Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1991-07-09
1996-11-19
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 54, 536 21, 536 54, 536112, 536118, A61K 31725, C08B 3710
Patent
active
055763049
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pharmaceutical compositions for the prevention of thrombotic conditions, particularly for the prophylaxis of deep vein thrombosis following major surgery.
Heparin has been used for many years as an agent for the treatment and the prevention of thrombosis. The mechanism of the anticoagulant activity of heparin is now essentially known. The coagulation of blood is a cascade-like process in which a number of proteolytic enzymes activate each other in a definite sequence. In the last stage fibrinogen is converted under the action of the proteolytic enzyme thrombin to insoluble fibrin which is the fundamental structure in a blood clot. The coagulation process is further regulated through the inhibiting activity of at least two plasma proteins i.e., antithrombin III (AT III) and heparin cofactor II (HC II). AT III and HC II are homologous proteins which differ in the range of proteases that each inhibits. HC II inhibits thrombin but not factor Xa while AT III inhibits both of these as well as several other proteases involved in coagulation and fibrinolysis.
When added to blood or plasma, heparin acts on various steps of the coagulation process. In particular, by forming complexes with AT III and HC II, it increases their inhibitory effect on most of the inhibition-sensitive enzymes. Thus, as heparin is able to simultaneously depress a large number of the clotting factors, its anti-clotting activity does not appear specific but general.
However, an essential aspect of the activity of heparin consists in the inhibition of factor Xa through activation of AT III. In the middle of the coagulation cascade, factor Xa has a central and important position since it is directly involved in the transformation of pro-thrombin into thrombin. The inhibition of thrombin formation is considered especially important to obtain an effective thrombosis-preventing effect.
It is known that whole heparin is an heterologous polysaccharide with respect both to the composition and the length of its oligosaccharide chain. Whole heparin is a mixture of components of molecular weight from 2 to 40 kD, having an average molecular weight of about 15 kD. Whole heparin may be fractionated by molecular weight, each fraction retaining a heparin-like activity.
The activity of heparin (whole heparin or heparin fragments) as an anti-thrombotic agent may be measured as its specific anti factor Xa activity in the Yin-Wessler test described in J. Lab. Clin, Med. (1973) 81: 298-310. As is well known, the Yin-Wessler activity is representative of the capacity of heparin to potentiate the inhibition of factor Xa by AT III. The specific activity of whole standard heparin for factor Xa is about 150 I.U./mg as defined according to the third International Heparin Standard.
The global anti-clotting activity, i.e. the capacity to prolong the clotting time of blood or plasma may be conveniently measured according to the activated partial thromboplastin time (APTT) method as described in Thrombosis Research (1976) 9: 575. The specific activity of whole standard heparin in the APTT test is fixed by definition so that the ratio between antifactor Xa and APTT specific activities is equal to 1:1, that is, it is also about 150 I.U./mg.
Although whole heparin turns out to be a valuable drug, its use is associated with the risk of haemorrhagic complications if too high a dose is given. Bleeding complications, which are believed to be related to the global anti-clotting action of heparin, especially to the interference with platelet/collagen interaction, are observed at concentration of heparin at which APTT is excessively prolonged. A crucial aspect of the problem is that the dosage must be balanced in such a manner that a good thrombosis protection is obtained simultaneously as bleeding complications are avoided. In general practice, the heparin dosage should be controlled such that the APTT clotting time does not exceed three times the initial clotting time measured in the absence of any anticoagulant agent. However, such a dosage is a delicate
REFERENCES:
patent: 4687765 (1987-08-01), Vairel et al.
patent: 4804652 (1989-02-01), Lormeau et al.
patent: 4908354 (1990-03-01), Seidel et al.
patent: 4973580 (1990-11-01), Mascellani et al.
patent: 5008253 (1991-04-01), Casu et al.
patent: 5164377 (1992-11-01), Van Dedem et al.
Yin, E. T. et al., J. Lab. Clin. Med. (1973) 81:298-310.
Anderson, L.-O. et al. Thrombosis Research (1976) 9:575.
Pulver, V. R. Arzneimittel-Forschung (1965) 15:11.
Copley et al; Biorheology 20:697-704 (1983).
Cade et al; Thrombosis Research 35:613-625 (1984).
Bianchini et al; Thrombosis Research 40:597-607 (1985).
Cella et al; Chemical Abstracts 106:211619d (1987).
Hatanaka et al; J. Med. Chem. 30:810-814 (1987).
Stassen et al; Chemical Abstracts 108:68585y (1988).
Scully et al; Chemical Abstracts 109:145162h (1988).
Ofosu et al; Chemical Abstracts 110:50984j; 50985k (1989).
Kakkar Vijay V.
Scully Michael F.
Dreger Walter H.
Fonda Kathleen Kahler
Kunz Gary L.
Thrombosis Research Institute
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