Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-08-04
2001-03-27
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S455000
Reexamination Certificate
active
06207658
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compositions and methods for the protection of tissues, cells, and organs during their removal from a donor, their storage, and their implantation into the recipient.
BACKGROUND
Preservation of the viability of cells in an organ or tissue during transplantation is problematic. The probability that a tissue will survive the process of transplantation depends on many factors including the status of the tissue prior to removal, the duration of time that the tissue remains outside the body and the procedure utilized to initiate reperfusion of the tissue in the recipient.
One source of injury that affects the success of tissue and organ transplantation is oxygen deprivation. In jury of organs, tissues, and cells occurs when the regular flow of oxygenated blood to the tissue and cells is interrupted. This occurs during surgical procedures to remove the organ from a living or recently deceased donor and subsequently during storage ex vivo prior to transplantation into a recipient. However, the most problematic stage in the transplantation process is the grafting of tissue into the recipient and reperfusion of the grafted tissue with oxygenated blood. When reperfusion occurs and energy metabolism starts up again, free radicals accumulate in the cells where anti-oxidant capacity has been diminished. The accumulation of free radicals contributes to post-transplantation injury in tissue giving rise to an increased number of damaged cells and an enhanced immune response by the recipient host. The immune response to transplanted cells includes inflammation caused by cellular antigens exposed by the damaged implanted cells.
Current attempts to reduce damage to tissues during transplantation rely on two general approaches. These are: 1) cooling the tissue to slow metabolic rate; and 2) minimizing the time between removal of the organ or the tissue from the donor and implantation of the tissue or organ into the recipient. During the time in which the body part is readied for transplantation, it is maintained in an isotonic solution. In addition, various investigators have explored the effect of adding anti-oxidants to cells and tissues in isotonic solution prior to implantation into a recipient. These antioxidants include alpha tocopherol (vitamin E), normally found in plasma membranes and membranes of the mitochondria and found to positively impact graft survival (Demirbas et al., Transplantation Proceetlings (1993) 25:2274; Ikeda et al. (1996) Life Sciences 59:781-8; Laue et al. (1995) Tranvsplantation Proceediings: 1875-6;); a compound (EPC-K1), a phosphodiester linkage between vitamin E and vitamin C (Tanemoto et al., Acta-Med-Okayama (1993) 47:121-7); 2-mercapto-imidazole derivatives (Chaudiere et al., WO 9,5 1 8,108); alpha keto-glutarate containing infusible compounds (Ekroth et al., WO 9,534,301); amino acids (Kramer et al., WO 9519768); creatine analogs (Elgebaly et al., WO 9,426,261); and ginkgolide (Ramwell et al., U.S. Pat. No. 5,002,965). In addition, monitoring of isotonic conditions has been found useful in reducing adverse effects on transplanted tissues. (Martindale et al., U.S. Pat. No. 5051352). In studies on the fate of transplant tissue after insertion into the recipient, Foegh et al. (1995) (Journal of Heart and Lung Transplantation (1995) vol. 14, p. S170) reported that estrogen attenuated transplant atherosclerosis by inhibiting abnormal cell growth of smooth muscle under transplant conditions.
There is a need for methods to improve the viability of cells removed from a donor, maintained outside of the body, and implanted into a recipient, such that cell damage is minimized thereby increasing the likelihood of a successful graft through improved viability of the cells and reduced problems resulting from adverse immune reactions.
SUMMARY
The present invention is directed to a method for enhancing cell viability in a population of graft cells during a transplantation procedure that includes the steps of selecting an effective dose of a polycyclic phenolic compound in a physiological acceptable formulation, exposing the population of araft cells to the formulation containing the compound within a time that is effectively proximate to the transplantation procedure, and conferring cytoprotection on the population of graft cells. The polycyclic compound may include a four ring, a three ring, or a two ring structure, having a molecular weight of less than 1000 Daltons. The compound may have a molecular weight of greater than 170 Daltons. The effective dose of the compound may achieve concentrations less than 200 nM or greater than 0.2 nM. The method may further comprise the step of exposing the graft cells to the compound prior to removal from the donor, during storage in vitro or during reperfusion in the recipient animal.
In a preferred embodiment of the invention, a method is provided for optimizing incorporation of graft cells into a recipient subject that includes the steps of selecting an effective dose of a polycyclic phenolic compound in a physiological acceptable formulation; and administering the compound to at least one of; the donor of the graft cells at an effective time prior to removal of the graft cells; the ex vivo storage medium for the graft cells; and the recipient subject at an effective time prior to receipt of the cells.
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Green Pattie S.
Gridley Kelly E.
Simpkins James W.
Bromberg & Sunstein LLP
Jagoe Donna
Krass Frederick
University of Florida Research Foundation Inc.
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