis.

14. The method of claim 8, wherein the drug addiction is selected from anxiety addiction to tobacco, to nicotine, to alcohol, to narcotics, to drugs, and to an analgesic used in weaning-off from these addictive states.

15. The method according to claim 1, wherein the living animal body is selected from children, the elderly, patients with hepatic and/or renal insufficiency, patients receiving treatment that induces hepatic or renal organ and/or tissue toxicity, patients receiving treatment for a heart condition, patients receiving treatment that induces cardiovascular side-effects, and patients having a history of cardiovascular disease and/or suffering from cardiovascular disorders.

16. The method according to claim 15, wherein the history of cardiovascular disease and/or cardiovascular disorders are chosen among myocardial infarct, cardiac rhythm disorders (tachycardia, bradycardia, palpitations), blood pressure disorders (hypo- or hypertensive patients) and heart disease.

17. A method for limiting the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity in the treatment of a living animal body afflicted with depression, which comprises administering to the living animal body: a) a mixture of enantiomers substantially pure in the (1S,2R) enantiomer of milnacipran as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran, and b) at least one active compound selected from the psychotropic, in particular antidepressants, and antimuscarinic agents, as associated products for use simultaneously, separately or staggered in time.

18. The method according to claim 17, wherein the depression is selected from deep depression, resistant depression, depression in the elderly, psychotic depression, depression induced by treatment with interferon, depressive state, manic-depressive syndrome, seasonal depressive episodes, depressive episodes related to general health status, depressive episodes related to mood-altering substances.

19. A method for limiting the risks of organ and/or tissue toxicity in the treatment of a living animal body afflicted with conditions or disorders which may be treated by double inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake, which comprises administering to the living animal body: a) a mixture of enantiomers substantially pure in the (1S,2R) enantiomer of milnacipran as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran, and b) at least one other active substance selected from the active compounds tat induce organ toxicity and the active compounds that induce cell toxicity, in particular hepatic and/or renal, as associated products for use simultaneously, separately or staggered in time.

20. A method for limiting the risks of cardiovascular disturbances in the treatment of a living animal body afflicted with conditions or disorders which may be treated by double inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake, which comprises administering to the living animal body: a) a mixture of enantiomers substantially pure in the (1S,2R) enantiomer of milnacipran as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran, and b) at least one other active substance selected from the active compounds that induce cardiovascular side-effects, as associated products for use simultaneously, separately or staggered in time.

21. A method for treating conditions or disorders by double inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake in a living animal body, while limiting the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, which comprises administering to the living animal body an effective amount of a mixture of enantiomers of milnacipran (Z(.+-.)-2-(amino methyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide) as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, such mixture being substantially pure in the (1S,2R) enantiomer wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran.

22. The method of claim 21, wherein the cardiovascular disturbance corresponds to an increase in blood pressure and/or an increase in heart rate.

23. The method of claim 22, wherein the increase in blood pressure corresponds to an increase in diastolic blood pressure.

24. The method of claim 21, wherein the organ toxicity is cardiac toxicity and the tissue toxicity is hepatic and/or renal toxicity.

25. The method of claim 21, wherein mass/mass ratio between the (1S,2R) enantiomer and (1R,2S) enantiomer in the mixture is greater than 95:5 ((1S,2R):(1R,2S)).

26. The method of claim 21, wherein mass/mass ratio between the (1S,2R) enantiomer and (1R,2S) enantiomer in the mixture is greater than 99:1 ((1S,2R):(1R,2S)).

27. The method of claim 21, wherein mass/mass ratio between the (1S,2R) enantiomer and (1R,2S) enantiomer in the mixture is greater than 99.5:0.5 ((1S,2R):(1R,2S)).

