AU660449B2 - Prostacycline and carbacycline derivatives as agents for treating feverish complaints - Google Patents

Description

Prostacyclin and carbacylin derivatives as agents for treatment of febrile diseases This invention relates to agents for the treatment of diseases, that are accompanied by fever or disseminated intravascular coagulopathy and can be accompanied by cerebral complications.

These agents contain prostacyclin and carbacyclin derivatives and usual adjuvants and vehicles. The invention also relates to the use of these prostacyclin and carbacyclin derivatives for the production of the mentioned agents.

Pharmacological effects of the prostacyclin and carbacyclin derivatives that mainly can be attributed to the cardiovascular and thrombo-aggregation-inhibiting effect are already known from EP 11591, EP 55208, EP 99538, EP 119949 and EP 84856.

It has now been found that agents containing prostacyclin and carbacyclin derivatives are suitable for the treatment of diseases that are accompanied by fever or disseminated intravascular coagulopathy and can be accompanied by cerebral complications. Also the salts of these prostacyclin and carbacyclin derivatives with physiologically compatible bases and their p-cyclodextrin clathrates can also be used for the treatment of the mentioned diseases.

The diseases, that are accompanied by fever or disseminated intravascular coagulopathy and in many cases lead to cerebral complications, include, for example, septic shock, AIDS, rabies, mumps and diseases caused by arboviruses or trypanosomas as well as all consumptive diseases tumors, tuberculosis) These (iseases are accompanied by an elevated tumor necrosis factor (TNF)-serum level. Monoclonal antibodies can indeed block TNF, but cannot influence the synthesis.

Surprisingly it has now been found that the mentioned prostacyclin and carbacyclin derivatives dependent on dosage inhibit the synthesis of TNF at the stage of TNF-messenger-RNA.

Prostacyclins and carbacyclins inhibit the TNF synthesis on the mRNA-level. Thus they are preferable as therapeutic agents to the monoclonal antibodies, that are directed only against already existing TNF. The monoclonal antibodies act only on the already secreted TNF. The formed TNF-aTNF-immunity complexes have to be degraded again, which can lead to clinical complications. Moreover the mentioned prostacyclins and carbacyclins can be used prophylactically for these diseases, which is out of the question for the monoclonal antibodies.

In comparison with PGE 2 the advantage of the new agents lies in the marked reduction of side effects. PGE 2 itself produces fever, leads to increased constriction of the smooth muscles and, in addition, has an abortive effect. The new g*e agents, on the other hand, have a vessel protective and antiedematous effect.

Iloprost, cicaprost, eptaloprost, beraprost and ciprostene *0* have proven to be especially suitable prostacyclin and 4* S. carbacyclin derivatives.

Inorganic and organic bases, as they are known to one skilled in the art for the formation of physiologically compatible salts are suitable for the salt formation with the free acids. 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 ethanol amine, diethanol amine, triethanol amine, Nmethylglucamine, morpholine, tris-(hydroxymethyl)-methyl amine, etc. The p-cyclodextrin clathrate formation takes place corresponding to EP 259468.

The production of the mentioned prostacyclin and carbacyclin derivatives is described in detail in EP 11591, 55208, 119949, 99538 and 84856.

In these patent specifications the following pharmacological properties are described for the prostacyclin and carbacyclin derivatives: reduction of the peripheral arterial and coronary vascular resistance, inhibition of the thrombocyte aggregation and dissolution of platelet blood clots, myocardial cytoprotection; reduction of the systemic blood pressure without at the same time reducing cardiac output and coronary blood circulation; treatment of stroke, prophylaxis and treatment of coronary heart diseases, coronary thrombosis, of myocardial infarctions, peripheral arterial diseases, arteriosclerosis and thrombosis, treatment of shock, inhibition of bronchoconstriction, inhibition of stomach acid secretion and cytoprotection of the gastric and intestinal mucous membrane; antiallergic properties, reduction of pulmonary vascular resistance and of pulmonary blood pressure, promotion of renal blood 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 toxicoses, raising of the cerebral blood circulation and antiproliferation.

