CA2104024A1 - Prostacyclin and carbacylin derivatives as agents for treatment of febrile diseases - Google Patents
Prostacyclin and carbacylin derivatives as agents for treatment of febrile diseasesInfo
- Publication number
- CA2104024A1 CA2104024A1 CA002104024A CA2104024A CA2104024A1 CA 2104024 A1 CA2104024 A1 CA 2104024A1 CA 002104024 A CA002104024 A CA 002104024A CA 2104024 A CA2104024 A CA 2104024A CA 2104024 A1 CA2104024 A1 CA 2104024A1
- Authority
- CA
- Canada
- Prior art keywords
- prostacyclin
- agents
- treatment
- diseases
- derivatives
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
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 cerabral complications.
Description
2 ~
Pro~t~cycli~ ~nd aarbaaylin derivatives a~ agent~ ~or treatment of ~ebrile disea~es 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 119~49 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 ~-cyclodextrin clathrates can also be used for the treatment of the mentioned diseases.
The diseases, that are accompanied by fever or disseminated intrava~cular coagulopathy and in many cases lead to cerebral complications, in~lude, for example, septic shock, AIDS, rabies, ---mumps and diseases caused by arboviruses or trypanosomas as well ' - - : ' . . . ' .: . - . , : .
.' . : . ' .
- . . : , . .
.
, , , ~ . ' :
' '",, ~ .: ' ''" :'' - ' .. . . . . .
2~ ~4~2~ ~
as all consumptive diseases (e.g., tumors, tuberculosis, diabetes). These diseases are accompanied by an elevated tumor necrosis factor (TNF)-serum level. Monoclonal antibodi~s 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 mnnoclonal antibodies, that are directe~ only against already existing TNF. The monoclonal antibodies act only on the already secreted TNF. rrhe formed TNF-~TNF-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 PGE2 the advantage of the new agents lies in the marked reduction of side effects. PGE2, eOg., itself produces fever, leads to increased constriction of the smooth muscles andJ in addition, has an abortive e~f~ct. The new agents, on the other hand, have a vessel protective and antiedematous effect.
Iloprost, cicaprost, eptaloprost, beraprost and ciprostene have provsn to be especially suitable prostacyclin and carbacyclin derivatives.
Inorganic and organic bases, as they are known to one skilled in the art for the formation of physiologically . . . ~
, ,,', ............ ~' ' ' . :
Pro~t~cycli~ ~nd aarbaaylin derivatives a~ agent~ ~or treatment of ~ebrile disea~es 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 119~49 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 ~-cyclodextrin clathrates can also be used for the treatment of the mentioned diseases.
The diseases, that are accompanied by fever or disseminated intrava~cular coagulopathy and in many cases lead to cerebral complications, in~lude, for example, septic shock, AIDS, rabies, ---mumps and diseases caused by arboviruses or trypanosomas as well ' - - : ' . . . ' .: . - . , : .
.' . : . ' .
- . . : , . .
.
, , , ~ . ' :
' '",, ~ .: ' ''" :'' - ' .. . . . . .
2~ ~4~2~ ~
as all consumptive diseases (e.g., tumors, tuberculosis, diabetes). These diseases are accompanied by an elevated tumor necrosis factor (TNF)-serum level. Monoclonal antibodi~s 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 mnnoclonal antibodies, that are directe~ only against already existing TNF. The monoclonal antibodies act only on the already secreted TNF. rrhe formed TNF-~TNF-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 PGE2 the advantage of the new agents lies in the marked reduction of side effects. PGE2, eOg., itself produces fever, leads to increased constriction of the smooth muscles andJ in addition, has an abortive e~f~ct. The new agents, on the other hand, have a vessel protective and antiedematous effect.
Iloprost, cicaprost, eptaloprost, beraprost and ciprostene have provsn to be especially suitable prostacyclin and carbacyclin derivatives.
Inorganic and organic bases, as they are known to one skilled in the art for the formation of physiologically . . . ~
, ,,', ............ ~' ' ' . :
3 2~Q~
compatible salts are suitable for the sal.t 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, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methyl amine, etc. The ~-cyclodextrin clathrate formation takes place corresponding to EP 259~68.
The production of the mentioned prostacyclin and carbacyclin derivatives is described in detail in EP 11591, 55208, 119949, ~953B and 84856.
In these patent specifications the following pharmacological properties are describ~d for the prostacyclin and cârbacyclin derivative~: 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 tr~atment of coronary heart disea~es, coxonary thrombosis, of ~yocardial 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 resi~tance and of pulmonaxy blood pressure, promotion of renal blood circulation, use instead of heparin or as adjuvant in : : , . . . . . .
. , . ,~ , . . .
. : . : . . : ~ . -. ' ', :: . ' . . . , :' . ' . . ...................... . . . . . .
compatible salts are suitable for the sal.t 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, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methyl amine, etc. The ~-cyclodextrin clathrate formation takes place corresponding to EP 259~68.
