Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.</p> <p>Methods</p> <p>The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.</p> <p>Results</p> <p>Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.</p> <p>Conclusions</p> <p>In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.</p

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic β-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of β-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to >1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering Cmax and pharmacokinetic coordination of drug combinations

Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model

Neurogenesis is a life long process, but the rate of cell proliferation and differentiation decreases with age. In Alzheimer's patients, along with age, the presence of Aβ in the brain inhibits this process by reducing stem cell proliferation and cell differentiation. GLP-1 is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and the GLP-1 analogue liraglutide has been shown to increase cell proliferation in an Alzheimer's disease (AD) mouse model. Here we investigated acute and chronic effects of liraglutide on progenitor cell proliferation, neuroblast differentiation and their subsequent differentiation into neurons in wild type and APP/PS-1 mice at different ages. APP/PS1 and their littermate controls, aged 3, 6, 12, 15 months were injected acutely or chronically with 25 nmol/kg liraglutide. Acute treatment with liraglutide showed an increase in cell proliferation in APP/PS1 mice, but not in controls whereas chronic treatment increased cell proliferation at all ages (BrdU and Ki67 markers). Moreover, numbers of immature neurons (DCX) were increased in both acute and chronic treated animals at all ages. Most newly generated cells differentiated into mature neurons (NeuN marker). A significant increase was observed with chronically treated 6, 12, 15 month APP/PS1 and WT groups. These results demonstrate that liraglutide, which is currently on the market as a treatment for type 2 diabetes (VictozaTM), increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD

Growth of Nile tilapia Oreochromis niloticus fed diets with different levels of proteins of yeast

This experiment was based on observations of 72 juveniles of Nile tilapia (Oreochromis niloticus), sexually reverted with an initial mean weight of 37.27 ± 4.92g, distributed in 12 cages of 100 l to evaluate the effects of the yeast inclusion as proteins source in the diet. The fishes were distributed in a completely randomized design with four treatments (0; 20; 40; and 60%) of yeast protein in substitution to the protein of traditional sources with three repetitions. Effects of the treatments were not observed (p > 0.05) on the survival and to food conversion. It was observed a quadratic effect on weight gain (Y = 73.39 + 0.173X - 0.0034X²; R²= 0.9986). It was concluded the best level of yeast inclusion as source proteins in the diet for reversed Nile tilapia juvenile was 25.44%.<br>Foram utilizados 72 juvenis de tilápia do Nilo (Oreochromis niloticus) sexualmente revertidos com peso médio inicial de 37.27 ± 4.92g. distribuídos em 12 gaiolas de 100L para avaliar os efeitos da inclusão de levedura como fonte protéica na dieta. Os peixes foram distribuídos em um delineamento inteiramente casualizados com quatro tratamentos (0; 20; 40; e 60%) de proteína de levedura em substituição à proteína de fontes tradicionais com três repetições. Não foram observados efeitos dos tratamentos (p > 0.05) sobre a sobrevivência e conversão alimentar. Foi observado efeito quadrático sobre o ganho de peso (Y = 73.39 + 0.173X - 0.0034X²; R² = 0.9986). Concluiu-se que o melhor nível de inclusão de levedura como fonte protéica na dieta para juvenis revertidos de tilápias do Nilo é de 25.44%

Growth and survival of tilapia Oreochromis niloticus (Linnaeus, 1758) submitted to different temperatures during the process of sex reversal Crescimento e sobrevivência de tilápias Oreochromis niloticus (Linnaeus, 1758) submetidas a diferentes temperaturas durante o processo de inversão sexual

The objective of this research was to evaluate the sex reversal technique using 17&#945;--methyltestosterone (MT) hormone, submitted to temperature modification of fry Nilo tilapia storage, aiming to get the data of sex reversal combined with growth performance and fry survival. The experiment was performed at UFLA Fish Culture Station, using tilapia fry (0,008 ± 0.002 g e 0,9 ± 0.1 cm) obeying a totally randomized experimental delineation in a factorial scheme 4x4, in 4 temperatures (26º, 28º, 30º, 32ºC) and 4 hormonal doses (0, 20, 40, 60mg of MT/kg of ration) during 28 days, with 5 repetitions. As temperature raised, weight gain rate, size and survival increased (p<0.01); however, this temperature raise was not effective in modifying males ratio (p>0.01), which occurred only due to the used hormone treatment. The dose of 40 mg of MT/kg of ration provided similar results to those of 60mg of MT/kg of ration. Hence, the temperature band from 26º to 32ºC does not affect sex reversal rate, but temperatures around 30ºC improves the performance of tilapias related to the growth and survival, and the dose of 40 mg of MT/kg of ration is enough to achieve monosex populations.<br>Objetivou-se, neste trabalho, avaliar a técnica de inversão sexual utilizando hormônio 17&#945;-metiltestosterona (MT), submetidas à modificação da temperatura de estocagem das pós-larvas de tilápia, visando obter os melhores dados de inversão sexual aliado à performance de crescimento e sobrevivência das pós-larvas. O experimento foi conduzido na Estação de Piscicultura da UFLA, utilizando pós-larvas (0,008 ± 0,002 g e 0,9 ± 0,1 cm) de tilápia em delineamento experimental inteiramente casualizado em esquema fatorial 4x4, com 4 temperaturas (26º, 28º, 30º e 32ºC) e 4 doses hormonais (0, 20, 40 e 60mg de MT/kg de ração) durante 28 dias, com 5 repetições. À medida que se elevou a temperatura, a taxa de ganho de peso, o tamanho e a sobrevivência foram maiores (p<0,01); entretanto, esse aumento na temperatura não foi suficiente para alterar a proporção de machos (p>0,01), que ocorreu apenas em função do hormônio utilizado. A dose de 40 mg de MT/kg de ração proporcionou resultados semelhantes aos da dose de 60 mg de MT/kg de ração. Portanto, a faixa de temperatura entre 26º e 32ºC não influencia na taxa de inversão sexual, mas temperaturas em torno de 30ºC melhoram o desempenho das tilápias quanto ao crescimento e à sobrevivência, e a dose de 40 mg de MT/kg de ração é suficiente para a obtenção de populações monossexo