28. The method of claim 21, wherein the disorder or condition is selected from depression, bi-polar disease, schizophrenia, generalised anxiety, morose and marasmic states, stress-related diseases, panic attacks, phobias, obsessive-compulsive disorders, behavioural disorders, oppositional disorders, post-traumatic stress disorder, depression of the immune system, fatigue and the associated pain syndromes, chronic fatigue syndrome, fibromyalgia, and other functional somatic disorders, autism, disorders characterised by attention deficit due to general health status, attention disorders due to hyperactivity, eating disorders, neurotic bulimia, neurotic anorexia, obesity, psychotic disorders, apathy, migraine, pain, irritable bowel syndrome, cardiovascular diseases, neuro-degenerative diseases and the associated anxiety-depressive syndromes (Alzheimer's disease, Huntington's chorea, Parkinson's disease), urinary incontinence, drug addiction.

29. The method of claim 28, wherein depression is selected from deep depression, resistant depression, depression in the elderly, psychotic depression, depression induced by treatments with interferon, depressive state, manic-depressive syndrome, seasonal depressive episodes, depressive episodes related to general health status, depression related to mood-altering substances.

30. The method of claim 28, wherein the phobia is agoraphobia.

31. The method of claim 28, wherein the pain is chronic pain.

32. The method of claim 28, wherein the cardiovascular disease is selected from anxiety-depressive syndrome in myocardial infarct or in hypertension.

33. The method of claim 28, wherein the urinary incontinence is selected from urinary incontinence related to stress and enuresis.

34. The method of claim 28, wherein the drug addiction is selected from anxiety addiction to tobacco, to nicotine, to alcohol, to narcotics, to drugs, and to an analgesic used in weaning-off from these addictive states.

35. The method of claim 21, wherein the living animal body is selected from children, the elderly, patients with hepatic and/or renal insufficiency, patients receiving treatment that induces hepatic or renal organ and/or tissue toxicity, patients receiving treatment for a heart condition, patients receiving treatment that induces cardiovascular side-effects, patients having a history of cardiovascular disease and/or suffering from cardiovascular disorders.

36. The method of claim 35, wherein the history of cardiovascular disease and/or cardiovascular disorders are chosen among myocardial infarct, cardiac rhythm disorders (tachycardia, bradycardia, palpitations), blood pressure disorders (hypo- or hypertensive patients) and heart disease.

37. A method for treating depression in a living animal body, while limiting the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity which comprises administering to said living animal body: a) a mixture of enantiomers substantially pure in the (1S,2R) enantiomer of milnacipran as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran, and b) at least one active compound selected from the psychotropics, in particular antidepressants, and antimuscarinic agents, as associated products for use simultaneously, separately or staggered in time.

38. The method according to claim 37, wherein the depression is selected from deep depression, resistant depression, depression in the elderly, psychotic depression, depression induced by the treatment with interferon, depressive state, manic-depressive syndrome, seasonal depressive episodes, depressive episodes related to general health status, depressive episodes related to mood-altering substances.

39. A method for treating conditions or disorders by double inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake, in a living animal body, while limiting the risks of organ and/or tissue toxicity which comprises administering to said living animal body: a) a mixture of enantiomers substantially pure in the (1S,2R) enantiomer of milnacipran as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran, and b) at least one other active substance selected from the active compounds that induce organ toxicity and the active compounds that induce cell toxicity, in particular hepatic and/or renal, as associated products for use simultaneously, separately or staggered in time.

40. A method for treating conditions or disorders by double inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake, in a living animal body, while limiting the risk of cardiovascular disturbances which comprises administering to said living animal body: a) a mixture of enantiomers substantially pure in the (1S,2R) enantiomer of milnacipran as well as their pharmaceutically-acceptable salts, other than the hydrochloride salt, wherein the administration of said mixture limits the risks of cardiovascular disturbances and/or the risks of organ and/or tissue toxicity, relative to administration of racemic milnacipran, and b) at least one other active substance selected from the active compounds that induce cardiovascular side-effects, as associated products for use simultaneously, separately or staggered in time.

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