DE3331459A1 - Composition for tumour treatment containing diazoxide, and the use thereof - Google Patents
Composition for tumour treatment containing diazoxide, and the use thereofInfo
- Publication number
- DE3331459A1 DE3331459A1 DE19833331459 DE3331459A DE3331459A1 DE 3331459 A1 DE3331459 A1 DE 3331459A1 DE 19833331459 DE19833331459 DE 19833331459 DE 3331459 A DE3331459 A DE 3331459A DE 3331459 A1 DE3331459 A1 DE 3331459A1
- Authority
- DE
- Germany
- Prior art keywords
- diazoxide
- tumor
- preparation
- composition
- treatment containing
- 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.)
- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 15
- 229960004042 diazoxide Drugs 0.000 title claims abstract description 10
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 title claims abstract 6
- 239000000203 mixture Substances 0.000 title claims abstract 3
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 229960002985 medroxyprogesterone acetate Drugs 0.000 claims description 3
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 claims description 3
- 229960001603 tamoxifen Drugs 0.000 claims description 3
- 230000004614 tumor growth Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims 4
- 238000004806 packaging method and process Methods 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 230000003388 anti-hormonal effect Effects 0.000 claims 1
- 230000003139 buffering effect Effects 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003995 emulsifying agent Substances 0.000 claims 1
- 239000000839 emulsion Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 230000003054 hormonal effect Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 5
- 201000008275 breast carcinoma Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 4
- GDLBFKVLRPITMI-UHFFFAOYSA-N diazoxide Chemical compound ClC1=CC=C2NC(C)=NS(=O)(=O)C2=C1 GDLBFKVLRPITMI-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 3
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 2
- VFZRZRDOXPRTSC-UHFFFAOYSA-N DMBA Natural products COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 2
- 208000007241 Experimental Diabetes Mellitus Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- PPQNQXQZIWHJRB-UHFFFAOYSA-N Methylcholanthrene Chemical compound C1=CC=C2C3=CC4=CC=C(C)C(CC5)=C4C5=C3C=CC2=C1 PPQNQXQZIWHJRB-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 150000007658 benzothiadiazines Chemical class 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 201000005857 malignant hypertension Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Beschreibung:Description:
In den letzten 15 Jahren wurden drei tierexperimentelle Untersuchungen veriffentlicht, in denen nahezu übereinstimmend ein langsames Wachstum oder eine Remission von Tumoren in diabetischen Versuchstieren beschrieben. wird. Beim DM8A-induzierten %mma-Carcinom der Ratte wurde von Heuson und Legros eine erhebliche Verkleinerung von 90« der Tumoren beschrieben, nachdem bei den Tieren ein Alloxan-Diabetes induziert worden war (Europ.There have been three animal studies in the past 15 years published in which a slow growth or a nearly consistent Remission of tumors in diabetic test animals is described. will. When the DM8A-induced % mma carcinoma in the rat was a substantial reduction in size by Heuson and Legros of 90% of the tumors described after alloxan diabetes was induced in the animals had been (Europ.
J. Cancer 6 (1970),.349). Eine deutliche Reduktion des Tumorwachstums nach Diabetes-Induktion mit Alloxan konnte von Puckett und Shingleton bei einem Mamma-Carcinom der C3H-'1us (Cancer Res. 32 (1972), 789) und von Pavelic beim Methylcholanthren-induzierten Fibrosarkom der Maus (Europ.J. Cancer, 6: 349 (1970)). A significant reduction in tumor growth After diabetes induction with alloxan, von Puckett and Shingleton could in one Mammary carcinoma of C3H-'1us (Cancer Res. 32 (1972), 789) and of Pavelic in the case of methylcholanthrene-induced Mouse fibrosarcoma (Europ.
J. Cancer 16 (1980), 279) beobachtet werden.J. Cancer 16: 279 (1980)).
Die eigentliche biochemische Ursache der erwähnten Remissionsinduktion bzw. Wachstumsverzögerung scheint derzeit noch nicht bekannt zu sein.The actual biochemical cause of the remission induction mentioned or growth retardation does not seem to be known yet.
Umgekehrt ist jedoch die ebenfalls beschriebene und in der Mehrzahl der Fälle gefundene Wachstumsförderung maligner Tumoren durch Insulin wahrscheinlich nicht durch einen metabolischen Effekt, sondern durch eine Wirkung auf das DNS-produzierende Enzym-System bedingt (Heuson und Legros: Cancer Res. 31 (1971), 59).However, the reverse is also described and in the majority of the cases found, growth of malignant tumors is likely to be promoted by insulin not by a metabolic effect, but by an effect on the DNA-producing one Due to the enzyme system (Heuson and Legros: Cancer Res. 31 (1971), 59).
Auch beim Menschen scheint ein Diabetes mellitus einen günstigeren Verlauf des metastasierenden Mamma-Carcinoms zu bewirken. Rhomberg fand bei diabetischen Mamma-Carcinam-Patientinnen eindeutig g längere Oberlebenszeiten sowie ein Ansprechen auf verschiedene Formen der Hormontherapie in 18 von 24 Fällen gegenüber ca. 30«, bei den übrigen Patientinnen (Dtsch. Med.Diabetes mellitus also appears to be more favorable in humans To effect the course of the metastatic breast carcinoma. Rhomberg found in diabetic Mamma carcinam patients clearly had longer survival times and a response on different forms of hormone therapy in 18 of 24 cases compared to approx. 30 «, in the other patients (German Med.
Wschr. 100 (1975), 2422). Der Schluß scheint somit zulässig, daß Versuche am DMBA-induzierten Mamma-Carcinom der Ratte einen Vergleich mit der menschlichen Situation ermöglichen.Wschr. 100: 2422 (1975)). The conclusion thus seems admissible that experiments in the DMBA-induced mammary carcinoma of the rat a comparison with that of humans Enable situation.
