DE4308504A1 - New use of a combination of verapamil and trandolapril - Google Patents
New use of a combination of verapamil and trandolaprilInfo
- Publication number
- DE4308504A1 DE4308504A1 DE4308504A DE4308504A DE4308504A1 DE 4308504 A1 DE4308504 A1 DE 4308504A1 DE 4308504 A DE4308504 A DE 4308504A DE 4308504 A DE4308504 A DE 4308504A DE 4308504 A1 DE4308504 A1 DE 4308504A1
- Authority
- DE
- Germany
- Prior art keywords
- combination
- verapamil
- trandolapril
- acid
- insulin
- 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.)
- Withdrawn
Links
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 title claims description 17
- 229960002051 trandolapril Drugs 0.000 title claims description 17
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 title claims description 16
- 229960001722 verapamil Drugs 0.000 title claims description 16
- 238000011282 treatment Methods 0.000 claims description 5
- 208000031773 Insulin resistance syndrome Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 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 14
- 241000700159 Rattus Species 0.000 description 9
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 6
- 239000005541 ACE inhibitor Substances 0.000 description 5
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 210000002027 skeletal muscle Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- VRYALKFFQXWPIH-PBXRRBTRSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-PBXRRBTRSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 206010018473 Glycosuria Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- PMMURAAUARKVCB-UHFFFAOYSA-N alpha-D-ara-dHexp Natural products OCC1OC(O)CC(O)C1O PMMURAAUARKVCB-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000004190 glucose uptake Effects 0.000 description 3
- 230000035780 glucosuria Effects 0.000 description 3
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 3
- 201000008980 hyperinsulinism Diseases 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 208000018914 glucose metabolism disease Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000001778 Coronary Occlusion Diseases 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- WMFYOYKPJLRMJI-UHFFFAOYSA-N Lercanidipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 WMFYOYKPJLRMJI-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000000923 atherogenic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- OYFJQPXVCSSHAI-QFPUQLAESA-N enalapril maleate Chemical compound OC(=O)\C=C/C(O)=O.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 OYFJQPXVCSSHAI-QFPUQLAESA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Es ist bereits bekannt, daß der Ca-Antagonist Verapamil (Merck-Index 1989, Nr. 9851) und der ACE-Inhibitor Trandolapril (= N-(1S-Carbethoxy-3-phenylpropyl)-S-alanyl-2S, 3aR, 7aS-octa hydroindol-2-carbonsäure, US-PS 4 933 361) blutdrucksenkende Eigenschaften besitzen. Dasselbe gilt für eine Kombination aus beiden Substanzen (DE 41 09 134).It is already known that the Ca antagonist Verapamil (Merck Index 1989, No. 9851) and the ACE inhibitor trandolapril (= N- (1S-carbethoxy-3-phenylpropyl) -S-alanyl-2S, 3aR, 7aS-octa hydroindole-2-carboxylic acid, US Pat. No. 4,933,361) hypotensive Possess properties. The same applies to a combination of two substances (DE 41 09 134).
Die vorliegende Erfindung betrifft die Verwendung einer Kombi nation aus Verapamil und Trandolapril im Verhältnis 670 : 1 bis 20 : 1 zur Herstellung von Arzneimitteln zur Vorbeugung und Behand lung des Insulinresistenz-Syndroms.The present invention relates to the use of a station wagon nation of verapamil and trandolapril in a ratio of 670: 1 to 20: 1 for the manufacture of medicines for prevention and treatment Insulin resistance syndrome.
Das angegebene Verhältnis bezieht sich auf Gewichtsteile. Bevorzugt ist ein Verhältnis von 300 : 1 bis 50 : 1.The ratio given relates to parts by weight. A ratio of 300: 1 to 50: 1 is preferred.
In der Kombination kann das Verapamil in Form eines physiologisch verträglichen Salzes vorliegen. Zur Salzbildung mit Verapamil kommen insbesondere Salzsäure, Schwefelsäure, Phosphorsäure, Essigsäure, Malonsäure, Bernsteinsäure, Fumarsäure, Maleinsäure, Zitronensäure, Weinsäure, Milchsäure, Amidosulfonsäure und Oxal säure in Betracht. Bevorzugtes Salz ist das Hydrochlorid.In combination, the verapamil can be in the form of a physiological compatible salt. For salt formation with verapamil come in particular hydrochloric acid, sulfuric acid, phosphoric acid, Acetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, Citric acid, tartaric acid, lactic acid, amidosulfonic acid and oxal acid into consideration. The preferred salt is the hydrochloride.
