RESUMEN
OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo-controlled, partially double-blinded multicenter study. SETTING: Adult AIDS Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. RESULTS: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Recuento de Linfocito CD4 , Didanosina/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Infecciones por VIH/inmunología , VIH-1/fisiología , Humanos , Masculino , ARN Viral/sangre , Estavudina/uso terapéutico , Carga Viral , Zidovudina/uso terapéuticoRESUMEN
We performed a pilot study that examined the clinical and pharmacokinetic interactions between zidovudine (ZDV) and a pyridinone derivative, L-697-661. The results indicate that the drugs were well tolerated, with no important pharmacokinetic interactions, when administered concomitantly for as long as 8 weeks. Although the number of study participants was small, we noted rapid emergence of resistance to L-697,661 among ZDV-naive study subjects who were administered L-697,661 as monotherapy but did not observe isolates of human immunodeficiency virus type 1 (HIV-1) resistant to L-697,661 among those who were administered concomitant ZDV. These results suggest a potential interaction between development of resistance to L-697,661 and ZDV. Although the clinical development of L-697,661 has been halted, our results support the need for further studies to test whether specific interactions among antiretroviral agents administered in combination and the molecular target can delay the emergence of isolates that exhibit resistance to all drugs in the regimen.
Asunto(s)
Antivirales/uso terapéutico , Benzoxazoles/uso terapéutico , Seropositividad para VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Piridonas/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Antipirina , Antivirales/farmacocinética , Antivirales/farmacología , Secuencia de Bases , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Estudios Cruzados , Cartilla de ADN/química , ADN Viral/química , Interacciones Farmacológicas , Farmacorresistencia Microbiana , Quimioterapia Combinada , Femenino , Genes pol/genética , Genotipo , Seropositividad para VIH/metabolismo , VIH-1/genética , Humanos , Masculino , Datos de Secuencia Molecular , Proyectos Piloto , Piridonas/farmacocinética , Piridonas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Zidovudina/farmacocinética , Zidovudina/farmacologíaRESUMEN
Cytotoxic T lymphocytes (CTL) specific for human immunodeficiency virus type 1 (HIV-1) are thought to play an important role in controlling HIV-1 infection. HIV-1-specific CTL are readily demonstrated in unstimulated peripheral blood mononuclear cells (PBMC) of HIV-infected adults but less frequently in PBMC from vertically infected children. HIV-1-specific CTL lines were derived from a long-term survivor of vertical HIV-1 infection using PBMC stimulated with a CD3-specific monoclonal antibody and interleukin-2; these lines had Gag- or reverse transcriptase (RT)-specific cytotoxicity. Cytotoxicity was restricted by major histocompatibility complex class I antigen and blocked by antibody to the T cell receptor complex. Fluorescence-activated cell sorting analysis demonstrated their phenotype to be CD3+CD4-CD8+. Unstimulated PBMC from this patient had no detectable HIV-1-specific cytotoxicity when tested against autologous HIV-1 envelope-, Gag-, or RT-expressing target cells. Thus, this child with vertically acquired HIV-1 infection likely has HIV-1-specific CTL precursors despite the absence of circulating, activated HIV-1-specific CTL.
Asunto(s)
Productos del Gen gag/inmunología , Infecciones por VIH/inmunología , VIH-1 , ADN Polimerasa Dirigida por ARN/inmunología , Linfocitos T Citotóxicos/inmunología , Complejo CD3/biosíntesis , Antígenos CD8/biosíntesis , Línea Celular , Niño , Citotoxicidad Inmunológica , Transcriptasa Inversa del VIH , Humanos , InmunofenotipificaciónRESUMEN
Bovine brain endothelial cells (EC) that were isolated and propagated in pure culture had increased (greater than 20-fold) levels of xanthine oxidase and xanthine dehydrogenase activity compared to whole brain homogenate. Brain EC also released superoxide anion (O2-) into the extracellular medium. Treatment of EC with tungsten decreased (P less than 0.05) both XO activity and O2- release. XO appears to be highly concentrated in cerebral vascular endothelium and may be an important source of O2-.
Asunto(s)
Encéfalo/irrigación sanguínea , Endotelio Vascular/enzimología , Superóxidos/metabolismo , Xantina Oxidasa/metabolismo , Animales , Encéfalo/enzimología , Capilares/enzimología , Bovinos , Células Cultivadas , Endotelio Vascular/citología , Xantina Deshidrogenasa/metabolismoRESUMEN
Exposure to hypoxia (PO2 = 9 +/- 1 torr) increased human peripheral blood mononuclear cell production and secretion of interleukin-1 (IL-1)alpha, IL-1 beta, and tumor necrosis factor (TNF) percent of control = 190% for IL-1 alpha, p = 0.014; 219% for IL-1 beta, p = 0.014; and 243% for TNF, p = 0.037) following treatment with endotoxin (1 ng/ml). Hypoxia potentiated the increased production of these inflammatory cytokines at subthreshold levels of endotoxin with potentiation increasing at lower O2 concentrations. Hypoxia also increased cytokine production induced by the tumor promoter phorbol myristate acetate, suggesting a generalized biologic response. We conclude that hypoxia increases IL-1 and TNF production and speculate that this mechanism aggravates a variety of pathologic conditions involving endotoxin such as adult respiratory distress syndrome (ARDS), multiple organ failure, and septic shock.