Durch tierexperimentelle Untersuchungen kann als gesichert gelten, daß verschiedene Tumoren nach Diabetes-Induktion ein verlangsamtes Wachstum zeigen oder in Remission gehen.Animal experiments can be considered to be certain that various tumors show slowed growth after the induction of diabetes or go into remission.
Dieser Effekt ist besonders gut für das DMBA-induzierte Mamma-Carcinom der Ratte nach Diabetes-Induktion mit Alloxan belegt (Literatur siehe 2.2).This effect is particularly good for DMBA-induced breast carcinoma the rat covered with alloxan after induction of diabetes (for literature see 2.2).
Der irreversible Alloxan-Diabetes ist zur Therapie menschlicher Tumoren nicht geeignet. Möglich wäre jedoch eine Behandlung mit Diazoxid, das ohne wesentliche Nebenwirkungen einen reversiblen Diabetes induziert (Kühnau und Martin, DMl; 79 (1972), 1870). Dieses Benzothiadiazinderivat findet bisher als Antihypoklämikum therapeutische Anwendung und wird auch bei maligner Hypertonie eingesetzt; es hemmt die Sekretion von Insulin aus den ß-Zellsn der Pankreas-Inseln.The irreversible alloxan diabetes is used to treat human tumors not suitable. A treatment with diazoxide would be possible, however, without essential Side effects induce reversible diabetes (Kühnau and Martin, DMl; 79 (1972), 1870). This benzothiadiazine derivative has so far been used as an antihypoclemic therapeutic application and is also used in malignant hypertension; it inhibits the secretion of insulin from the ß-cells of the pancreatic islets.
Erfindungsgemäß wurde nun festgestellt, daß im Tierversuch eine Therapie des DtABA-induzierten Mamma-Carcinoms mit Diazoxid das Tumorwachstum signifikant mindert, so daß sich die Möglichkeit anbietet, diesen Wirkstoff in der Behandlung menschlicher Tumoren zu erproben.According to the invention it has now been found that a therapy in animal experiments of DtABA-induced breast carcinoma with diazoxide significantly increased tumor growth reduces, so that there is the possibility of using this active ingredient in the treatment to test human tumors.
Es wurde außerdem festgestellt, daß die Remissionsdauer a-nsteigt, wenn Diazoxid mit Tamoxifen kombiniert wird. In der Kombination von Diazoxid mit Medroxyprogesteron-acetat steigt die Remissionsquote zwar an, die Remissionsdauer sinkt jedoch.It was also found that the remission duration a-n increases, when diazoxide is combined with tamoxifen. In the combination of diazoxide with Medroxyprogesterone acetate increases the remission rate and the duration of remission however, it sinks.
Die Erfindung wird durch die Patentansprüche näher gekennzeichnet und durch die folgenden Versuche belegt.The invention is further characterized by the claims and evidenced by the following experiments.
Dabei wird die Remission als die Verminderung des Tumorvolumens auf unter 50 % des Ausgangswertes definiert.Thereby the remission is based on the reduction of the tumor volume defined below 50% of the initial value.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833331459 DE3331459A1 (en) | 1982-08-31 | 1983-08-31 | Composition for tumour treatment containing diazoxide, and the use thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3232374 | 1982-08-31 | ||
| DE19833331459 DE3331459A1 (en) | 1982-08-31 | 1983-08-31 | Composition for tumour treatment containing diazoxide, and the use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE3331459A1 true DE3331459A1 (en) | 1984-03-01 |
| DE3331459C2 DE3331459C2 (en) | 1992-02-13 |
Family
ID=25804132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19833331459 Granted DE3331459A1 (en) | 1982-08-31 | 1983-08-31 | Composition for tumour treatment containing diazoxide, and the use thereof |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3331459A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993011757A1 (en) * | 1991-12-10 | 1993-06-24 | Orion-Yhtymä Oy | Drug formulations for parenteral use |
| WO1998049146A3 (en) * | 1997-04-28 | 1999-08-12 | Us Health | Cyclin dependent kinase (cdk)4 inhibitors and their use for treating cancer |
| EP1850663A4 (en) * | 2005-02-22 | 2008-03-19 | Cedars Sinai Medical Center | USE OF MINOXIDIL SULPHATE AS ANTI-TUMOR DRUG |
-
1983
- 1983-08-31 DE DE19833331459 patent/DE3331459A1/en active Granted
Non-Patent Citations (1)
| Title |
|---|
| Chem. Abstr. 70, 19, Nr. 85974 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993011757A1 (en) * | 1991-12-10 | 1993-06-24 | Orion-Yhtymä Oy | Drug formulations for parenteral use |
| US5571534A (en) * | 1991-12-10 | 1996-11-05 | Orion-Yhtyma Oy | Drug formulations for parenteral use |
| WO1998049146A3 (en) * | 1997-04-28 | 1999-08-12 | Us Health | Cyclin dependent kinase (cdk)4 inhibitors and their use for treating cancer |
| EP1850663A4 (en) * | 2005-02-22 | 2008-03-19 | Cedars Sinai Medical Center | USE OF MINOXIDIL SULPHATE AS ANTI-TUMOR DRUG |
| US7705010B2 (en) | 2005-02-22 | 2010-04-27 | Cedars-Sinai Medical Center | Use of minoxidil sulfate as an anti-tumor drug |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3331459C2 (en) | 1992-02-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8110 | Request for examination paragraph 44 | ||
| D2 | Grant after examination | ||
| 8364 | No opposition during term of opposition | ||
| 8330 | Complete disclaimer |