The production of the mentioned prostacyclin and carbacyclin derivatives is described in detail in EP 11591, 55208, 119949, ~953B and 84856.
In these patent specifications the following pharmacological properties are describ~d for the prostacyclin and cârbacyclin derivative~: 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 tr~atment of coronary heart disea~es, coxonary thrombosis, of ~yocardial 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 resi~tance and of pulmonaxy blood pressure, promotion of renal blood circulation, use instead of heparin or as adjuvant in : : , . . . . . .
. , . ,~ , . . .
. : . : . . : ~ . -. ' ', :: . ' . . . , :' . ' . . ...................... . . . . . .
4 ~ 2 ~ -dialysis or hemofiltration, preservation of dried blood plasma, especially of dried blood platelets, inhibition of labor pai.ns, treatment of gestational toxicoses, raising of the cerebral blood circulation and antiprolife.ration.
The new pharmacological properties for th~ mentioned prostacyclin and carbacyclin derivatives are not described and are also in no direct sonnection with the effects described in the EP patent specifications.
The dosage of the compoullds is 1-1500 ~g/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 conkinuous infusion in usual aqueous solvents, e.g., 0.9~ NaCl solution,^ preferably takes place in dosages between 0.1 ng/kg/min and 0.1 ~g/kg/min.
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 e.g., for the production of cerebrally acting agents.
The invention also relates to a process for the production o~ agents according to the invention, charact~rized 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.
- . . . .. . . .
: ... . . . .
~,. , , .
... .. - ; . . .
. . .
. . .
.
. - . . . . .
2 ~ 21~ ' ~E~ample 1 In vitro tests show that iloprost, dependent on dosage, inhibits the TNF-production of the N~RI-mice--peritoneal macrophages induced by 50 ~g/ml of LPS. (FigO 1,2).
By intraperitoneal injection of 2~ starch solution 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 ~g and 50 ~g/ml is used for activation of the macrophages.
A~ TNF assay the TNF-sensitive cell line WEHI 164 (obtainable commercially) is used. The extent of the cell lysis o~ WE~I 164 is proportional to the amount of TNF prësent. 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 ~TT-test.
The calculation is performed by the comparison with the ~tandard titration series of TMU-TNF by probit analysis.
The test makes possible a determination of up to O.5 U/ml of TNF. TNF~ and TNF~ can be differentiated by addition of an anti-TNF antiserum.
.
.. , . .. ~, . .. . ' ' .: . :
: . ' ' ' ' , ' -.. . . . . . . . .
.
, ~ ' ' '. " .'~ ' '.
2 ~
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 in3ection.
:: ' : , .
- : . : ' ' .: ' ~ ~ ..
The new pharmacological properties for th~ mentioned prostacyclin and carbacyclin derivatives are not described and are also in no direct sonnection with the effects described in the EP patent specifications.
The dosage of the compoullds is 1-1500 ~g/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 conkinuous infusion in usual aqueous solvents, e.g., 0.9~ NaCl solution,^ preferably takes place in dosages between 0.1 ng/kg/min and 0.1 ~g/kg/min.
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 e.g., for the production of cerebrally acting agents.
The invention also relates to a process for the production o~ agents according to the invention, charact~rized 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.
- . . . .. . . .
: ... . . . .
~,. , , .
... .. - ; . . .
. . .
. . .
.
. - . . . . .
2 ~ 21~ ' ~E~ample 1 In vitro tests show that iloprost, dependent on dosage, inhibits the TNF-production of the N~RI-mice--peritoneal macrophages induced by 50 ~g/ml of LPS. (FigO 1,2).
By intraperitoneal injection of 2~ starch solution 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 ~g and 50 ~g/ml is used for activation of the macrophages.
A~ TNF assay the TNF-sensitive cell line WEHI 164 (obtainable commercially) is used. The extent of the cell lysis o~ WE~I 164 is proportional to the amount of TNF prësent. 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 ~TT-test.
The calculation is performed by the comparison with the ~tandard titration series of TMU-TNF by probit analysis.
The test makes possible a determination of up to O.5 U/ml of TNF. TNF~ and TNF~ can be differentiated by addition of an anti-TNF antiserum.
.
.. , . .. ~, . .. . ' ' .: . :
: . ' ' ' ' , ' -.. . . . . . . . .
.
, ~ ' ' '. " .'~ ' '.
2 ~
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 in3ection.
:: ' : , .
- : . : ' ' .: ' ~ ~ ..
Claims (7)
1. Use of prostacyclin and carbacyclin derivatives for the production of agents for the treatment of diseases that are accompanied by fever or disseminated intravascular coagulopathy and can be accompanied by cerebral complications.
2. Use of prostacyclin and carbacyclin derivatives for the production of agents for the treatment of septic shock, AIDS, rabies, mumps, diseases caused by arboviruses and by trypanosomas and of consumptive diseases.
3. Agents for the treatment of diseases according to claim 1, containing prostacyclin or carbacyclin derivatives and usual adjuvants and vehicles.
