Assuntos
Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Quimiocina CCL5/análogos & derivados , Quimiocina CCL5/uso terapêutico , Infecções por HIV/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Administração Intravaginal , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Macaca mulatta , Vírus da Imunodeficiência Símia/efeitos dos fármacosRESUMO
Topical agents, such as microbicides, that can protect against human immunodeficiency virus (HIV) transmission are urgently needed. Using a chimeric simian/human immunodeficiency virus (SHIV SF162), which is tropic for the chemokine receptor CCR5, we report that topical application of high doses of PSC-RANTES, an amino terminus-modified analog of the chemokine RANTES, provided potent protection against vaginal challenge in rhesus macaques. These experimental findings have potentially important implications for understanding vaginal transmission of HIV and the design of strategies for its prevention.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Antagonistas dos Receptores CCR5 , Quimiocina CCL5/análogos & derivados , Quimiocina CCL5/uso terapêutico , Infecções por HIV/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vagina/virologia , Administração Intravaginal , Animais , Fármacos Anti-HIV/administração & dosagem , Anti-Infecciosos Locais/administração & dosagem , Anticorpos Antivirais/sangue , Quimiocina CCL5/administração & dosagem , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Macaca mulatta , Receptores CCR5/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/imunologiaRESUMO
BACKGROUND: Severe acute pancreatitis leads to a systemic inflammatory response characterized by widespread leucocyte activation and, as a consequence, distant lung injury. In CC chemokines the first two cysteine residues are adjacent to each other. The aim of this study was to evaluate the effect of Met-RANTES, a CC chemokine receptor antagonist, on pancreatic inflammation and lung injury in caerulein-induced acute pancreatitis in mice. METHODS: Acute pancreatitis was induced in mice by hourly intraperitoneal injection of caerulein. Met-RANTES was administered either 30 min before or 1 h after starting caerulein injections, and pancreatic inflammation and lung injury were assessed. There were five groups of eight mice each including controls. RESULTS: Treatment with Met-RANTES had little effect on caerulein-induced pancreatic damage. Met-RANTES, however, reduced lung injury when given either before administration of caerulein (mean(s.e.m.) lung myeloperoxidase (MPO) 1.47(0.19) versus 3.70(0.86)-fold increase over control, P = 0.024; mean(s.e.m.) microvascular permeability 1.15(0.05) versus 3.57(0.63) lavage to plasma fluorescein isothiocyanate-labelled albumin fluorescence ratio (L/P) per cent, P = 0.002) or after caerulein administration (lung MPO 1.96(0.27) versus 3.65(0.63)-fold increase over control, P = 0.029; microvascular permeability 0.94(0.04) versus 2.85(0.34) L/P per cent, P < 0.001). CONCLUSION: Treatment with Met-RANTES reduces lung damage associated with caerulein-induced pancreatitis in mice. Chemokine receptor antagonists may be of use for the treatment of the systemic complications of acute pancreatitis.