RESUMEN
OBJECTIVE: To assess the consequences of infant botulism that result from Clostridium botulinum strains that produce 2 botulinum toxin serotypes, termed "bivalent." STUDY DESIGN: Epidemiologic investigations used a standard questionnaire. Clostridium botulinum strains were isolated by standard methods. Botulinum neurotoxin (BoNT) serotypes and the relative amounts of toxins produced were identified using the standard mouse bioassay. BoNT subtypes and genomic locations were identified by DNA nucleotide sequencing. RESULTS: Thirty bivalent cases of infant botulism occurred in the 45 years (1976-2020), representing 2.0% of all California infant botulism cases, in the 3 geographic regions of southern California, the southern Central Valley, and mid-northern California. Toxin serotype combinations were Ba (n = 22), Bf (n = 7), and Ab (n = 1). More patients with illness caused by bivalent C botulinum Ba and Bf strains needed endotracheal intubation at hospital admission, 60.0% (18/30), than did patients with illness caused by monovalent BoNT/B strains, 34.3% (152/443). The Cbotulinum Ba and Bf strains produced BoNT/B5 and either BoNT/A4 or /F2. The Ab strain produced BoNT/A2 and /B1. All toxin gene clusters were on plasmids. CONCLUSIONS: Infant botulism caused by bivalent Cbotulinum strains occurs sporadically and in diverse locations in California. Affected patients with bivalent Ba and Bf strains lacked distinguishing epidemiological features but appeared to be more severely paralyzed at hospital presentation than patients with illness caused by only BoNT/B. These bivalent strains produced BoNT subtypes A2, A4, B1, B5, and F2, and all toxin gene clusters were on plasmids.
Asunto(s)
Botulismo , Clostridium botulinum , Animales , Ratones , Botulismo/diagnóstico , Botulismo/epidemiología , Clostridium botulinum/genética , California/epidemiologíaRESUMEN
The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB-001), a humanized monoclonal antibody to amyloid beta, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.5, or 5 mg/kg or placebo (6 active, 2 placebo for 0.5 and 1.5-mg/kg cohorts; 10 active, 4 placebo for 5.0-mg/kg cohort). Three patients in the highest dose cohort (5.0 mg/kg) developed magnetic resonance imaging abnormalities consistent with vasogenic edema, predominantly high signal abnormalities on fluid-attenuated inversion recovery sequences, all of which resolved over time. Plasma amyloid beta was elevated from baseline, peaking approximately 24 hours after infusion. PK analysis demonstrated a half-life of 21 to 26 days, supporting a 13-week dosing interval for bapineuzumab. This small, single-dose study demonstrated the safety profile and PK characteristics of bapineuzumab and was used to design later safety and efficacy trials.
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Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales/administración & dosificación , Nootrópicos/administración & dosificación , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Nootrópicos/efectos adversosRESUMEN
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αß by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/síntesis química , Etilaminas/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Alquilación , Enfermedad de Alzheimer , Animales , Encéfalo/metabolismo , Línea Celular , Perros , Diseño de Fármacos , Cobayas , Humanos , Indicadores y Reactivos , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Relación Estructura-ActividadRESUMEN
OBJECTIVES: We undertook an open-label, uncontrolled study of investigational recombinant botulinum vaccine for botulinum neurotoxin (BoNT) serotypes A and B (rBV A/B) to assess its safety and immunogenicity in healthy volunteers who had been previously immunized with investigational pentavalent botulinum toxoid. Study participants who wished to do so could donate their hyperimmune plasma for production of Human Botulism Immune Globulin Intravenous (BIG-IV, BabyBIG®). STUDY DESIGN: A single 0.5â¯ml (mL), 40-microgram intramuscular injection of rBV A/B was administered to study participants. Post-vaccination sera collected at approximately 2-week intervals were evaluated for anti-BoNT/A and anti-BoNT/B neutralizing antibody concentrations (NAC). Local and systemic treatment-emergent adverse events (TEAEs) were identified by clinical and laboratory monitoring for 12â¯weeks post-vaccination with a final telephone follow-up for additional safety assessment at 6â¯months. The primary endpoint for immunogenicity was a ≥4-fold rise in NAC in ≥50% of participants by Week 4 post-vaccination. RESULTS: All 45 enrolled participants completed the study. Forty-two of 45 participants (93.3%) experienced at least one TEAE. Overall, 138 of 218 (63.3%) reported TEAEs were treatment-related, the majority of which were mild injection-site reactions. No serious or unexpected adverse events occurred. The study achieved its primary immunogenicity endpoint with 37/45 (82.2%) participants and 39/45 (86.7%) participants having a ≥4-fold rise in NAC to anti-BoNT/A and to anti-BoNT/B, respectively, by Week 4 post-vaccination. CONCLUSION: A single 0.5â¯mL dose of rBV A/B was safe, well-tolerated and immunogenic in participants previously immunized with pentavalent botulinum toxoid. The tolerability and immunogenicity characteristics of rBV A/B vaccination of individuals with existing BoNT immunity support its potential future use to provide occupational protection to botulism laboratory workers. Almost all study participants donated hyperimmune plasma for production of BIG-IV. ClinicalTrials.gov registration number: NCT01701999.
Asunto(s)
Vacunas Bacterianas/inmunología , Botulismo/inmunología , Botulismo/prevención & control , Clostridium botulinum/inmunología , Inmunogenicidad Vacunal , Vacunas Sintéticas/inmunología , Adulto , Anciano , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/efectos adversos , Toxinas Botulínicas/inmunología , Agentes Comunitarios de Salud , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Vacunación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversosRESUMEN
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aß generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aß generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aß in the CSF of healthy human volunteers.