4. Agents for the treatment of diseases according to claim 2, containing prostacyclin or carbacyclin derivatives and usual adjuvants and vehicles.
5. Use of prostacyclin and carbacyclin derivatives iloprost, cicaprost, eptaloprost, beraprost and ciprostene for the production of an agent according to claim 1.
6. Use of iloprost, cicaprost, eptaloprost, beraprost and ciprostene for the production of an agent according to claim 2.
7. Agents for the treatment of diseases according to claim 2, containing iloprost, cicaprost, eptaloprost, beraprost or ciprostene and usual adjuvants and vehicles.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4104607.2 | 1991-02-12 | ||
| DE4104607A DE4104607A1 (en) | 1991-02-12 | 1991-02-12 | PROSTACYCLIN AND CARBACYCLINE DERIVATIVES AS A MEDIUM FOR TREATING FEVERED DISEASES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2104024A1 true CA2104024A1 (en) | 1992-08-13 |
Family
ID=6425075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002104024A Abandoned CA2104024A1 (en) | 1991-02-12 | 1992-02-11 | Prostacyclin and carbacylin derivatives as agents for treatment of febrile diseases |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0571462A1 (en) |
| JP (1) | JPH06507381A (en) |
| KR (1) | KR930702990A (en) |
| AU (1) | AU660449B2 (en) |
| CA (1) | CA2104024A1 (en) |
| DE (1) | DE4104607A1 (en) |
| WO (1) | WO1992014438A2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3230246B2 (en) * | 1991-04-11 | 2001-11-19 | 東レ株式会社 | Malignant tumor metastasis inhibitor |
| US5496850A (en) * | 1991-04-11 | 1996-03-05 | Toray Industries, Inc. | Antimetastasis agent of malignant tumors |
| DE4124693A1 (en) * | 1991-07-22 | 1993-01-28 | Schering Ag | Use of carbocycline derivs. - esp. iloprost, cicaprost, eptaloprost, beraprost or ciprostene, for treatment of vitiligo |
| DE4124695C2 (en) * | 1991-07-22 | 1994-12-22 | Blitstein Willinger Eveline Dr | Use of carbacyclin derivatives for the treatment of psoriasis vulgaris |
| DE4226615C1 (en) * | 1992-08-07 | 1994-05-19 | Schering Ag | Use of prostane derivatives for the treatment of chronic polyarthritis |
| DE19530884C2 (en) * | 1995-08-11 | 1997-07-31 | Schering Ag | Use of prostane derivatives and their combination with antibiotics for the treatment of bacterial meningitis |
| WO1998037895A1 (en) * | 1997-02-27 | 1998-09-03 | Toray Industries, Inc. | Drugs for ameliorating pulmonary circulation |
| WO1998041209A1 (en) * | 1997-03-14 | 1998-09-24 | Toray Industries, Inc. | Protective agents for cells constituting nervous system |
| JPH11228417A (en) * | 1998-02-06 | 1999-08-24 | Teijin Ltd | Neuropathy remedy |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2845770A1 (en) * | 1978-10-19 | 1980-04-30 | Schering Ag | NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| US4256883A (en) * | 1979-03-14 | 1981-03-17 | Research Corporation | Pyridoza prostacyclin analogues and N-oxides thereof |
| JPS58124778A (en) * | 1982-01-20 | 1983-07-25 | Toray Ind Inc | 5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivative |
| DE3226550A1 (en) * | 1982-07-13 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3740838A1 (en) * | 1987-11-27 | 1989-06-08 | Schering Ag | CYCLODEXTRINCLATHRATE OF 5-CYANO-PROSTACYCLINE DERIVATIVES AND THEIR USE AS MEDICINAL PRODUCTS |
| DE68918726T2 (en) * | 1988-02-23 | 1995-03-02 | Fujisawa Pharmaceutical Co | Antidiabetic agents containing isocarbacyclin derivatives. |
-
1991
- 1991-02-12 DE DE4104607A patent/DE4104607A1/en not_active Withdrawn
-
1992
- 1992-02-11 WO PCT/DE1992/000100 patent/WO1992014438A2/en not_active Application Discontinuation
- 1992-02-11 CA CA002104024A patent/CA2104024A1/en not_active Abandoned
- 1992-02-11 EP EP92904665A patent/EP0571462A1/en not_active Withdrawn
- 1992-02-11 AU AU12433/92A patent/AU660449B2/en not_active Ceased
- 1992-02-11 JP JP4504121A patent/JPH06507381A/en active Pending
-
1993
- 1993-08-11 KR KR1019930702386A patent/KR930702990A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992014438A3 (en) | 1993-01-07 |
| DE4104607A1 (en) | 1992-08-13 |
| AU1243392A (en) | 1992-09-15 |
| JPH06507381A (en) | 1994-08-25 |
| AU660449B2 (en) | 1995-06-29 |
| KR930702990A (en) | 1993-11-29 |
| EP0571462A1 (en) | 1993-12-01 |
| WO1992014438A2 (en) | 1992-09-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |