RESUMEN
Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side-effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 µM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug-target-adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme cyclooxygenase-1. The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Pruebas de Toxicidad/métodos , Plaquetas/efectos de los fármacos , Clorotrianiseno/efectos adversos , Clorotrianiseno/química , Clorotrianiseno/farmacología , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/farmacología , Bases de Datos Factuales , Estrógenos no Esteroides/efectos adversos , Estrógenos no Esteroides/farmacología , Predicción , Humanos , Modelos Biológicos , Terapia Molecular Dirigida/efectos adversos , Agregación Plaquetaria/efectos de los fármacos , Reproducibilidad de los Resultados , Especificidad por SustratoAsunto(s)
Altitud , Disnea/etiología , Embolia Pulmonar/complicaciones , Anciano , Clorotrianiseno/efectos adversos , Clorotrianiseno/uso terapéutico , Disnea/diagnóstico , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Embolia Pulmonar/inducido químicamente , Embolia Pulmonar/diagnósticoRESUMEN
We report 2 cases of mesenteric venous thrombosis in men taking estrogen for carcinoma of the prostate. The possible relationship between the estrogen therapy and mesenteric venous thromboses is stressed, as well as the potential danger of resumption of estrogen therapy without anticoagulation postoperatively.
Asunto(s)
Clorotrianiseno/efectos adversos , Dietilestilbestrol/efectos adversos , Oclusión Vascular Mesentérica/inducido químicamente , Neoplasias de la Próstata/tratamiento farmacológico , Trombosis/inducido químicamente , Anciano , Clorotrianiseno/uso terapéutico , Dietilestilbestrol/uso terapéutico , Humanos , Masculino , Venas MesentéricasRESUMEN
Coagulation changes and increased risk of thromboembolic disease may occur in association with estrogen administration. The puerperium is also a high-risk period for thromboembolism, and estrogen administration at this time may increase this risk. Patients with congenital deficiency of antithrombin III have recurrent venous thromboembolic disease, suggesting that low levels of this factor may be associated with "hypercoagulability" states. We studied 50 postpartum patients who received chlorotrianisene (Tace) or placebo for lactation suppression in a prospective, double-blind, randomized fashion. Antithrombin III values were significantly lower on the third day post partum in the treated group compared to the placebo group (p less than 0.05). In addition, our clinical data from a total of 99 patients support the previous evidence that estrogens delay rather than prevent breast engorgement. Thus, with questionable benefit and a possible increased thromboembolic risk, it would appear prudent to discontinue the practice of estrogen administration for lactation suppression.