Methods for elevating neurotrophic agents

• US 8,309,057 B2
• Filed: 06/10/2005
• Issued: 11/13/2012
• Est. Priority Date: 06/10/2005
• Status: Expired due to Fees

• Current Assignee: Gearbox LLC (Intellectual Ventures LLC)
• Original Assignee: The Invention Science Fund I, L.L.C. (Intellectual Ventures LLC)
• Inventors: Ishikawa, Muriel Y., Jung, Edward K. Y., Wood, Lowell L. Jr.
• Primary Examiner(s): Kolker, Daniel E
• Assistant Examiner(s): Dutt, Aditi
• Application Number:
  US11/150,861
• Publication Number:
  US 20060282062A1
• Time in Patent Office: 2,713 Days
• Field of Search: None
• US Class Current: 424/9.2
• CPC Class Codes: A61F 11/00 Methods or devices for treatment of the ears or hearing sense implantable prostheses that substitute or replace internal ear parts, e.g. ear-drums, A61F2/18; methods or devices to cause a change in the state of auditory consciousness A61M21/00; electrotherapy applying electrical stimulation of the auditory system, or circuits therefor A61N1/36; radiotherapy using optical stimulation of the auditory system A61N5/06; electro-acoustic hearing aids H04R25/00; Non-electric hearing aids; Methods or devices for enabling ear patients to achieve auditory perception through physiological senses other than hearing sense; Protective devices for the ears, carried on the body or in the hand headwear, e.g. caps or helmets, with means for protecting the ears A42B1/0188, A42B3/16
• 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 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61M 2005/1726 the body parameters being measured at, or proximate to, the infusion site
• CPC Class Codes: A61M 2210/0612 Eyes
• CPC Class Codes: A61M 2210/0618 Nose
• CPC Class Codes: A61M 2210/0643 Tongue
• CPC Class Codes: A61M 5/14276 specially adapted for implantation
• CPC Class Codes: A61M 5/1723 using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses

Abstract

Methods and systems are described that release one or both of a neurotrophin and an inhibitor of the degradation of the neurotrophin within or in the vicinity of a highly innervated tissue. In some embodiments, the method includes regulating the release of the neurotrophin and the inhibitor of degradation over time. In some embodiments, the method includes monitoring the concentration of the neurotrophin over time. The system may include a device or multiple devices for the release of the neurotrophin and the inhibitor as well as a controller. In some embodiments the system may include a sensor device and/or an imaging device capable of detecting the concentration of the neurotrophin over time. The release of the neurotrophin and inhibitor of degradation may be part of a controlled release system and regulated over time.

Claims

1. A method of elevating, in a highly innervated tissue in a subject, the concentrations of at least one neurotrophin and at least one inhibitor of degradation of said neurotrophin, comprising:

(a) introducing into a highly innervated tissue in a subject at least one neurotrophin to elevate a neurotrophin concentration of the at least one neurotrophin within the highly innervated tissue;

(b) introducing into the highly innervated tissue at least one inhibitor of degradation of the at least one neurotrophin to elevate an inhibitor concentration of the at least one inhibitor of degradation of said neurotrophin within the highly innervated tissue; and

(c) regulating the concentration of the neurotrophin over time, wherein regulating includes;

monitoring, with at least one implanted sensor device, the neurotrophin concentration to determine whether at least one desired neurotrophin concentration target level of the at least one neurotrophin is present; and

adding additional neurotrophin in a quantity sufficient to adjust the neurotrophin concentration toward the at least one desired neurotrophin concentration target level.

2. The method as in claim 1, wherein the subject is a human.

3. The method as in claim 1, wherein the highly innervated tissue is present in a central nervous system.

4. The method as in claim 1, wherein the highly innervated tissue is present in a peripheral nervous system.

5. The method as in claim 1, wherein monitoring the at least one neurotrophin concentration includes:

monitoring the neurotrophin concentration within the innervated tissue.

6. The method as in claim 1, wherein the at least one neurotrophin includes adenosine 3′

, 5′

-cyclic monophosphate (cAMP).

7. The method as in claim 1, wherein the step of introducing at least one neurotrophin includes releasing the at least one neurotrophin from a release device.

8. The method as in claim 7 wherein the release device includes a plurality of release devices.

9. The method as in claim 1, wherein the at least one neurotrophin is selected from the group consisting of:

nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-6 (NT-6), and neurotrophin-7 (NT-7).

