Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or... – Including perfusion; composition therefor
Patent
1994-12-06
1996-10-15
Naff, David M.
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
Including perfusion; composition therefor
514 61, 514832, 604 27, A01N 102, A01N 4304, A61M 100
Patent
active
055653170
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a solution for the preservation of organ or perfusate to be used when an organ is extirpated.
The drastic improvement of performance record of organ transplantation is attributable to the progress of organ storage solution or perfusate as well as the progress of surgical operations and the advancement of antibiotics and immunosuppressants.
In organ transplantation, perfusion of the transplanted organ is essential, but when perfusing the organ which is in an ischemic state, ischemic perfusion trouble is unavoidable. Thus, minimization of the cellular trouble caused in the process of perfusion is a key factor for the success of organ transplantation.
Hitherto, UW solution (JP-A-1-246201; a solution composed of potassium lactobionate, potassium dihydrogenphosphate, magnesium sulfate, sodium hydroxide, raffinose, adenosine, glutathione, insulin, bactrim, dexamethasone, allopurinol and hydroxyl ethyl starch) has been used as the storage solution, and Ringer's solution or Carolina Rinse solution (a solution composed of sodium chloride, potassium chloride, calcium chloride, sodium lactate, adenosine, allopurinol, desferrioxamine and glutathione) has been used as the perfusate. Further, the modified versions of these solutions featuring incorporation of proteinase inhibitors such as nafamostat mesilate in the compositions have been reported Shinryo to Shinyaku, Clinic and New Drugs, 29:194-197 (1992).
Of these organ storage solutions and perfusates, UW solution was developed by Belzer et al in 1987 and has phenomenally prolonged the organ preservable period. However, since this solution contains hydroxyl ethyl starch as noted from its composition, the solution is increased in viscosity in use, making it difficult to remove blood from the organ. Also, because of high potassium concentration, this solution gives detrimental effect to the vascular endothelium. This solution is also unsatisfactory in its buffering action. Further, it is costly as it contains insulin.
The organ preservable period of Ringer's solution or Carolina Rinse solution is 24 hours at most. This is rather unsatisfactory for a storage solution.
The object of the present invention is to provide an organ storage solution or perfusate at a low cost which is designed to safely preserve the organ to be transplanted or to protect the organ from cellular trouble caused in the process of perfusion.
The present inventors have tried to incorporate electrolyte, osmotic pressure regulator, proteinase inhibitor, etc., in various combinations in the storage solution or perfusate compositions and, as a result, completed the present invention to attain the desired end.
The organ storage solution or perfusate of the present invention comprises sodium lactobionate, sodium dihydrogenphosphate, raffinose, glutathione, allopurinol and nafamostat mesilate. The especially preferred organ storage solution or perfusate of the present invention is characterized by having the composition of 100-120 mM sodium lactobionate, 25-35 mM sodium dihydrogenphosphate, 25-35 mM raffinose, 2-4 mM glutathione, 1-2 mM allopurinol and 0.5-1 mM nafamostat mesilate, an osmotic pressure of 290-350 mOsm/l and a pH of 7.0-8.0.
Further, in the formulation of the present invention, in order to prevent the precipitation caused by compositional interaction, it is desirable to add an appropriate amount of cyclodextrin. As cyclodextrin, .alpha.-cyclodextrin, .beta.-cyclodextrin or .gamma.-cyclodextrin may be used singly, or a mixture of two or more of said types of cyclodextrin may be used.
Thus, the present invention further relates to an organ storage solution or perfusate comprising sodium lactobionate, sodium dihydrogenphosphate, raffinose, glutathione, allopurinol, nafamostat mesilate and cyclodextrin, and the especially preferred organ storage solution or perfusate of the present invention is characterized by having the composition of 100-120 mM sodium lactobionate, 25-35 mM sodium dihydrogenphosphate, 25-35 mM raffinose, 2-4 mM glutathione, 1-2 mM allopuriono
REFERENCES:
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patent: 4873230 (1989-10-01), Belzer et al.
patent: 4879283 (1989-11-01), Belzer et al.
patent: 4889634 (1989-12-01), El-Rashidy
patent: 4938961 (1990-07-01), Collins et al.
patent: 5145771 (1992-09-01), Lemasters et al.
Tsuyoshi Morimoto, "An Experimental Study On Futhan In Pancreas Transplantation", Shinryo to Shinyaku (Clinic and New Drugs), vol. 29, No. 1, pp. 194-197 (1992).
Yoshifumi Naka et al., "Prevention of Pulmonary Edema in Autoperfusing Heart-Lung Preparation by FUT-175 and Leukocyte Depletion" Transplantation Proceedings, vol. XXI, No. 1, Feb. 1989 pp. 1353-1356.
Takashi Urushihara et al., "Efficacy of Futhan Rinse Solution following Rat Heart Preservation" Chemical Abstracts, vol. 119, No. 1, 5 Jul. 1993, Columbus, Ohio, US; abstract no. 4342 & Nippon Geka Gakkai Zasshi, vol. 93, No. 12, 1 Dec. 1992 p. 1514.
N. Harada et al. "Effect of Fosfomycin Fosmicin On Experimental Acute Pancreatitis Induced by Deoxycholic Acid in Rats" Biological Abstracts, vol. 91, Philadelphia, PA, US; abstract no. 106059.
Harada N. et al., "Stabilization of Glutathione-Containing Compositions with Gamma Cyclodextrin" Chemical Abstracts: 111:132914(1989).
Miyagawa S et al, Transplant Proc 24(2): 483-484 (Apr. 1992).
Dohi Kiyohiko
Iwata Masanori
Urushihara Takashi
Naff David M.
Saucier S.
Torii Pharmaceutical Co., Ltd.
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