RESUMEN
Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Furanos/farmacología , Tiofenos/farmacología , Proteínas no Estructurales Virales/farmacología , Antivirales/química , Inhibidores Enzimáticos/química , Furanos/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Tiofenos/química , Proteínas no Estructurales Virales/químicaRESUMEN
OBJECTIVE: To establish the prevalence of depression and describe associated factors among fistula patients attending an obstetric fistula surgical camp in Kenya. METHODS: A cross-sectional study was conducted focusing on obstetric fistula patients attending a national fistula camp held in August 2008 at Kenyatta National Hospital, Nairobi, Kenya. A structured questionnaire was used to obtain sociodemographic data and medical histories for all consenting patients before surgery. Depression measures were obtained using the Patient Health Questionnaire-9. RESULTS: Of the 70 women interviewed, 2 (2.9%) and 12 (17.1%) reported a history of psychiatric illness and suicidal ideations, respectively. Depression was present in 51 (72.9%) patients, with 18 (25.7%) meeting criteria for severe depression. Depression was significantly associated with women older than 20 years of age (P=0.01), unemployment (P=0.03), lack of social support following fistula (P=0.04), and living with fistula for over 3 months (P=0.01). CONCLUSION: Women with obstetric fistula are predisposed to high levels of depression. A holistic management approach, including mental health care and family support, is recommended.