10. The method as in claim 1, wherein the at least one neurotrophin is selected from the group consisting of:

nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT-4/5), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor/cholinergic differentiation factor (LIF/CDF), cardiotrophin-1, basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), fibroblast growth factor-5 (FGF-5), insulin, insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), transforming growth factor β

1 (TGF β

1), transforming growth factor β

2 (TGF β

2), transforming growth factor β

3 (TGF β

3), activin, glial cell-derived neurotrophic factor (GDNF), midkine, heparin-binding neurotrophic factor (HBNF), pleiotrophin, epidermal growth factor (EGF), transforming growth factor α

(TGF α

), schwannoma-derived growth factor, heregulin (neuroregulin, ARIA), interleukin 1, interleukin 2, interleukin 3, interleukin 6, axon ligand-1 (Al-1), elf-1, ehk1-L, and LERK2.

11. The method as in claim 1, wherein the at least one neurotrophin includes a cellular second messenger.

12. The method as in claim 1, wherein the at least one neurotrophin is selected from the group consisting of:

forskolin, dibutyric-cAMP (db-cAMP), adenosine 3′

, 5′

-cyclic monophosphate benzyl ester (cAMP-Bn), 8-chloroadenosine-3′

,5′

-cyclic monophosphate (8-Cl-cAMP), 8-(4-Chlorophenylthio)-cAMP(CPT-cAMP), 8-bromo-cAMP (8Br-cAMP), N⁶,O²′

-dibutyryl-cAMP (Bt₂cAMP), and N⁶,O²′

-dioctanoyl-cAMP (O_CO2-cAMP).

13. The method as in claim 1, wherein the at least one neurotrophin is elevated extracellularly within the highly innervated tissue.

14. The method as in claim 1, wherein the at least one neurotrophin is elevated intracellularly within the highly innervated tissue.

15. The method as in claim 1, wherein the at least one inhibitor of degradation includes erythro-9-(2-hydroxy-3-nonyl)adenine.

16. The method as in claim 1, wherein the at least one inhibitor of degradation is selected from the group consisting of:

milrinone, aminone, pimobendan, and enoximone.

17. The method as in claim 1, wherein the at least one inhibitor of degradation is selected from the group consisting of:

rolipram, Ro 20-1724, denbufylline, RS 25344, CP80633, SB207499, RP 73401, CDP 840, and zadarverine.

18. The method as in claim 1, wherein the at least one inhibitor of degradation includes zaprinast.

19. The method as in claim 1, wherein the at least one inhibitor of degradation includes dipyridimole.

20. The method as in claim 1, wherein the desired target level of the at least one neurotrophin is a therapeutically effective level.

21. The method as in claim 1, wherein the desired target level of the at least one neurotrophin is a normal level.

22. The method as in claim 1, wherein the desired target level of the at least one neurotrophin is a baseline level.

23. A method of elevating, in a highly innervated tissue in a subject, the concentrations of at least one neurotrophin and at least one inhibitor of degradation of said neurotrophin, comprising:

(a) introducing into a highly innervated tissue in a subject at least one neurotrophin to elevate a neurotrophin concentration of the at least one neurotrophin within the highly innervated tissue;

(b) introducing into the highly innervated tissue at least one inhibitor of degradation of the at least one neurotrophin to elevate an inhibitor concentration of the at least one inhibitor of degradation of said neurotrophin within the highly innervated tissue; and

(c) regulating the concentration of said at least one inhibitor of degradation of the neurotrophin over time, wherein regulating includes;

monitoring, with at least one implanted sensor device, the inhibitor concentration to determine whether at least one desired inhibitor concentration target level of the at least one inhibitor of degradation is present; and

adding additional inhibitor of degradation in a quantity sufficient to adjust the inhibitor concentration toward the at least one desired inhibitor concentration target level.

24. The method as in claim 23, wherein the subject is a human.

25. The method as in claim 23, wherein the highly innervated tissue is present in a central nervous system.

26. The method as in claim 23, wherein the highly innervated tissue is present in a peripheral nervous system.

27. The method as in claim 23, wherein monitoring the at least one inhibitor of degradation concentration includes:

monitoring the inhibitor concentration within the innervated tissue.

28. The method as in claim 23, wherein the at least one neurotrophin includes adenosine 3′

, 5′

-cyclic monophosphate (cAMP).