Das Trandolapril kann in der Kombination ebenfalls als Salz vor liegen. Da Trandolapril sowohl eine saure als auch basische Gruppe besitzt, kann es sowohl mit den oben genannten Säuren als auch mit physiologisch verträglichen Basen, wie Alkali- oder Erd alkalihydoxiden, Salze bilden. Bevorzugt ist das freie Trando lapril.The combination of trandolapril can also be used as a salt lie. Because trandolapril is both an acidic and basic Group, it can be used both with the acids mentioned above also with physiologically compatible bases, such as alkali or earth alkali hydroxide, salts. Free Trando is preferred lapril.
Kardiovaskuläre Erkrankungen, die unverändert die Mehrzahl der Todesfälle in den westlichen Ländern verursachen, unterliegen traditionell hauptsächlich folgenden drei Risikofaktoren: Hyper tonie, Hypercholesterinämie und Rauchen. Daneben ist in den letz ten Jahren das Insulinresistenzsyndrom (Synonym: Syndrom X, meta bolic cardiovascular syndrome mit Hyperinsulinämie) als vierter Risikofaktor erkannt worden [Diabetes 37, 1595 (1988), J. Cardio vasc. Pharmac. 20 (Suppl. 8) S. 5-S. 10 (1992)]. Insulinresi stenz ist definiert als eine pathophysiologische Situation, in der der Skelettmuskel nur noch reduziert auf Insulin anspricht, d. h. nur reduziert Glukose aufnimmt. Das führt kompensatorisch zu einer erhöhten Insulinproduktion, so daß eine Hyperinsulinämie resultiert. Aus diesem Zustand kommt es dann zu einem Übergang in den nicht insulinabhängigen Diabetes mit individuell stark wechselnder Progredienz. Es gilt inzwischen als wissenschaftlich gesichert, daß die bei diesem Syndrom auftretende Hyperinsulin ämie durch die mitogene Wirkung des Insulins ein atherogenes Potential darstellt, das morphologische Veränderungen in der Gefäßwand (z. B. Koronarokklusion) zur Folge hat [J. Cardiovasc. Pharmac. 20 (Suppl. 11) S. 1-S. 16 (1992]. Im Rahmen der Thera pie kommt der Beachtung dieses metabolischen Syndroms besondere Bedeutung deshalb zu, weil inzwischen bekannt ist, daß pharmako therapeutisch verwendete Diuretika und β-Blocker die Insulinresi stenz fördern, Kalziumantagonisten dagegen metabolisch neutral sind und ACE-Inhibitoren die Insulinresistenz sogar abzuschwächen vermögen [J. Cardiovasc. Pharmac. 20 (Suppl. 11), S. 77-S. 84 (1992)]. Präklinische Befunde geben nun Hinweise dafür, daß eine Kombination eines ACE-Inhibitors und eines Kalziumantagonisten überraschenderweise nicht nur die Insulinresistenz bessern, sondern sogar zu einer Herstellung der normalen Insulinsensiti vität führen.Cardiovascular disease, which remains the majority of the Cause deaths in western countries are subject to Traditionally the following three main risk factors: Hyper tonia, hypercholesterolemia and smoking. In addition, in the last insulin resistance syndrome (synonym: Syndrome X, meta bolic cardiovascular syndrome with hyperinsulinemia) as fourth Risk factor has been identified [Diabetes 37, 1595 (1988), J. Cardio vasc. Pharmac. 20 (Suppl. 8) p. 5-p. 10 (1992)]. Insulin resistance stenz is defined as a pathophysiological situation in that the skeletal muscle only responds to insulin to a reduced extent, d. H. only absorbs reduced glucose. This leads to compensatory an increased insulin production, so that hyperinsulinemia results. From this state there is a transition to the non-insulin dependent diabetes with individually strong changing progression. It is now considered scientific ensured that the hyperinsulin occurring in this syndrome anemia due to the mitogenic effect of insulin an atherogenic Represents potential that morphological changes in the Vessel wall (e.g. coronary occlusion) [J. Cardiovasc. Pharmac. 20 (Suppl. 11) pp. 1-p. 16 (1992) as part of Thera Pie comes special attention to this metabolic syndrome Importance because it is now known that pharmaco therapeutically used diuretics and β-blockers the insulin resi Encourage tendon, while calcium antagonists are metabolically neutral and ACE inhibitors even weaken insulin resistance assets [J. Cardiovasc. Pharmac. 20 (Suppl. 11), pp. 77-S. 84 (1992)]. Preclinical findings now indicate that a Combination of an ACE inhibitor and a calcium channel blocker surprisingly not only improve insulin resistance, but even to produce the normal insulin sensitivity lead vity.
