RESUMEN
Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.
Asunto(s)
Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Pteridinas/administración & dosificación , Pteridinas/farmacología , Adulto , Anciano , Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/farmacología , Citocinas/sangre , Citocinas/inmunología , ADN Viral/sangre , Método Doble Ciego , Quimioterapia Combinada , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/sangre , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Interferón-alfa/sangre , Interferón-alfa/inmunología , Masculino , Persona de Mediana Edad , Pteridinas/efectos adversos , Seroconversión , Tenofovir/administración & dosificación , Tenofovir/efectos adversos , Tenofovir/farmacología , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Adulto JovenRESUMEN
OBJECTIVE: To assess the outcome of the Pippi Salle (Kropp onlay) urethral lengthening procedure in the treatment of neuropathic urinary incontinence. PATIENTS AND METHODS: Twenty-eight patients (12 males and 16 females, mean age at surgery 12.6 years, range 7-32) were identified who underwent the procedure between 1993 and 1997 in the United Kingdom. Outcomes were assessed by a review of the case notes. RESULTS: Of the 28 patients, 18 (64%) were rendered continent by day, and 17 (61%) by day and night. Twelve of the 16 females were completely dry, and a further girl was dry by day, giving overall daytime continence in 13 patients; five males were rendered continent (P=0.03, chi-square test). Four patients required revision surgery; in five patients (two females and three males) the method was abandoned and they underwent an alternative procedure, and a further four are being reassessed. CONCLUSION: The Pippi Salle procedure should be considered as a first-line treatment option for neuropathic incontinence in females. Its place in the management of incontinent males is less convincing.
Asunto(s)
Uretra/cirugía , Incontinencia Urinaria/cirugía , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Resultado del Tratamiento , Reino Unido , Vejiga Urinaria Neurogénica/complicaciones , Incontinencia Urinaria/etiologíaRESUMEN
We have studied the ability of synthetic analogs of lipid A to mimic lipopolysaccharide (LPS) for activation of 70Z/3 pre-B cells (expression of surface Igs) or to antagonize this effect. The results indicate that the presence of glucosamine (mono- or disaccharide) as a 'backbone' for the attachment of fatty acids is not necessary for activation of cells of the B lineage. Phosphate groups are not necessary either. Other structural features such as the configuration of particular asymmetric carbons, and the distance between an anionic group and an N-acyl chain, seem to be much more critical parameters for activation of B cells. Among the synthetic lipids which were unable to activate 70Z/3 cells, one compound, consisting of N,N-acylated and bisphosphorylated 2,3-dideoxy-2,3-diamino-D-glucose, behaved as a specific LPS antagonist and blocked also the activation triggered by the other synthetic inducers. The influence of the synthetic lipids on the entry of mature mouse B lymphocytes into the G1A phase of the cell cycle (cell enlargement) was also investigated. A high correlation was observed between the potency to activate pre-B cells and the ability to induce blast formation in mature B cells.