RESUMO
OBJECTIVES: although melatonin prescribing in England has been increasing in recent years, there have been no large scale studies on the safety of melatonin compared to other medical treatments for insomnia. The primary aim of this study was to examine the association between exposure to melatonin, hypnotic benzodiazepines (temazepam, nitrazepam) or Z-drugs (zolpidem, zopiclone) and fracture risk. DESIGN: retrospective cohort study. SETTING: 309 general practices contributing to The Health Improvement Network (THIN) between 2008 and 2013. PARTICIPANTS: 1,377 patients aged 45 years and older prescribed melatonin; 880 patients prescribed hypnotic benzodiazepines; 1,148 patients prescribed Z-drugs and 2,752 unexposed controls matched by age, gender and practice. MAIN OUTCOME: fracture following prescription of study drugs ascertained from practice records. RESULTS: the unadjusted hazard ratios for fracture during the follow-up period were 1.90 (95% CI 1.41-2.57) for melatonin, 1.70 (95% CI 1.18-2.46) for hypnotic benzodiazepines and 2.03 (95% CI 1.45-2.84) for Z-drugs. After adjustment for 26 covariates, the hazard ratios were 1.44 (95% CI 1.01-2.04) for melatonin, 1.26 (95% CI 0.82-1.92) for hypnotic benzodiazepines and 1.52 (95% CI 1.04-2.23) for Z-drugs. Only patients with three or more melatonin prescriptions had elevated risk. The mean time to fracture was 1.04 years and there was no significant difference in mean time to fracture between the cohorts. CONCLUSIONS: in this large cohort of patients attending UK primary care, prescriptions for melatonin and Z-drugs were associated with a significantly increased risk of fracture. With the use of melatonin increasing steadily overtime, this study adds to the literature on the safety profile of this drug.
Assuntos
Compostos Azabicíclicos/efeitos adversos , Fraturas Ósseas/epidemiologia , Hipnóticos e Sedativos/efeitos adversos , Melatonina/efeitos adversos , Nitrazepam/efeitos adversos , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Temazepam/efeitos adversos , Idoso , Comorbidade , Registros Eletrônicos de Saúde , Feminino , Fraturas Ósseas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Atenção Primária à Saúde , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologia , ZolpidemRESUMO
Moderate to severe osteogenesis imperfecta is associated with multiple fractures in childhood. There are no published data regarding the effects of third-generation bisphosphonates in these children. This randomized study investigated which of three different doses of risedronate was most effective in reducing fracture incidence. We randomly assigned 53 children with moderate to severe osteogenesis imperfecta to receive 0.2, 1, or 2 mg/kg per week of risedronate. We assessed safety, fracture incidence, and bone measurement outcomes at 3, 6, 12, 18, and 24 months. At 24 months, 69% of children assigned 0.2 mg/kg per week had had new fractures compared with 44% receiving 1 mg/kg per week and 75% receiving 2 mg/kg per week. Poisson regression with age and prior fracture as covariates showed that there was no difference in incident nonvertebral fracture between groups. Fracture rate diminished in each group during the trial compared with previous the 2 years (p = .005). Lumbar spine bone mineral density increased significantly (p = .009) only in the 2 mg/kg per week group. Long bone bowing deformities reduced more in children receiving 1 or 2 mg/kg per week of risedronate [odds ratio (OR) 0.67, 95% confidence interval (CI) 0.48-0.93 per unit increase in risedronate dose, p = .015]. There were no serious adverse events. Bone mass increased and bowing deformities reduced with increasing risedronate dose. Children suffered fewer fractures irrespective of risedronate dose. The most appropriate dose of risedronate for children with moderate to severe osteogenesis imperfecta in this study was 2 mg/kg per week.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Ácido Etidrônico/análogos & derivados , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/patologia , Absorciometria de Fóton , Administração Oral , Adolescente , Determinação da Idade pelo Esqueleto , Conservadores da Densidade Óssea/efeitos adversos , Criança , Pré-Escolar , Demografia , Relação Dose-Resposta a Droga , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/uso terapêutico , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/epidemiologia , Humanos , Incidência , Ácido Risedrônico , Coluna Vertebral/patologia , Resultado do Tratamento , Reino Unido/epidemiologiaRESUMO
The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.
Assuntos
Química Farmacêutica/métodos , Química Farmacêutica/normas , Animais , Química Farmacêutica/tendências , Humanos , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/normas , Controle de Qualidade , Fatores de TempoRESUMO
The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.