Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1993-12-03
1995-11-14
Goldberg, J. D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
A61K 3119, A61K 31557
Patent
active
054667135
DESCRIPTION:
BRIEF SUMMARY
This invention relates to an agent for treating cerebral malaria, which contains iloprost as active ingredient, as well as a process for the production of this agent.
Lancet, 1982, 609, already reported on the successful treatment of cerebral malaria, the most severe complication of Plasmodium falciparum malaria, with prostacyclin (PGI.sub.2) on a single patient.
In addition, the WHO report "Severe and Complicated Malaria, Second Edition, Vol. 84, Suppl. 2, 1990, 1-65" mentions 2 additional unpublished cases, which were also treated with prostacyclin.
It has now been found that iloprost (I), its ##STR1## salts with physiologically compatible bases and its .beta.-cyclodextrin clathrate are suitable in an advantageous way for treating cerebral malaria.
Although iloprost, in contrast to PGI.sub.2 a stable prostacyclin derivative, has been known since 1980 by European patent application EP 11591, no other prostacyclin derivative has previously been tested in this indication. It is therefore reasonable to assume that a spontaneous healing is involved in the published case.
It has now been found, surprisingly, that iloprost is effective in the case of cerebral malaria.
For salt formation of iloprost, inorganic and organic bases are suitable, as they are known to one skilled in the art for the formation of physiologically compatible salts. For example, there can be mentioned: alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.
The .beta.-cyclodextrin clathrate formation takes place according to EP 259468.
The production of iloprost is described in detail in EP 11591.
In EP 11591, the following pharmacological properties are described for the carbacyclin derivatives described there:
Lowering of the peripheral arterial and coronary vascular resistance, inhibition of the platelet aggregation and dissolution of platelet clots, myocardial cytoprotection; lowering of the systemic blood pressure without lowering stroke volume and coronary blood circulation at the same time; treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, of myocardial infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, treatment of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion and cytoprotection of the gastric and intestinal mucous membrane; antiallergic properties, lowering of the pulmonary vascular resistance and the pulmonary blood pressure, stimulation of renal circulation, use instead of heparin or as adjuvant in dialysis or hemofiltration, preservation of dried blood plasma, especially of dried blood platelets, inhibition of labor pains, treatment of gestational toxemia, increase of cerebral blood circulation and antiproliferation.
The treatment of cerebral malaria by iloprost is not described and is also not directly connected with the other pharmacological properties described in EP 11591.
The dose of iloprost is 1-1500 .mu.g/kg/day, if it is administered to human patients. The individual dose for the pharmaceutically acceptable vehicle is 0.01-100 mg.
The dosage of an i.v. administration as a continuous infusion in usual aqueous solvents, e.g., 0.9% NaC1 solution, takes place preferably in dosages between 0.1 ng/kg/min and 0.1 .mu.g/kg/min.
The invention thus relates also to pharmaceutical agents based on iloprost and usual adjuvants and vehicles.
The active ingredient according to the invention is to be used in connection with the auxiliary agents known and usual in galenicals, e.g., for the production of agents against cerebral malaria.
The invention also relates to a process for the production of the agent according to the invention, which is characterized in that in a way known in the art, the compound acting against cerebral malaria is put in a galenical formulation with the adjuvants and vehicles known in the art.
EXAMPLES
Mouse model
REFERENCES:
patent: 4497830 (1985-02-01), Skuballa et al.
Sliwa et al., "Prevention of Murine Cerebral Malaria by a Stable Prostacyclin Analog", Infection And Immunity, vol. 59, No. 10 (Oct. 1991), pp. 3846-3848.
The Lancet, vol. 84, Supplement 2 (Jul.-Dec. 1982), edited by M. J. Weston et al., "Prostacyclin in falciparim malaria", p. 609.
S. Palaoglu et al., "Cytoprotective effect of iloprost on isolated cortical brain tissue grafts in rats", Chemical Abstracts, Abstract No. 53008s, vol. 113, No. 7 (1990).
Borzeix et al., "Effects of new chemically and metabolically stable prostacyclin analogues (iloprost and ZK 96480) on early consequences of a transient cerebral oligemia, in the rat", Prostaglandins, vol. 35, No. 5 (May 1988), pp. 652-664.
Blitstein-Willinger Eveline
Sliwa-Hahnle Karin
Goldberg J. D.
Schering Aktiengesellschaft
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