RESUMO
A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.
Assuntos
Amidoidrolases/antagonistas & inibidores , Amino Álcoois/química , Analgésicos/química , Inibidores Enzimáticos/química , Pirimidinas/química , Amidoidrolases/metabolismo , Amino Álcoois/farmacocinética , Amino Álcoois/uso terapêutico , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Encéfalo/metabolismo , Domínio Catalítico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Simulação de Acoplamento Molecular , Neuralgia/tratamento farmacológico , Ligação Proteica , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
PURPOSE: To compare updated prospective 5-year survival outcomes of cervical cancer patients living with and without human immunodeficiency virus (HIV) infection who initiated curative chemoradiation therapy (CRT) in a resource-limited setting. METHODS & MATERIALS: Women in Botswana with locally advanced cervical cancer were enrolled in a prospective, observational, cohort study from July 2013 through January 2015. Survival outcomes were analyzed after 5 years of follow-up. RESULTS: This cohort included 143 women initiating curative CRT. Sixty-seven percent (n = 96) of cohort were women living with HIV (WLWH), all of whom were receiving antiretroviral therapy (ART) at the time of treatment initiation and boasted a median CD4 count of 481 cells/µL (IQR, 351-579 µL). The 5-year overall survival (OS) rates were 56.8% (95% CI, 40.0-70.5%) for patients without HIV infection and 55.1% (95% CI, 44.2-64.7%) for WLWH (p = 0.732). Factors associated with superior 5-year OS on multivariate analyses included baseline hemoglobin > 10 g/dL (hazard ratio (HR) 0.90, 95% CI, 0.83-0.98, p = 0.015), lower stage at diagnosis (stage I and II vs. III and IV) (HR 1.39, 95% CI 1.09-1.76, p = 0.007), and higher EQD2 (HR 0.98, 95% CI 0.97-0.99, p = 0.001). CONCLUSIONS: Five-year OS was not impacted by HIV status in this population of WLWH with well-managed infection who initiated curative treatment for cervical cancer in Botswana. Regardless of HIV status, hemoglobin levels and stage at diagnosis were associated with survival. These findings suggest that treatment for cervical cancer in WLWH with well-controlled infection need not be altered solely due to HIV status.