Für die neue Indikation kann die Kombination in üblicher Weise oral verabfolgt werden.The combination can be used in the usual way for the new indication administered orally.
Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab. In der Regel beträgt die tägli che Dosis zwischen 50 und 480 mg Verapamil und 0,2 bis 4 mg Tran dolapril.The dosage depends on the age, condition and weight of the patient as well as on the type of application. As a rule, the daily is dose between 50 and 480 mg verapamil and 0.2 to 4 mg tran dolapril.
Die Kombination kann in den gebräuchlichen galenischen Applika tionsformen fest oder flüssig angewendet werden, z. B. als Tablet ten, Filmtabletten, Retardtabletten, Kapseln, Pulver, Granulate, Dragees, Pellets, Retardpellets oder Lösungen. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füll stoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließ reguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln und/oder Anti oxidantien verarbeitet werden (vgl. H. Sucker et al: Pharma zeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Die so erhaltenen Applikationsformen enthalten den Wirkstoff normaler weise in einer Menge von 10 bis 90 Gew.-%.The combination can be found in the usual galenical applications tion forms are applied solid or liquid, e.g. B. as a tablet film-coated tablets, prolonged-release tablets, capsules, powders, granules, Dragees, pellets, slow release pellets or solutions. These are in manufactured in the usual way. The active ingredients can with the usual pharmaceutical auxiliaries such as tablet binders, filling substances, preservatives, tablet disintegrants, flow regulating agents, plasticizers, wetting agents, dispersing agents, Emulsifiers, solvents, retardants and / or anti oxidants are processed (see H. Sucker et al: Pharma zeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The so Application forms obtained contain the active ingredient more normally in an amount of 10 to 90 wt .-%.
In der Kombination können sowohl Verapamil alleine als auch beide Einzelstoffe in retardierter Form vorliegen. Das Verapamil liegt vorzugsweise als Retardform und das Trandolapril in einer Instant-Release-Form vor. In combination, both Verapamil alone and both can Individual substances are in delayed form. The verapamil lies preferably as a sustained release form and the trandolapril in one Instant release form.
Die pharmakologische Untersuchung der Kombination wurde an zwei verschiedenen Modellerkrankungen der Ratte durchgeführt, nämlich an der obesen Zucker-Ratte sowie an der spontan hypertensiven Ratte des Stroke-prone-Stammes (SHRSP). Die ZUCKER-Ratte wurde als Modell für die Insulinresistenz des Menschen verwendet, und sie ist durch die typischen Merkmale Hyperinsulinämie und redu zierte Glukoseaufnahme in den Skelettmuskel in Gegenwart von Insulin gekennzeichnet. Hochdruck-Ratten weisen als Ausdruck der Glukose-Stoffwechselstörung eine erhöhte Ausscheidung von Glukose mit dem Harn (Glukosurie) auf.The pharmacological study of the combination was carried out on two various model diseases of the rat, namely on the above sugar rat as well as on the spontaneously hypertensive Stroke-prone strain (SHRSP) rat. The SUGAR rat was used as a model for human insulin resistance, and it is characterized by the typical characteristics of hyperinsulinemia and redu graced glucose uptake in the skeletal muscle in the presence of Labeled insulin. High-pressure rats show as an expression of Glucose metabolism disorder is an increased excretion of glucose with the urine (glucosuria).
