Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K
| Autor: | L. Lammens, Werner Coussement, Marie-Paule Bouche, Sandra De Jonghe, Sophie Lachau-Durand, B. Willems, Johan Verbeeck, Sofie Starckx, Petra Vinken |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Efavirenz Vitamin K Cardiomyopathy Administration Oral Toxicology Hemorrhagic Disorders Pathology and Forensic Medicine chemistry.chemical_compound Mice Troponin T Internal medicine Vitamin K deficiency Nitriles Medicine Animals Molecular Biology Blood Coagulation Clotting factor Prothrombin time Reverse-transcriptase inhibitor medicine.diagnostic_test business.industry Heart Cell Biology medicine.disease Diet Pyridazines Endocrinology Pyrimidines chemistry Coagulation Area Under Curve Prothrombin Time Reverse Transcriptase Inhibitors Female Partial Thromboplastin Time Vitamin K Deficiency business Cardiomyopathies medicine.drug Partial thromboplastin time |
| Zdroj: | Toxicologic pathology. 36(2) |
| ISSN: | 1533-1601 |
| Popis: | Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage. The syndrome was reproduced in only 1 male mouse after continuous dietary dosing, and TMC125 was demonstrated to affect coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [APTT], clotting factors II, VII and XI), particularly in males. This was counteracted by vitamin K supplementation, supporting the hypothesis that the effects were mediated via a vitamin K deficiency. It is therefore concluded that the observed cardiac changes were not caused by a direct cardiotoxic effect but occurred after a state of disabled clotting ability with subsequent effects on mouse cardiac muscle. Therefore, clotting times can be used as adequate safety biomarkers in clinical trials. To date, no changes have been observed at therapeutic doses of TMC125, following human monitoring of PT and APTT. One other NNRTI, Efavirenz (Sustiva), has been reported to cause prolongation of coagulation times in rats and monkeys. |
| Databáze: | OpenAIRE |
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