Method for preventing damage to or rejuvenating a cellular blood component using mitochondrial enhancer

• US 7,220,747 B2
• Filed: 05/06/2003
• Issued: 05/22/2007
• Est. Priority Date: 07/20/1999
• Status: Expired due to Fees

• Current Assignee: Terumo BCT Biotechnologies, LLC (Terumo Corporation)
• Original Assignee: Gambro, Inc. (DaVita Incorporated)
• Inventors: Goodrich, Raymond P. Jr., Dumont, Larry Joe
• Primary Examiner(s): Marschel; Ardin H.
• Assistant Examiner(s): Gembeh; Shirley V.
• Application Number:
  US10/430,896
• Publication Number:
  US 20030216285A1
• Time in Patent Office: 1,477 Days
• Field of Search: 435/173.3, 435/2, 514/457
• US Class Current: 514/251
• CPC Class Codes: A61K 31/525 Isoalloxazines, e.g. riboflavins, vitamin B2
• CPC Class Codes: A61K 35/19 Platelets; Megacaryocytes
• CPC Class Codes: A61K 41/17 by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
• CPC Class Codes: A61L 2/0005 for pharmaceuticals, biologicals or living parts
• CPC Class Codes: A61L 2/0011 using physical methods
• CPC Class Codes: A61L 2/0082 using chemical substances
• CPC Class Codes: A61L 2/0088 Liquid substances
• CPC Class Codes: A61L 2/08 Radiation
• CPC Class Codes: A61L 2/10 Ultraviolet radiation
• CPC Class Codes: A61M 1/0213 with isolated sections of the tube used as additive reservoirs
• CPC Class Codes: A61M 1/3681 by irradiation
• CPC Class Codes: A61M 1/3683 using photoactive agents
• CPC Class Codes: A61M 1/3693 using separation based on different densities of components, e.g. centrifuging
• CPC Class Codes: A61M 2202/0078 changed by chemical action
• CPC Class Codes: A61M 2202/0413 Blood
• CPC Class Codes: A61M 2202/0427 Platelets; Thrombocytes
• CPC Class Codes: A61M 2205/051 with radiation therapy
• CPC Class Codes: A61M 2205/123 with incorporated reservoirs

Abstract

This invention provides methods for treating cellular blood components and other cells containing mitochondria to improve vital qualities of the cells by contacting the cells with a mitochondrial enhancer to the cells. Mitochondrial enhancers prevent damage to and rejuvenate mitochondria and cells containing mitochondria. Mitochondrial enhancers include alloxazines and related compounds, such as riboflavin. Cells are optionally treated with photoradiation to reduce pathogens with may be present, before, after, and/or during treatment with mitochondrial enhancer. Treating with mitochondrial enhancer enables utilization of higher photoradiation energies, which achieves better pathogen reduction. When platelets are treated with mitochondrial enhancer, treated platelets may be stored for longer times than untreated platelets before they are administered to patients.

Claims

1. A method for increasing the storage life of platelets, said method comprising adding an amount of a mitochondrial enhancer to a fluid comprising said platelets, wherein said amount is effective to increase amount and/or rate of oxygen consumption of said platelets compared to amount and/or rate of oxygen consumption of platelets in a fluid to which mitochondrial enhancer has not been added, and wherein said amount is substantially non-toxic;

wherein said mitochondrial enhancer is selected from the group consisting of endogenous alloxazines and non-endogenous alloxazines, and vitamin K1, vitamin K1 oxide, vitamin K2, vitamin K5, vitamin K6, vitamin K7, vitamin K-S (II) and vitamin L, whereby the storage life of the platelets is increased such that said platelets can be administered to a patient after seven days of storage.

2. The method of claim 1 wherein the concentration of said mitochondrial enhancer in said fluid is about one to about 200 micromolar.

3. The method of claim 1 wherein said platelets have not been exposed to photoradiation greater than ambient light.

4. The method of claim 1 also comprising exposing said fluid comprising said platelets to photoradiation of sufficient energy to activate a photosensitizer in said fluid.

5. The method of claim 4 wherein said photoradiation is performed using light in the ultraviolet spectrum.

6. The method of claim 4 wherein exposing said fluid to photoradiation is performed at a time selected from the group consisting of before, after, and simultaneously with treating said platelets with said mitochondrial enhancer.

7. The method of claim 4 wherein said photoradiation is of sufficient energy to substantially reduce pathogens which may be present in said fluid.

8. The method of claim 7 wherein said pathogens are selected from the group consisting of extracellular and intracellular viruses, bacteria, bacteriophages, fungi, blood-transmitted parasites, and protozoa, and mixtures of any two or more of the foregoing.