Die Experimente wurden wie folgt durchgeführt:The experiments were carried out as follows:
1. Obese Zucker-Ratten erhielten an 14 aufeinanderfolgenden Tagen oral Trandolapril (1 mg/kg/Tag p.o.) oder Verapamil (20 mg/kg/Tag p.o.) oder die Kombination beider Substanzen in den vorgenannten Dosierungen. Als Kontrolle dienten placebo behandelte Tiere desselben Stammes. Von den so vorbehandelten Tieren wurde ein Skelettmuskel der Extremität (Musculus trochlearis) entnommen und in vitro 20 min in Gegenwart von Insulin (2 ml Units/ml) und metabolisch stabiler Desoxygly kose inkubiert. Gemessen wurde die pro Zeit in die Muskulatur aufgenommene Menge an 2 Desoxyglukose. Die Befunde sind in der Tabelle 1 dargestellt und zeigen, daß die Kombination von Verapamil und Trandolapril zu einer signifikant stärkeren Glukoseaufnahme in den Skelettmuskeln führt als bei Gabe von Trandolapril bzw. Verapamil allein. Die Glukoseaufnahme unter der Kombinationsbehandlung übertrifft sogar diejenige von gesunden Kontrolltieren (mageren Zucker-Ratten).1. Obese sugar rats were given on 14 consecutive Days orally trandolapril (1 mg / kg / day po) or verapamil (20 mg / kg / day p.o.) or the combination of both substances in the aforementioned dosages. Placebo served as a control treated animals of the same tribe. Of the so pretreated Animals became a skeletal muscle of the extremity (Musculus trochlearis) and in vitro 20 min in the presence of Insulin (2 ml units / ml) and metabolically stable deoxygly incubated. It was measured in the muscles per time amount of 2 deoxyglucose ingested. The findings are in shown in Table 1 and show that the combination of Verapamil and Trandolapril to a significantly stronger Glucose uptake in the skeletal muscles leads than when Trandolapril or verapamil alone. Glucose uptake under the combination treatment even exceeds that of healthy control animals (lean sugar rats).
2. SHRSP wurden 16 Wochen lang täglich mit Verapamil (20 mg/kg/ Tag p.o.) oder Trandolapril (0,03 mg/kg/Tag p.o.) oder der Kombination beider in den vorgenannten Dosierungen behandelt. Am Ende der Behandlung wurde die renale Glukoseausscheidung dieser Tiere im Vergleich zu placebobehandelten Kontrollen für 24 h gemessen. Die in der Tabelle 2 dargestellten Ergeb nisse zeigen, daß die Kombination die Glukosurie signifikant stärker reduziert als bei Behandlung mit dem Kalziumantago nisten oder dem ACE-Inhibitor allein.2. SHRSP were taken daily with verapamil (20 mg / kg / Day p.o.) or trandolapril (0.03 mg / kg / day p.o.) or the Combination of both treated in the above dosages. At the end of the treatment, renal excretion of glucose of these animals compared to placebo-treated controls measured for 24 h. The results shown in Table 2 Nisse show that the combination made glucosuria significant more reduced than with treatment with calcium antago nest or the ACE inhibitor alone.
Länger dauernde Anwendung einer Kombination des Kalziumantago nisten Verapamil und des ACE-Inhibitors Trandolapril führen bei Ratten mit einer Glukose-Stoffwechselstörung (Insulinresistenz) zu einer überraschenden protektiven Wirkung, die den Effekt der Gabe der Einzelsubstanz signifikant übertrifft. Das an diesen Modellen gefundene synergistische Verhalten beider Wirkstoffe läßt erwarten, daß diese Kombination erfolgreich bei der Behand lung des Risikofaktors Insulinresistenzsyndrom bei Menschen ein gesetzt werden kann und in der Lage ist, die Entwicklung vom latenten zum manifesten Diabetes, beispielsweise zu insulinresi stenten Hypertonieformen und insbesondere zu arteriosklerotischen Folgeerkrankungen, aufzuhalten und die Mortalitätsrate dieser Erkrankung zu senken.Prolonged use of a combination of calcium antago nest verapamil and the ACE inhibitor trandolapril Rats with glucose metabolism disorder (insulin resistance) to a surprising protective effect, the effect of Administration of the individual substance significantly exceeded. That about these Models found synergistic behavior of both active ingredients suggests that this combination is successful in the treatment insulin resistance syndrome in humans can be set and is able to develop from latent to overt diabetes, for example insulinresi constant forms of hypertension and especially arteriosclerotic ones Consequences, and the mortality rate of these Lower disease.
In eine Hartgelatinekapsel wurden eine Verapamil-HCl-Retard tablette mit 120 mg Wirkstoff und ein Trandolapril-Granulat mit 0,5 mg nicht reardiertem Trandolapril gefüllt und anschließend die Kapsel verschlossen.A Verapamil-HCl-Retard was placed in a hard gelatin capsule tablet with 120 mg of active ingredient and a trandolapril granulate with 0.5 mg trandolapril not reared and then filled the capsule closed.