29. The method as in claim 23, wherein the step of introducing at least one inhibitor of degradation includes releasing the at least one inhibitor of degradation from a release device.

30. The method as in claim 29 wherein the release device includes a plurality of release devices.

31. The method as in claim 23, wherein the at least one neurotrophin is selected from the group consisting of:

nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-6 (NT-6), and neurotrophin-7 (NT-7).

32. The method as in claim 23, wherein the at least one neurotrophin is selected from the group consisting of:

nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT-4/5), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor/cholinergic differentiation factor (LIF/CDF), cardiotrophin-1, basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), fibroblast growth factor-5 (FGF-5), insulin, insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), transforming growth factor β

1 (TGF β

1), transforming growth factor β

2 (TGF β

2), transforming growth factor β

3 (TGF β

3), activin, glial cell-derived neurotrophic factor (GDNF), midkine, heparin-binding neurotrophic factor (HBNF), pleiotrophin, epidermal growth factor (EGF), transforming growth factor α

(TGF α

), schwannoma-derived growth factor, heregulin (neuroregulin, ARIA), interleukin 1, interleukin 2, interleukin 3, interleukin 6, axon ligand-1 (Al-1), elf-1, ehk1-L, and LERK2.

33. The method as in claim 23, wherein the at least one neurotrophin includes a cellular second messenger.

34. The method as in claim 23, wherein the at least one neurotrophin is selected from the group consisting of:

forskolin, dibutyric-cAMP (db-cAMP), adenosine 3′

, 5′

-cyclic monophosphate benzyl ester (cAMP-Bn), 8-chloroadenosine-3′

,5′

-cyclic monophosphate (8-Cl-cAMP), 8-(4-Chlorophenylthio)-cAMP(CPT-cAMP), 8-bromo-cAMP (8Br-cAMP), N⁶,O²-dibutyryl-cAMP (Bt₂cAMP), and N⁶,O²-dioctanoyl-cAMP (O_CO2-cAMP).

35. The method as in claim 23, wherein the at least one inhibitor of degradation includes erythro-9-(2-hydroxy-3-nonyl)adenine.

36. The method as in claim 23, wherein the at least one inhibitor of degradation is selected from the group consisting of:

milrinone, aminone, pimobendan, and enoximone.

37. The method as in claim 23, wherein the at least one inhibitor of degradation is selected from the group consisting of:

rolipram, Ro 20-1724, denbufylline, RS 25344, CP80633, SB207499, RP 73401, CDP 840, and zadarverine.

38. The method as in claim 23, wherein the at least one inhibitor of degradation includes zaprinast.

39. The method as in claim 23, wherein at the at least one inhibitor of degradation includes dipyridimole.

40. The method as in claim 23, wherein the desired target level of the at least one inhibitor of degradation is a therapeutically effective level.

41. The method as in claim 23, wherein the desired target level of the at least one inhibitor of degradation is a normal level.

42. The method as in claim 23, wherein the desired target level of the at least one inhibitor of degradation is a baseline level.

43. A method of elevating, in a highly innervated tissue in a subject, the concentrations of at least one neurotrophin and at least one inhibitor of degradation of said neurotrophin, comprising:

(a) introducing into a highly innervated tissue in a subject at least one neurotrophin to elevate a neurotrophin concentration of the at least one neurotrophin within the highly innervated tissue;

(b) introducing into the highly innervated tissue at least one inhibitor of degradation of the at least one neurotrophin to elevate an inhibitor concentration of the at least one inhibitor of degradation of said neurotrophin within the highly innervated tissue; and

(c) regulating the concentration of said at least one inhibitor of degradation of the neurotrophin over time, wherein regulating includes;

monitoring the inhibitor concentration to determine whether at least one desired inhibitor concentration target level of the at least one inhibitor of degradation is present; and

adding additional inhibitor of degradation in a quantity sufficient to adjust the inhibitor concentration toward the at least one desired inhibitor concentration target level; and

(d) regulating the concentration of the neurotrophin over time, wherein regulating includes;

monitoring, with at least one implanted sensor device, the neurotrophin concentration to determine whether at least one desired neurotrophin concentration target level of the at least one neurotrophin is present; and

adding additional neurotrophin in a quantity sufficient to adjust the neurotrophin concentration toward the at least one desired neurotrophin concentration target level.