Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1993-07-28
1995-12-05
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 21, A61K 31725, C08B 3710
Patent
active
054729530
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the use of heparin with low affinity for antithrombin III for the preparation of a medicament in the treatment of malaria.
BACKGROUND
Heparin is best known as an inhibitor of the blood coagulation system and is thus widely used as an anticoagulant but has a number of other biological activities (Jaques 1979). It is a heterogeneous mixture of related molecules that can be fractioned according to size or affinity for antithrombin (Andersson et al 1976). Such heparin fractions vary considerably in their anticoagulant activity (Andersson et al 1976), which is dependent on antithrombin binding.
Heparin has been used for treatment of patients with Plasmodium falciparum malaria (Mitchell 1974; Munir et al 1980; Smitskamp and Wolthius 1971), with ambiguous results. In studies of Rhesus monkeys infected with Plasmodium knowlesi, treatment with heparin has, according to some authors (Dennis and Conrad 1968), efficiently cured the monkeys, while others have found it to be inefficient (Howard and Collins 1972; Reid and Sucharit 1972). In vitro heparin has been shown to inhibit invasion and development of P. falciparum (Butcher et al 1988; Sivaraman and Chowdhuri 1983) and in one of these studies the 50% inhibitory dose of heparin and of heparin fractions with high or low affinity for antithrombin III were reported to be the same; 1 mg/ml (Butcher et al 1988).
DESCRIPTION OF THE INVENTION
In order to further study the effect of heparin on the malaria parasite we have used different P. falciparum strains to analyse the invasion inhibition capacity in vitro of heparin and various heparin fractions differing in affinity for antithrombin III or in average molecular weight. We have also analysed the ability of the different heparin fractions to disrupt spontaneously formed P. falciparum erythrocyte rosettes, a phenomenon thought to be involved in the pathogenesis of cerebral malaria. Our studied heparin fraction include: HA-heparin, heparin with high affinity for AT III LA-heparin, heparin with low affinity for AT III HMW-heparin, high molecular weight heparin LMW-heparin, low molecular weight heparin N-acetylated HM heparin, high molecular weight heparin with low anticoagulant activity.
The invention relates to the use of heparin with low affinity for antithrombin III, LA-heparin, for the preparation of a medicament in the treatment of malaria. More specific the therapeutic dose of the heparin with low affinity for antithrombin III is between 2 and 200 mg in the medicament. The heparin with low affinity for antithrombin III has preferably a reduced bleeding time prolongation in comparision with heparin. The specific anticoagulant activity of the used LA-heparin is preferably .ltoreq.30 IU/mg as determined by APTT. A daily dose could be 0.05-5 mg per kg. The heparin with low affinity for antithrombin III could be used in combination with other medicaments for the treatment of malaria.
The invention also covers a method for the treatment of malaria, wherein a therapeutically effective amount of heparin with low affinity for antithrombin III is administered to a patient in need of such treatment.
It is preferred that the administration is made by injection or infusion. A suitable effective amount of the heparin is such as to result in a daily dose of from about 2 to about 200 mg.
The medicament for the treatment of malaria prepared in accordance with the present invention may thus be formulated in accordance with traditional pharmaceutical practice for use for therapeutic purposes. Such compositions may include the active ingredient heparin with low affinity for antithrombin III, in combination with a pharmaceutically acceptable carrier, which may be solid, semisolid or liquid. The compositions constituting such medicament may be designed for administration through different routes.
Suitable forms of the composition used in applying the techniques of the present invention include tablets, capsules, syrups, suspensions, solutions and forms suitable for injection or infusion. The latter forms int
REFERENCES:
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Sigma Chemical Company Catalog, 1989, p. 691.
Carlson Johan
Ekre Hans-Peter
Kulane Asli A.
Perlmann Peter
Wahlgren Mats
Fonda Kathleen Kahler
Robinson Douglas W.
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