RESUMO
Apixaban (BMS-562247; 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 µM⻹/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug-drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases.
Assuntos
Descoberta de Drogas/história , Inibidores Enzimáticos , Inibidores do Fator Xa , Fibrinolíticos , Pirazóis , Piridonas , Animais , Avaliação Pré-Clínica de Medicamentos/história , Inibidores Enzimáticos/química , Inibidores Enzimáticos/história , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Fibrinolíticos/química , Fibrinolíticos/história , Fibrinolíticos/farmacocinética , Fibrinolíticos/uso terapêutico , História do Século XX , Humanos , Pirazóis/química , Pirazóis/história , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridonas/química , Piridonas/história , Piridonas/farmacocinética , Piridonas/uso terapêutico , Tromboembolia/tratamento farmacológicoAssuntos
Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/história , Piperidinas/efeitos adversos , Piperidinas/história , Pirazóis/efeitos adversos , Pirazóis/história , Fármacos Antiobesidade/uso terapêutico , Dronabinol/química , Aprovação de Drogas , França , História do Século XXI , Humanos , Obesidade/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Receptores de Canabinoides/efeitos dos fármacos , RimonabantoAssuntos
Doenças Cardiovasculares/induzido quimicamente , Inibidores de Ciclo-Oxigenase/efeitos adversos , Lactonas/efeitos adversos , Sulfonas/efeitos adversos , Aspirina/uso terapêutico , Celecoxib , Inibidores de Ciclo-Oxigenase/história , Aprovação de Drogas/história , Interações Medicamentosas , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/história , História do Século XX , História do Século XXI , Humanos , Lactonas/história , Inibidores da Agregação Plaquetária/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/história , Sulfonamidas/efeitos adversos , Sulfonamidas/história , Sulfonas/história , Estados Unidos , United States Food and Drug AdministrationRESUMO
The use of naturally occurring plant materials for the relief of pain dates back to 3,000 B.C., although rapid advances in antipyretic analgesic therapy have been made more recently. Salicylic acid was synthesized in 1860, and the pyrazolone group, first represented by antipyrine, in 1883. Phenacetin was developed in 1886. Acetaminophen has been in use since the 1890s.
