RESUMEN
BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. METHODS: Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. RESULTS: Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). CONCLUSION: This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.
Asunto(s)
Angioedemas Hereditarios , Humanos , Angioedemas Hereditarios/tratamiento farmacológico , Resultado del Tratamiento , Proteína Inhibidora del Complemento C1/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
AIM: Indirect comparison of efficacy and safety of vedolizumab with adalimumab in biologic-naïve patients with moderate to severe ulcerative colitis (UC). METHODS: Vedolizumab is a gut-selective medication for moderate to severe UC. Since no comparative trials are available for direct comparison of vedolizumab vs adalimumab in UC, a systematic review of literature databases was conducted to identify randomized, placebo-controlled trials of the two drugs in patients with moderate to severe UC after failure of conventional treatment. Studies were screened for eligibility by two reviewers based on predefined inclusion criteria. Bucher's adjusted indirect comparison was used to compare vedolizumab and adalimumab indirectly through placebo as common comparator. RESULTS: One vedolizumab study (GEMINI 1) and three adalimumab studies (ULTRA 1, ULTRA 2 and M10-447) met the eligibility criteria. Baseline characteristics of the included populations were similar in biologic-naïve UC patients across study arms. Although no statistically significant differences between treatments were found for induction efficacy endpoints, there was a trend toward a benefit of vedolizumab over adalimumab. There were also no significant differences between treatments for any maintenance efficacy endpoints, with no clear trend favoring either agent. Vedolizumab exhibited statistically superior maintenance safety compared with adalimumab, with significant reductions in risks of adverse events (relative risk 0.67 [95% confidence interval 0.57-0.80]; p < .0001), serious adverse events (0.20 [0.09-0.42]; p < .0001) and adverse events leading to discontinuation (0.14 [0.05-0.43]; p = .0006). CONCLUSION: This analysis indicates that vedolizumab has comparable efficacy to adalimumab with improved safety in biologic-naïve patients with moderate to severe UC.
Asunto(s)
Adalimumab/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Productos Biológicos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Humanos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
INTRODUCTION: Perianal fistulas (PF) are presumably a frequent extraintestinal manifestation of Crohn's disease (CD), causing significant functional impairment. This study aims to gain representative data on the prevalence, characteristics, and treatment of CD patients suffering from PF in Germany. MATERIALS AND METHODS: A retrospective cross-sectional analysis of claims data from several German company health insurance funds included adult patients with CD and PF in 2015. The dataset comprised in- and outpatient services with diagnoses, drug prescriptions, and other patient data. It is representative for age, gender, and region and allows extrapolation to the total German statutory health insurance (SHI) population. A systematic literature review was conducted to discuss these results in the international context. RESULTS: A CD prevalence of 299 per 100â000 and a PF prevalence in CD patients of 3.4â% was observed in this cross-sectional study. PF are most prevalent in young age groups (<â24 to 39). One-third of patients with PF received biologics and surgery. Surgical procedures were performed in 31.3â% of PF patients in the inpatient setting and in 4.4â% of PF patients in the outpatient setting. All complicated perianal fistula patients received at least 1 inpatient surgery and 44.8â% received biologic therapy. DISCUSSION: This claims data analysis in German patients estimates a CD prevalence in the SHI population that corresponds well to previously reported data. The prevalence rate for PF in CD patients is comparable with a previous cross-sectional German claims data analysis but is markedly lower than cumulative risks reported in longitudinal cohort studies. PF patients are young and treatment intensive with one-third requiring biologic treatment or inpatient surgery.
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Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/economía , Administración Financiera , Costos de la Atención en Salud/estadística & datos numéricos , Revisión de Utilización de Seguros/estadística & datos numéricos , Fístula Rectal/etiología , Adulto , Enfermedad de Crohn/patología , Estudios Transversales , Alemania , Humanos , Revisión de Utilización de Seguros/economía , Prevalencia , Fístula Rectal/patología , Estudios RetrospectivosRESUMEN
The aim of this work was to transfer the established chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes in solution on the solid phase. For this purpose, (S)-configured amino acids, (S)-alanine, and (S)-leucine, with a small methyl and a larger isobutyl moiety were attached to the solid support 9 by reductive amination. After five reaction steps on the solid support, the 1,4-diazepanes (S)-19a,b were cleaved off and reductively alkylated to afford the 1,2,4-trisubstituted 1,4-diazepanes (S)-20a and (S)-21b, respectively. Both compounds show high σ1 affinity and selectivity over the σ2 subtype.
Asunto(s)
Azepinas/farmacología , Receptores sigma/antagonistas & inhibidores , Animales , Azepinas/síntesis química , Azepinas/química , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Cobayas , Ligandos , Hígado/efectos de los fármacos , Hígado/metabolismo , Estructura Molecular , Ratas , Receptores sigma/metabolismo , Relación Estructura-Actividad , Receptor Sigma-1RESUMEN
Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15, 26, and 39. The configuration in 2-position does not influence the σ1 affinity and selectivity over related receptors. A cyclohexylmethyl or a butyl group are the preferred substituents in 4-position, whereas a methyl moiety in 2-position and a (substituted) benzyl moiety in 1-position result in the highest σ1 affinity. These results fit nicely to the reported σ1 pharmacophore models. The compounds did not inhibit the structurally related fungal enzyme sterol Δ8,7-isomerase, but showed inhibition of diverse enzymes in late cholesterol biosynthesis at high concentrations. In a screening against more than 50 target proteins, (2S)-1-benzyl-4-(4-methoxybenzyl)-2-methyl-1,4-diazepane ((S)-28b, Ki(σ1)=0.86nM) showed a clean receptor profile. The dose dependent potentiation of electrically stimulated contractions of guinea pig vas deferens indicates σ1 agonistic activity of (S)-28b. Even at a dose of 100mg/kg (S)-28b did not induce severe toxic or behavioral effects in the Irwin screen. Clear cognition enhancing effects were observed for (S)-28b after inducing amnesia by scopolamine.