Methods and compositions for therapeutic treatment

• US 20060111308A1
• Filed: 11/16/2005
• Published: 05/25/2006
• Est. Priority Date: 11/16/2004
• Status: Abandoned Application

• Current Assignee: Limerick Neurosciences, Inc.
• Original Assignee: Limerick Neurosciences, Inc.
• Inventors: Robbins, Wendye
• Application Number:
  US11/281,984
• Publication Number:
  US 20060111308A1
• Time in Patent Office: Days
• US Class Current: 514/27
• 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 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• 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 31/7024 Esters of saccharides
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 23/02 Local anaesthetics
• 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 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system

Abstract

Methods and compositions are described for the modulation of central nervous system and/or fetal effects of substances. Methods and compositions are described for the modulation of efflux transporter activity to increase the efflux of drugs and other compounds out of a physiological compartment and into an external environment. In particular, the methods and compositions disclosed herein provide for the increase of efflux transporter activity at blood-brain, blood-CSF and placental-maternal barriers to increase the efflux of drugs and other compounds from physiological compartments, including central nervous system and fetal compartments.

Claims

1. A composition comprising a therapeutic agent and an blood-brain barrier (BBB) transport protein modulator, wherein the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BBB transport protein modulator is present in an amount sufficient to decrease a central nervous system (CNS) effect of the therapeutic agent by an average of at least about 10%, compared to the CNS effect without the BBB transport protein modulator, when the composition is administered to an animal.

2. The composition of claim 1 wherein the BBB transport protein is an ABC transport protein.

3. The composition of claim 1 wherein the BBB transport protein modulator is a BBB transport protein activator.

4. The composition of claim 1 wherein the BBB transport protein modulator is a modulator of P-gP.

5. The composition of claim 1 wherein the BBB transport protein modulator comprises a polyphenol.

6. The composition of claim 5 wherein the polyphenol is a flavonoid.

7. The composition of claim 5 wherein the polyphenol is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

8. The composition of claim 7 wherein the flavonoid is quercetin.

9. The composition of claim 1 wherein the CNS effect is selected from the group consisting of drowsiness, impaired concentration, sexual dysfunction, sleep disturbances, habituation, dependence, alteration of mood, respiratory depression, nausea, vomiting, dizziness, memory impairment, neuronal dysfunction, neuronal death, visual disturbance, impaired mentation, tolerance, addiction, hallucinations, lethargy, myoclonic jerking, endocrinopathies, and combinations thereof.

10. The composition of claim 1 wherein the therapeutic agent is selected from the group consisting of antihypertensives, vasodilators, barbiturates, membrane stabilizers, cardiac stabilizers, glucocorticoids, and antiinfectives.

11. The composition of claim 10 wherein the therapeutic agent is an antihypertensive agent.

12. The composition of claim 1 wherein a therapeutic effect of the therapeutic agent is increased an average of at least about 10% compared to the therapeutic effect without the BBB transport protein modulator, when the composition is administered to an animal.

13. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable excipient.

14. The composition of claim 1 wherein the molar ratio of the therapeutic agent and the BBB transport protein modulator is about 0.001:

1 to about 10;

1.

15. The composition of claim 1 wherein the therapeutic agent is present in an amount of about 1 to 1000 mg and the BBB transport protein modulator is present in an amount of about 10 to 1000 mg.

16. A kit comprising the composition of claim 1 and instructions for use of the composition.

17. The composition of claim 1 wherein the therapeutic agent and the BBB transport protein activator are present in a single container.

18. The composition of claim 1 wherein the therapeutic agent and the BBB transport protein activator are admixed in the composition.

19. A method of treating a condition comprising administering to an animal suffering from the condition an effective amount of a therapeutic agent and an amount of an BBB transport protein activator sufficient to reduce or eliminate a CNS effect of the therapeutic agent.

20. The method of claim 19 wherein the activator reduces or eliminates a plurality of CNS effects of the therapeutic agent.

21. The method of claim 19 wherein the therapeutic agent and the BBB transport protein activator are co-administered.

22. The method of claim 21 wherein the therapeutic agent and the BBB transport protein activator are administered in a single composition.

23. The method of claim 22 wherein the therapeutic agent and the BBB transport protein activator are admixed in the composition.

24. The method of claim 22 wherein the therapeutic agent is present in the composition in an amount sufficient to produce a therapeutic effect, and wherein the BBB transport protein activator is present in the composition in an amount sufficient to reduce a central nervous system effect of the therapeutic agent.

25. The method of claim 22 wherein the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BBB transport protein activator is present in an amount sufficient to decrease a CNS effect of the therapeutic agent by an average of at least about 5%, compared to the effect without the BBB transport protein activator.

26. The method of claim 19 or 22 wherein the administration is oral administration.

27. The method of claims 19 or 22 wherein the administration is transdermal administration.

28. The method off claim 19 wherein the animal is a mammal.

29. The method of claim 19 wherein the animal is a human.

30. The method of claim 19 wherein the BBB transport protein modulator is an activator of P-gP.

31. The method of claim 19 wherein the BBB transport protein modulator comprises a polyphenol.

32. The method of claim 28 wherein the polyphenol is a flavonoid.

33. The method of claim 28 wherein the polyphenol is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

34. The method of claim 32 wherein the flavonoid is quercetin.

35. The method of claim 19 wherein the therapeutic agent is selected from the group consisting of antihypertensives, vasodilators, barbiturates, membrane stabilizers, cardiac stabilizers, glucocorticoids, and antiinfectives.

36. The method of claim 19 wherein the individual suffers from a condition selected from the group consisting of diseases of the heart, circulation, lipoprotein metabolism, hemostasis and thrombosis, respiratory system, kidney, gastrointestinal tract, endocrine system, reproductive system, and hemopoeitic system.

37. The method of claim 19 wherein the therapeutic agent is administered about 1-6 times per day and the BBB transport protein activator is administered about 1-6 times per day.

38. The method of claim 37 wherein the administration of either the therapeutic agent or the BBB transport protein activator continues for less than about 7 days.

39. The method of claim 37 wherein the administration continues for more than about 6 days.

40. The method of claim 19 wherein the molar ratio of the amount of therapeutic agent administered and the amount of BBB transport protein modulator administered is about 0.001:

1 to about 10;

1.

41. A method for reversing a central nervous system effect of an agent in a human comprising administering to the human an amount of a BBB transport protein modulator sufficient to partially or completely reverse a central nervous system effect of the agent, wherein said human has received an amount of said agent sufficient to produce a central nervous system effect.

42. The method of claim 41 wherein the agent is a general anesthetic.

43. The method of claim 41 wherein the human continues to experience peripheral effects of the agent.

44. The method of claim 41 wherein the BBB transport protein modulator is a polyphenol.