The new pharmacological properties for the mentioned prostacyclin and carbacyclin derivatives are not described and are also in no direct connection with the effects described in the EP patent specifications According to one embodiment of the present invention there is provided a method of treatment and/or prophylaxis of humans or animals suffering from, or prone to suffer from diseases that are accompanied by fever or disseminated intravascular coagulopathy comprising treating said human or animal with an effective amount of one or more prostacyclin or carbacyclin derivatives, their salts with physiologically compatible bases and/or their p-cyclodextrin clathrates, optionally in association with one or more pharmaceutically acceptable adjuvants or vehicles.

The dosage of the compounds is 1-1500 ug/kg/day, if administered to human patients. The unit dose for the pharmaceutically acceptable vehicle is 0.01-100 mg.

The dosage of an i.v. administration as continuous infusion in usual equeous .:.solvents, 0.9% NaCl solution, preferably takes place in dosages between 0.1 ng/kg/min and 0.1 p.g/kg/min.

20 Thus the invention also relates to pharmaceutical agents based on the compounds of general formula I and usual adjuvants and vehicles.

The active ingredients according to the invention are to be used in connection with the adjuvants known and usual in galenicals for the production of cerebrally acting agents.

25 The invention also relates to a process for the production of agents according S.I to the invention, characterized in that in a way known in the art the compounds effective in cerebral complications are brought into a galenical formulation with the adjuvants and vehicles known in the art.

-Example 1 In vitro tests show that iloprost, dependent on dosage, inhibits the TNF-production of the NMRI-mice-peritoneal macrophages induced by 50 Ag/ml of LPS. (Fig. 1,2).

By intraperitoneal injection of 2% starch sclution a local sterile inflammation is placed in NMRI-mice. After 3-5 days the animals are.killed and the macrophages are obtained.

The nonadhering cells are separated.

Lipopolysaccharide (LPS) in a concentration of 1.5 pg and Ag/ml is used for activation of the macrophages.

As TNF assay the TNF-sensitive cell line WEHI 164 (obtainable commercially) is used. The extent of the cell lysis of WEHI 164 is proportional to the amount of TNF present. The culture supernatants and sera are titrated in a dilution series in 96 cup flat bottom microtiter plates. A titration series with TMU-TNF is used as standard.

The number of surviving cells is determined based on the colorimetric MTT-test.

The calculation is performed by the comparison with the standard titration series of TMU-TNF by probit analysis.

The test makes possible a determination of up to 0.5 U/ml of TNF. TNFa and TNFP can be differentiated by addition of an anti- TNF antiserum.

6 Example 2 The serum TNF levels of the untreated mice and the mice treated with iloprost are studied.

Iloprost also significantly inhibited the TNF level in the serum even 4 days after the last injection.

Claims (3)

1. A method of treatment and/or prophylaxis of humans or animals suffering from, or prone to suffer from diseases that are accompanied by fever or disseminated intravascular coagulopathy comprising treating said human or animal with an effective amount of one or more prostacyclin or carbacyclin derivatives, their salts with physiologically compatible bases and/or their 3- cyclodextrin clathrates, optionally in association with one or more pharmaceutically acceptable adjuvants or vehicles.

2. The method as claimed in claim I whereir the diseases include septic shock, AIDS, rabies, mumps, disease caused by arboviruses or trypanosomas and consumptive diseases (excluding diabetes).

3. The method as claimed in either claim 1 or f iain 2 wherei the prostacyclin or carbacyclin derivatives are one or more of iloprost, cicaprost, eptaloprost, beraprost and ciprostene. DATED this 21st day of April 1995. SCHERING AKTIENGESELLSCHAFT By Its Patent Attorneys DAVIES COLLISON CAVE ft "t '*\,oByIs atn Atrny DVE CLIONCV 8 Abstract This invention relates to the use of prostacyclin and carbacyclin derivatives for the production of an agent for the treatment of diseases that are accompanied by fever or disseminated intravascular coagulopathy and can be accompanied by cerebral complications. 9 Key to figures TNF Produktion =TNF prodiuction NMRI Peritonealmakrophagen NMRI peritoneal macrophages spontan spontaneous Hemmung durch iloprost. inhibition by iloprost,