9. The method of claim 6 wherein said photoradiation is between about 5 J/cm² and about 50 J/cm².

10. The method of claim 4 wherein said photosensitizer is said mitochondrial enhancer.

11. The method of claim 10 wherein the concentration of said photosensitizer is about 1 to about 200 micromolar.

12. The method of claim 1 wherein said platelets are not stored prior to adding said mitochondrial enhancer.

13. The method of claim 1 wherein said platelets are stored prior to adding said mitochondrial enhancer.

14. The method of claim 13 wherein said platelets are stored for more than about one hour prior to adding said mitochondrial enhancer.

15. The method of claim 13 wherein said platelets are stored for an amount of time between about 1 hour and about 7 days prior to adding said mitochondrial enhancer.

16. The method of claim 1 wherein said mitochondrial enhancer is selected from the group consisting of 7,8-dimethyl-10-ribityl isoalloxazine, 7,8-dimethylalloxazine, 7,8,10-trimethylisoalloxazine, alloxazine mononucleotide, isoalloxazine-adenosine dinucleotide, vitamin K1, vitamin K1 oxide, vitamin K2, vitamin K5, vitamin K6, vitamin K7, vitamin K-S(II), and vitamin L.

17. The method of claim 1 wherein said mitochondrial enhancer is 7,8-dimethyl-10-ribityl isoalloxazine.

18. The method of claim 1 wherein the concentration of said 7,8-dimethyl-10-ribityl isoalloxazine in said fluid is about one to about 200 micro molar.

19. The method of claim 1 wherein said mitochondrial enhancer is of the formula:

20. The method of claim 19, wherein R1, R2, R3, R4, R5 and R6 are, independently from one another, selected from the group consisting of hydrogen, optionally substituted alcohol, straight chain or cyclic saccharide, amino acid, amine, polyamine, polyether, polyalcohol, sulfate, phosphate, carbonyl, glycol, halogen selected from the group consisting of chlorine, bromine and iodine, aldehyde, ketone, carboxylic acid and ascorbate.

21. The method of claim 1 wherein said oxygen consumption is increased by at least about 5%.

22. The method of claim 1 wherein rate of lactate production of said platelets is decreased by at least about 5%.

23. The method of claim 1 wherein pH of said fluid is increased by at least about 0.1 units.

24. The method of claim 1 wherein hypotonic shock response of said platelets is increased by at least about 5%.

25. The method of claim 1 wherein glucose consumption of said platelets is decreased by at least about 10%.

26. The method of claim 1 wherein platelet swirl of said platelets is increased by at least about 5%.

27. The method of claim 1 wherein platelet aggregation of said platelets is decreased by at least about 5%.

28. The method of claim 1 wherein carbon dioxide production of said platelets is increased by at least about 5%.

29. The method of claim 1 wherein cell count of said platelets is increased by at least about 5%.

30. The method of claim 1 wherein extent of shape change of said platelets is increased by at least about 5%.

31. The method of claim 1 wherein activation of said platelets is decreased by at least about 5%.

32. The method of claim 1 wherein said platelets are stored for more than about one hour after said treating.

33. The method of claim 1 also comprising a step selected from the group consisting of adding nitric oxide to said fluid, adding quencher to said fluid, adding process enhancer to said fluid, adding oxygen to said fluid, and adding glycolysis inhibitor to said fluid.

34. A method for treating a fluid comprising platelets to reduce pathogens which may be present therein and to allow said platelets to be administered to a patient after being stored for seven days, said method comprising the steps of:

(a) adding a reduction-effective, substantially non-toxic amount of a photosensitizer to said fluid;

(b) adding an amount of a mitochondrial enhancer different from said photosensitizerto said fluid;

wherein said amount is effective to increase amount and/or rate of oxygen consumption of said platelets compared to the amount and/or rate of oxygen consumption of platelets in a fluid to which mitochondrial enhancer has not been added, and wherein said amount is substantially non-toxic; and

(c) exposing said fluid to photoradiation of sufficient energy to activate said photosensitizer, for a sufficient time to substantially reduce said pathogens;

wherein said mitochondrial enhancer is selected from the group consisting of endogenous alloxazines and non-endogenous alloxazines, vitamin K1, vitamin K1 oxide, vitamin K2, vitamin K5, vitamin K6, vitamin K7, vitamin K-S (II) and vitamin L and said platelets can be administered to a patient after seven days of storage.

35. The method of claim 34 wherein said energy is greater than an amount selected from the group consisting of 30 J/cm², 50 J/cm², 80 J/cm², 100 J/cm², 120 J/cm², and 180 J/cm².

36. The method of claim 34 wherein said energy is between about 5 J/cm² and about 360 J/cm².

37. The method of claim 34 wherein said energy is between about 25 J/cm² and about 180 J/cm².

38. The method of claim 34 wherein said energy is between about 75 J/cm² and about 120 J/cm².

39. The method of claim 34 wherein said energy is between about 120 J/cm² and about 180 J/cm².