Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1990-08-15
1993-03-23
Rollins, John W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 46, 530317, 536 2731, A61K 3116, A61K 3170
Patent
active
051964023
DESCRIPTION:
BRIEF SUMMARY
This invention relates to therapeutic compositions and method for the treatment of pancreatitis and in particular for the immuno-suppressive treatment of the graft rejection after pancreas transplant.
Pancreatitis is a painful condition which may resolve spontaneously or may kill the sufferer from haemorrhagic necrosis or cause recurrent pain from chronic destruction of the gland. There is no specific treatment for it.
Transplantation of organs or tissue from a donor to a recipient is carried out frequently as a means for replacing failing or diseased organs or tissue by healthy alternatives from another host (allogeneic graft), but this procedure suffers from the danger that the transplanted or grafted organ or tissue will be rejected by the recipient, unless the donor and the recipient are genetically identical (syngeneic graft). Such rejection can be reduced by use of various known drugs which have an immuno-suppressive effect--i.e. they reduce the activity of the mechanism by which the body rejects the implanted material. The mechanism is not fully understood, and there is great need for new treatment agents and methods which can reduce the rejection rate more effectively.
We now have found, surprisingly, that the compound S-adenosylmethionine has valuable properties in the treatment of pancreatitis and as synergizing agent of the immuno-suppressive effect of cyclosporine in combating graft rejection after the pancreas transplant.
The subject to be treated by the method of the invention may be human or animal. We find that the method is applicable to all forms of pancreatitis but especially to the treatment and/or prevention of haemorrhagic pancreatic necrosis and also especially to the treatment of rejection in genetically high responder recipients of transplanted pancreas which is particularly susceptible to inflammatory damage.
The S-adenosyl-methionine is a known compound, described in the literature and available commercially (for example from Bioresearch Spa, Milan, Italy and from Sigma Chemical Company).
The L-enantiomer, S-adenosyl-L-methionine is preferred.
As the compound forms a variety of salts derived from various acids and some of these salts (for example the chloride and, to a lesser degree, the iodide) can be unstable, we prefer to use the compound in the form of a salt which is relatively stable at ambient temperatures, for example the p-toluenesulphonate (available from Sigma Chemical Company, Catalogue No. A.2408).
According to the invention we also provide pharmaceutical compositions, useful for the treatment of inflammatory or graft-rejection conditions, comprising S-adenosyl-methionine as active ingredient.
The S-adenosyl-methionine may be administered in the form of conventional compositions, which may be solutions, dispersions or suspensions in conventional diluent or carrier media appropriate for the systemic introduction of the compound into the body of the recipient to be treated. Thus it may be administered in any appropriate conventional medium compatible with it, for example 0.2M disodium phosphate.
Administration to the body to be treated or protected may be by injection or infusion using conventional techniques, for example intramuscularly, intravenously or intraperitoneally, or by oral means, or by any combination of such techniques. As it appears that the compound can be gradually destroyed in the body, it is highly desirable to maintain a continuing supply of the compound by following up with administration of further doses by the preferred technique. Thus, for example, it is conveniently administered on a "three times per day" basis.
The dosage level may vary according to the severity of the condition and/or the particular subject being treated, but is usually in the range 10 mg to 2.5 g per kg body weight, and preferably in the range 25 mg to 1.0 g per kg body weight. Administration is conveniently effected as a solution in a pharmaceutically acceptable solvent (e.g. water) at a concentration of the order of 25 mg/ml. Higher or lower proportions and dosages may be u
REFERENCES:
Loeser et al., "Inhibitory Effect of Acute and Chronic Application of Cyclosporin on Ornithinearboxylase (ODC), S-Adenosylmethionine Decarboxylase (SAM-DC), Polyamines and Trophic Parameters in Camostate-Induced Pancreatic Growth in Rats", Abstract No. 98, XXI Meeting of the European Pancreatic Club, Glasgow, Scotland, Sep. 20-23, 1989, in Digestion, 43(3), 160 (1989).
Squifflet et al., "Six human pancreas transplants: results and perioperative management", Acta Anesthesiologica Belgica, 37(2), 107-112 (1986).
Grillo et al., "S-Adenosylmethionine Decarboxylase in Liver, Heart and Pancreas of Pyridoxine-deficient Chickens", Ital. J. Biochem., 26(5), 342-346 (1977).
Dyer et al., "Evidence for Altered Methionine Methyl-Group Utilization in the Diabetic Rat's Brain", Neurochemical Research, 13(6), 517-523 (1988).
Vandenbark et al., "Inhibition of Lymphocyte Transformation by a Naturally Occurring Metabolite: 5'-methylthioadenosine", Cell Immunol., 49(1), 26-33 (1980).
Budavari et al. (eds.), "The Merck Index, 11th Ed.", Merck and Co., Rahway, N.J., 1989, see p. 26, entry No. 146.
DiPadova et al., "Inhibition of Lymphocyte Function by a Naturally Occurring Nucleoside: 5'-methylthioadenosine (MTA)", Int. J. Immunopharmacology, 7(2), 193-198 (1985).
Cavallo-Perin et al., "The Pharmacological Effect of S-Adenosyl-Methionine (SAMe) on Glucose Metabolism in Normal Subjects and Diabetic Patients", Current Therapeutic Research, 26(6), 982-989 (1979).
Loser et al., "Dose-dependant Inhibition of the Induction of Pancreatic Ornithine Decarboxylase and Polyamines in Rats by Cyclosporine A", Eur. J. Clin. Invest., 19, A42 (1989).
The Merck Manual, (1987), pp. 322-329, 335.
Braganza Joan M.
Hutchinson Ian V.
Bioresearch S.p.A.
Crane L. Eric
Rollins John W.
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