RESUMEN
BACKGROUND AND AIM: Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. METHODS: Treatment-naive patients (20-70 years; baseline viral load, ≥ 100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, ≥ 100,000 IU/mL) received daclatasvir plus asunaprevir. RESULTS: In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). CONCLUSION: Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin.
Asunto(s)
Antivirales/administración & dosificación , Hepatitis C/tratamiento farmacológico , Imidazoles/administración & dosificación , Interferón-alfa/administración & dosificación , Isoquinolinas/administración & dosificación , Oligopéptidos/administración & dosificación , Polietilenglicoles/administración & dosificación , Ribavirina/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , Anciano , Pueblo Asiatico , Carbamatos , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Pirrolidinas , Proteínas Recombinantes/administración & dosificación , Resultado del Tratamiento , Valina/análogos & derivados , Adulto JovenRESUMEN
A 74-year-old man was referred to our hospital for examination of an abnormal chest shadow. A chest computed tomography (CT) scan revealed a 5-cm mass attached to the pleura involving the right upper lobe, and a nodule in the right middle lobe. Transbronchial lung biopsy was performed twice, but no definitive diagnosis was achieved. 18-fluorodeoxyglucose positron emission tomography showed abnormal uptake in the chest lesion. Chemotherapy was initiated for advanced-stage lung cancer, but was not effective. Histopathologic and immunohistochemical examinations after CT-guided needle biopsy revealed malignant mesothelioma. The tumor cells were positive for calretinin and thrombomodulin, and negative for CEA, TTF-1, and SP-A. There was local tumor invasion and metastasis in the lung and brain, without diffuse pleural spread. This is a rare and important case of localized malignant mesothelioma pathologically confirmed by biopsy.
Asunto(s)
Neoplasias Pleurales/patología , Tumor Fibroso Solitario Pleural/patología , Anciano , Humanos , MasculinoRESUMEN
An enzyme involved in the metabolic activation of thalidomide has been investigated using embryo fibroblast proliferation as a marker. Thalidomide (30 microM) induced-suppression of embryo fibroblast proliferation was detected in the presence of liver microsomes from rabbit but not from mouse. The addition of a selective inhibitor of CYP1A, alpha-naphthoflavone (4 microM), or furafylline (4 microM), to the incubation mixture abolished the thalidomide-induced suppression. Furthermore, addition of anti-rat CYP1A1 antibody also resulted in inhibition of suppression. The thalidomide-induced suppression was also observed with the microsomal system from human HepG2 cells pretreated with 3-methylcholanthrene (10 microM) but not from those pretreated with the vehicle. Both CYP1A1 and CYP1A2 proteins were detected in the rabbit liver microsomes by immunoblot analyses, but only CYP1A2 protein was detected in the mouse liver microsomes. In addition, CYP1A1 protein was detected in microsomes from HepG2 cells pretreated with 3-methylcholanthrene but not with the vehicle. These results strongly suggest the involvement of CYP1A1 in the thalidomide-induced suppression of embryo fibroblast proliferation.
Asunto(s)
Citocromo P-450 CYP1A1/metabolismo , Fibroblastos/efectos de los fármacos , Talidomida/farmacología , Animales , Anticuerpos/farmacología , Antioxidantes/farmacología , Western Blotting , Recuento de Células/métodos , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocromo P-450 CYP1A1/inmunología , Citocromo P-450 CYP1A2/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Embrión de Mamíferos/citología , Inhibidores Enzimáticos/farmacología , Femenino , Fibroblastos/citología , Inmunosupresores/metabolismo , Inmunosupresores/farmacología , Hígado/citología , Hígado/efectos de los fármacos , Ratones , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Placenta/citología , Placenta/efectos de los fármacos , Embarazo , Conejos , Talidomida/metabolismoRESUMEN
An in vitro system for detection of embryotoxins has been developed by using primary cultures of embryo fibroblasts. Various embryotoxins, including benzo[a]pyrene and thalidomide, have trivial cytotoxicity in embryo fibroblast systems, which is at least in part due to a lack of capacity for metabolic activation. Introduction of steps for microsomal pre-incubation and calcium-precipitation prior to chemical contact resulted in the clear appearance of embryotoxicity toward thalidomide and benzo[a]pyrene. This pre-incubation method will offer advantages for the detection of embryotoxins, which require maternal metabolic activation, and for understanding the mechanisms of their metabolic activations.
Asunto(s)
Bioensayo/métodos , Teratógenos/metabolismo , Teratógenos/farmacología , Animales , Benzo(a)pireno/metabolismo , Benzo(a)pireno/toxicidad , Bioensayo/estadística & datos numéricos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Ratones , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Embarazo , Conejos , Talidomida/metabolismo , Talidomida/toxicidadRESUMEN
Microsomal epoxide hydrolase (mEH) catalyzes the hydrolysis of epoxide intermediates derived from drugs and environmental chemicals. The response of in vivo (embryo) and in vitro (embryo fibroblast) tests were analyzed using mEH-null and wild-type mice to determine the relative role of maternal and embryonic mEH in the developmental toxicity induced by 7,12-dimethylbenz[a]anthracene (DMBA). Embryos derived from DMBA-treated [50mg/kg, daily from gestational day (GD) 11 to GD 15] dams were analyzed. Although weight (P=0.0009) and crown-rump length (P=0.0003) of wild-type fetuses on GD 18 were significantly lower than those of mEH-null fetuses, respectively, no significant difference was found between mEH-null and heterozygous fetuses of mEH-null dams. Cell viability was decreased to 50% in wild-type mouse embryo fibroblasts (MEFs) treated with 3 microM DMBA, but no significant decrease was found in mEH-null MEFs. DMBA-3,4-diol produced a significant decrease in cell viability and suppressed the proliferation of wild-type MEFs at a 10-fold lower concentration than did DMBA. Although mEH protein was expressed in liver microsomes from wild-type embryos (GD 15), DMBA-3,4-diol was not detected among the DMBA metabolites. However, it was detected in the serum of wild-type pregnant mice treated with DMBA, but not in that of mEH-null mice. These results suggest that maternal mEH plays a major role in DMBA-induced developmental toxicity, and embryonic mEH is less involved in the toxicity.