RESUMEN

GSK3335065 is an inhibitor of kynurenine monooxygenase (KMO) being developed for the treatment of acute pancreatitis. Healthy male volunteers were administered ascending doses of GSK3335065 or matched placebo as a single intravenous bolus injection to assess safety, tolerability, pharmacokinetics and pharmacodynamics. GSK3335065 displayed an apparent volume of distribution between 20.6 L and 44.6 L, a clearance between 0.462 L/h and 0.805 L/hr and a terminal half-life between 31.3 and 34.5 hr. In the single subject who received 1.3 mg GSK3335065, changes in tryptophan pathway metabolites were observed consistent with the changes seen in preclinical species suggesting that KMO enzyme activity was partially inhibited. However, a broad complex ventricular tachycardia was observed in this subject, which was judged to be a Serious Adverse Event (SAE) and resulted in early termination of the study. While development of GSK3335065 was subsequently discontinued, significant confounding factors hinder a clear interpretation that the tachycardia was directly related to administration of the compound.

Asunto(s)

Quinurenina , Pancreatitis , Enfermedad Aguda , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Oxigenasas de Función Mixta

RESUMEN

Multiple strains of Acinetobacter baumannii have developed multidrug resistance (MDR), leaving colistin as the only effective treatment. The cecropin-α-melittin hybrid BP100 (KKLFKKILKYL-NH2) and its analogs have previously shown activity against a wide array of plant and human pathogens. In this study, we investigated the in vitro antibacterial activities of 18 BP100 analogs (four known and 14 new) against the MDR A. baumannii strain ATCC BAA-1605, as well as against a number of other clinically relevant human pathogens. Selected peptides were further evaluated against strains of A. baumannii that acquired resistance to colistin due to mutations of the lpxC, lpxD, pmrA, and pmrB genes. The novel analogue BP214 showed antimicrobial activity at 1 to 2 µM and a hemolytic 50% effective concentration (EC50) of >150 µM. The lower activity of its enantiomer suggests a dual, specific and nonspecific mode of action. Interestingly, colistin behaved antagonistically to BP214 when pmrAB and lpxC mutants were challenged.

Asunto(s)

Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Oligopéptidos/farmacología , Acinetobacter baumannii/genética , Acinetobacter baumannii/metabolismo , Aciltransferasas/genética , Aciltransferasas/metabolismo , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Secuencia de Aminoácidos , Antibacterianos/síntesis química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Colistina/farmacología , Farmacorresistencia Bacteriana/genética , Eritrocitos/efectos de los fármacos , Expresión Génica , Hemólisis/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mutación , Oligopéptidos/síntesis química , Técnicas de Síntesis en Fase Sólida , Relación Estructura-Actividad , Factores de Transcripción/genética , Factores de Transcripción/metabolismo