Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1992-11-19
2000-11-21
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 54, 536 2153, 536 535, 536124, A01N 4304
Patent
active
061503428
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel heparin derivatives for treatment of ischemic heart disease and related vascular disorders and process for the preparation thereof.
BACKGROUND
Heparin is sulfate-containing polysaccharide which on a large scale is isolated from intestinal mucus from swine or lung from cattle. The average molecular weight for standard bovine heparin is more than 9,000 and for standard porcine heparin more than 12,000. Traditionally the clinical use of heparin has been associated with its anticoagulant and antithrombotic properties (Jorpes, R. 1946, Heparin in Treatment of Thrombosis, 2nd Ed. Oxford Medical Publications). Heparin has also been found to accelerate coronary collateral development in dogs (Fujita, M. Mikuniya, A. Takahashi, M. Gaddis, R. Hartley, J. McKnown, D. and Franklin, D. 1987, Japanese Circulation Journal, 51, 395-402) and to improve collateral circulation in patients with effort angina (Fujita, M. Sasayama, S. Asanoi, H. Nakijama, H. Sakai, O. and Ohino, A. 1998, Circulation, 77, 1022-1029). Other effects such as the "anti-complimentary power of heparin" recognized by Ecker, E. E. and Gross, P. (1929) in J. Infect. Dis. 44, 250-253 and the finding by Clowes, A. W. and Karnovsky, M. J. (1977) in Nature 265, 625-626 that heparin infusion following experimental injury suppressed the proliferation of smooth muscle cells, have not led to any widespread use of heparin for the treatment of diseases related to inflammation or to arteriosclerosis, which are associated with complement activation and smooth muscle cell proliferation respectively. The risk of haemorrhage is considered to be the main limitation for the clinical use of heparin in non-antithrombotic indications.
The patent application EP 287 477-A discloses heparin products with low molecular weight and this document gives a good review of prior art relating to oxidation of heparin by periodate and to low molecular weight heparins obtained in this manner. Reference is herein given to this document.
In EP 287 477, it was shown that, when heparin obtained from porcine intestinal mucosa was subjected to treatment with periodate at pH 5 followed by depolymerization by treatment with a strong base at a pH above 11 and then reduced by a reducing agent, a low molecular weight heparin was obtained which had 70% of its molecular weight of distributed between 4800-9000 Da and a peak molecular weight of 5500-6000 Da as determined by HPLC. This low molecular heparin is used for regulation of the physiological system.
We have now found that the low molecular weight heparins (heparin fragments) corresponding to EP 287 477 did not significantly accelerate the coronary collateral development. However, unexpectedly, we have found that our novel heparin derivatives of a molecular weight equal to or larger than standard heparin which have an enhanced sulfur content, retain the valuable physiological properties of standard heparin such as the enhancement of coronary collateral development. In addition we have also shown a much smaller effect on the bleeding time for our novel heparin derivatives than for heparin itself. We have also shown a potent antithrombotic activity of our novel heparin derivatives at a dose in which the bleeding time is not prolonged. Thus our novel heparin derivatives are superior to the products claimed in EP 287 477 and will constitute useful drugs for treatment of ischemic heart disease such as angina and related vascular disorders, e.g. to prevent restenosis after percutaneous transluminal angioplasty (PTCA).
Patients suffering from ischemic heart disease generally show a narrowing of the arteries in the heart. Progressive narrowing of the lumen of coronary arteries gives rise to the symptoms of angina and finally often to a myocardial infarction (MI). Excessive uncontrolled growth of smooth muscle cells (SMC) constitutes a major contribution to the progressive narrowing of the coronary vessel. The final occlusion of a stenotic vessel, which precipitates the myocardial infarction, is most frequently ca
REFERENCES:
patent: 4727063 (1988-02-01), Naggi et al.
patent: 4745098 (1988-05-01), Michaeli
patent: 4948881 (1990-08-01), Naggi et al.
patent: 4966894 (1990-10-01), Herr et al.
patent: 5013724 (1991-05-01), Petitou et al.
patent: 5039529 (1991-08-01), Bergendal et al.
patent: 5164378 (1992-11-01), Conti et al.
Shively et al; Biochemistry 15(18):3932-3942 (1976).
Fransson; Carb. Res. 62:235-244 (1978).
Fransson et al; Febs Lett. 97(1):119-123 (1979).
Fransson et al; Carb. Res. 80:131-145 (1980).
Fransson et al; Eur. J. Biochem. 106:59-69 (1980).
Folkman et al; Science 221:719-725 (1983).
Folkman; Adv. Cancer Res. 43:175-203 (1985).
Casu et al; Arzneim. Forsch./Drug Res. 36(I), 4:637-642 (1986).
"Webster's New Ninth Collegiate Dictionary" Merriam-Webster Inc., Springfield, MA, 1990, p. 85.
Mattsson Christer Jan
Svahn Carl Magnus Erik
Weber Michael Per
Fonda Kathleen K.
Pharmacia & Upjohn Aktiebolag
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