Claims (1)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4308504A DE4308504A1 (en) | 1993-03-18 | 1993-03-18 | New use of a combination of verapamil and trandolapril |
IL10888194A IL108881A0 (en) | 1993-03-18 | 1994-03-07 | Pharmaceutical compositions containing a combination of verapamil and trandolapril |
PCT/EP1994/000766 WO1994021285A1 (en) | 1993-03-18 | 1994-03-11 | New use of a combination of verapamil and trandolapril |
AU63766/94A AU6376694A (en) | 1993-03-18 | 1994-03-11 | New use of a combination of verapamil and trandolapril |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4308504A DE4308504A1 (en) | 1993-03-18 | 1993-03-18 | New use of a combination of verapamil and trandolapril |
Publications (1)
Publication Number | Publication Date |
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DE4308504A1 true DE4308504A1 (en) | 1994-09-22 |
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ID=6483047
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Application Number | Title | Priority Date | Filing Date |
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DE4308504A Withdrawn DE4308504A1 (en) | 1993-03-18 | 1993-03-18 | New use of a combination of verapamil and trandolapril |
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AU (1) | AU6376694A (en) |
DE (1) | DE4308504A1 (en) |
IL (1) | IL108881A0 (en) |
WO (1) | WO1994021285A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2733911A1 (en) * | 1995-05-09 | 1996-11-15 | Takeda Chemical Industries Ltd | Compsn. contg. delapril and manidipine to prevent or treat cardiovascular and renal diseases |
WO2001015673A2 (en) * | 1999-08-27 | 2001-03-08 | Aventis Pharma Deutschland Gmbh | Pharmaceutical formulations and use thereof in the prevention of stroke, diabetes and/or congestive heart failure |
WO2003032965A2 (en) * | 2001-10-17 | 2003-04-24 | King Pharmaceuticals Research And Development, Inc | Use of ace inhibitors for reducing type 2 diabetes in high risk patients |
US7368469B2 (en) | 1999-08-30 | 2008-05-06 | Sanofi-Aventis Deutschland Gmbh | Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0318094D0 (en) * | 2003-08-01 | 2003-09-03 | Pfizer Ltd | Novel combination |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4109134A1 (en) * | 1991-03-20 | 1992-09-24 | Knoll Ag | PRODUCTS CONTAINING VERAPAMIL AND TRANDOLAPRIL |
-
1993
- 1993-03-18 DE DE4308504A patent/DE4308504A1/en not_active Withdrawn
-
1994
- 1994-03-07 IL IL10888194A patent/IL108881A0/en unknown
- 1994-03-11 AU AU63766/94A patent/AU6376694A/en not_active Withdrawn
- 1994-03-11 WO PCT/EP1994/000766 patent/WO1994021285A1/en active Application Filing
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2733911A1 (en) * | 1995-05-09 | 1996-11-15 | Takeda Chemical Industries Ltd | Compsn. contg. delapril and manidipine to prevent or treat cardiovascular and renal diseases |
ES2119682A1 (en) * | 1995-05-09 | 1998-10-01 | Takeda Chemical Industries Ltd | Compsn. contg. delapril and manidipine to prevent or treat cardiovascular and renal diseases |
WO2001015673A2 (en) * | 1999-08-27 | 2001-03-08 | Aventis Pharma Deutschland Gmbh | Pharmaceutical formulations and use thereof in the prevention of stroke, diabetes and/or congestive heart failure |
WO2001015673A3 (en) * | 1999-08-27 | 2002-03-07 | Aventis Pharma Gmbh | Pharmaceutical formulations and use thereof in the prevention of stroke, diabetes and/or congestive heart failure |
EP1437131A1 (en) * | 1999-08-27 | 2004-07-14 | Aventis Pharma Deutschland GmbH | Use of an ACE inhibitor for the prevention of diabetes in a patient with no preexisting congestive heart failure |
US7368469B2 (en) | 1999-08-30 | 2008-05-06 | Sanofi-Aventis Deutschland Gmbh | Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events |
WO2003032965A2 (en) * | 2001-10-17 | 2003-04-24 | King Pharmaceuticals Research And Development, Inc | Use of ace inhibitors for reducing type 2 diabetes in high risk patients |
WO2003032963A2 (en) * | 2001-10-17 | 2003-04-24 | Aventis Pharma Deutschland Gmbh | Method of reducing type 2 diabetes in high risk patients |
WO2003032965A3 (en) * | 2001-10-17 | 2003-11-27 | King Pharmaceuticals Res & Dev | Use of ace inhibitors for reducing type 2 diabetes in high risk patients |
WO2003032963A3 (en) * | 2001-10-17 | 2003-12-24 | Aventis Pharma Gmbh | Method of reducing type 2 diabetes in high risk patients |
Also Published As
Publication number | Publication date |
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IL108881A0 (en) | 1994-06-24 |
AU6376694A (en) | 1994-10-11 |
WO1994021285A1 (en) | 1994-09-29 |
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