Organoprotective solutions

Details Organoprotective solutions Organoprotective solutions

1999-01-22

2001-11-06

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S053000, C514S056000, C514S060000

Reexamination Certificate

active

06313104

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to the use of polysulfated glycosaminoglycans having a sulfur content of at least 12.5% for producing pharmaceutical preparations for inhibiting the &ggr;-interferon-induced upregulation of the MHC Class I and MHC Class II proteins and ICAM-1. The invention furthermore relates to organoprotective solutions comprising polysulfated glycosaminoglycans and to a process for the ex-vivo protection of transplant organs.
The use of glycosaminoglycans and specifically of heparins and heparinoids for producing pharmaceutical preparations for treating perfusion disorders is well known.
The use of glycosaminoglycans for a number of other diseases has recently been described. Thus, U.S. Pat. No. 5,236,910 claims the use of glycosaminoglycans for treating diabetic nephropathy and neuropathy. The use of low molecular weight heparins for the same indication is described by van der Pijl et al. (J. Americ. Soc. Nephrol. 8 (1997), 456-462).
U.S. Pat. No. 5,032,679 claims the use of glycosaminoglycans for inhibiting the proliferation of smooth muscle cells and the diseases associated therewith.
U.S. Pat. No. 4,966,894 claims polysulfated heparins for treating diseases caused by retroviruses.
Granlinski et al. describe the modulation of the complement system by polysulfated heparins.
In Clin. Exp. Immunol. 107 (1997), 578-584, Douglas et al. study antagonization of the inflammation-promoting activity of &ggr;-inteferon with heparin, heparan sulfate or heparin-like molecules. Heparin is capable of influencing the immunogenic effect of &ggr;-inteferon.
In the transplantation of organs, undesirable rejections are frequently observed. A large number of different approaches have been used to prevent these rejections. Thus, first, the histo-compatibility antigens of donor and recipient are compared. Only those organs are transplanted whose donor and recipient have, if possible, identical, or very similar, histocompatibility antigens. Inspite of this, undesirable organ rejections are frequently observed. For example, an acute renal allograft rejection is observed, whose main effect is the recognition of the allo-MHC antigens by T lymphocytes, resulting in a lysis of the tubular cells. Also observed is the “graft versus host reaction”, a strong reaction of the immune cells of the donor, which are transplanted with the organ, against the recipient. Cytotoxic T cells and antibodies against the host organism are formed.
To further reduce the risk of a graft rejection, the organs are cooled immediately after harvest and stored in an organo-protective solution. Furthermore, drugs are administered to the recipient to suppress the immune response of the recipient.
A large number of organoprotective solutions are described in the literature. Thus, Collins et al. (Lancet 2 (1969), 1219) describe intracellular electrolyte solutions for preserving the organs. Sacks S. A. (Lancet 1 (1973), 1024) describes solutions having an osmotically stabilizing effect. ATP-MgCl
2
, AMP-MgCl
2
and inosine are described as being advantageous agents in such solutions (Siegel, N. J. et al., Am. J. Physiol. 254 (1983), F530, Belzer et al., Transpl. Proc. 16 (1984), 161). U.S. Pat. No. 4,920,004 claims a solution containing mannitol, adenosine and ATP-MgCl
2
. U.S. Pat. Nos. 4,798,824 and 4,873,230 claim an organoprotective solution which contains hydroxyethyl starch. U.S. Pat. No. 4,879,283 claims a solution which contains KH
2
PO
4
, MgSO
4
, adenosine, allopurinol, raffinose and hydroxyethylcellulose. This solution is known as University of Wisconsin solution (=UW-solution) and is described as having been used for successful preservation of liver, kidneys and heart (Jamieson et al., Transplantation 46 (1988), 517, Ploeg et al., Transplantation 46 (1988) 191 and Wicomb, W. N., Transplantation 47 (1988), 733). In U.S. Pat. No. 5,200,398, glucoronic acid, and salts and esters thereof are described for use as a further additive in these protective solutions.
Inspite of the successes that have been achieved in the protection of organs for transplantation and in suppressing undesirable organ rejections, there is still a demand for further improvement.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide further improvements both in organoprotection prior to and during transplantation and to further reduce the risk of organ rejection.
We have found that this object is achieved by using polysulfated glycosaminoglycans having a sulfur content of at least 12.5% by weight for producing pharmaceutical preparations for inhibiting the &ggr;-interferon-induced upregulation of the MC Class I and MHC Class II proteins and ICAM-1.
The invention furthermore relates to organoprotective solutions which comprise such an amount of a polysulfated glycosaminoglycan having a sulfur content of at least 12.5% by weight that it is effective in maintaining cell integrity and cell vitality.


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