Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis

<p>Abstract</p> <p>Background</p> <p>Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences.</p> <p>Results</p> <p>For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed.</p> <p>Conclusion</p> <p>In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.</p

Assessing the ecological risks from the persistence and spread of feral populations of insect-resistant transgenic maize

One source of potential harm from the cultivation of transgenic crops is their dispersal, persistence and spread in non-agricultural land. Ecological damage may result from such spread if the abundance of valued species is reduced. The ability of a plant to spread in non-agricultural habitats is called its invasiveness potential. The risks posed by the invasiveness potential of transgenic crops are assessed by comparing in agronomic field trials the phenotypes of the crops with the phenotypes of genetically similar non-transgenic crops known to have low invasiveness potential. If the transgenic and non-transgenic crops are similar in traits believed to control invasiveness potential, it may be concluded that the transgenic crop has low invasiveness potential and poses negligible ecological risk via persistence and spread in non-agricultural habitats. If the phenotype of the transgenic crop is outside the range of the non-transgenic comparators for the traits controlling invasiveness potential, or if the comparative approach is regarded as inadequate for reasons of risk perception or risk communication, experiments that simulate the dispersal of the crop into non-agricultural habitats may be necessary. We describe such an experiment for several commercial insect-resistant transgenic maize events in conditions similar to those found in maize-growing regions of Mexico. As expected from comparative risk assessments, the transgenic maize was found to behave similarly to non-transgenic maize and to be non-invasive. The value of this experiment in assessing and communicating the negligible ecological risk posed by the low invasiveness potential of insect-resistant transgenic maize in Mexico is discussed

Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

Adaptation of Saccharomyces cerevisiae Cells to High Ethanol Concentration and Changes in Fatty Acid Composition of Membrane and Cell Size

BACKGROUND: Microorganisms can adapt to perturbations of the surrounding environment to grow. To analyze the adaptation process of the yeast Saccharomyces cerevisiae to a high ethanol concentration, repetitive cultivation was performed with a stepwise increase in the ethanol concentration in the culture medium. METHODOLOGY/PRINCIPAL FINDINGS: First, a laboratory strain of S. cerevisiae was cultivated in medium containing a low ethanol concentration, followed by repetitive cultivations. Then, the strain repeatedly cultivated in the low ethanol concentration was transferred to medium containing a high ethanol concentration and cultivated repeatedly in the same high-ethanol-concentration medium. When subjected to a stepwise increase in ethanol concentration with the repetitive cultivations, the yeast cells adapted to the high ethanol concentration; the specific growth rate of the adapted yeast strain did not decrease during repetitive cultivation in the medium containing the same ethanol concentration, while that of the non-adapted strain decreased during repetitive cultivation. A comparison of the fatty acid composition of the cell membrane showed that the contents in oleic acid (C(18:1)) in ethanol-adapted and non-adapted strains were similar, but the content of palmitic acid (C(16:0)) in the ethanol-adapted strains was lower than that in the non-adapted strain in media containing ethanol. Moreover, microscopic observation showed that the mother cells of the adapted yeast were significantly larger than those of the non-adapted strain. CONCLUSIONS: Our results suggest that activity of cell growth defined by specific growth rate of the yeast cells adapted to stepwise increase in ethanol concentration did not decrease during repetitive cultivation in high-ethanol-concentration medium. Moreover, fatty acid content of cell membrane and the size of ethanol-adapted yeast cells were changed during adaptation process. Those might be the typical phenotypes of yeast cells adapted to high ethanol concentration. In addition, the difference in sizes of the mother cell between the non-adapted and ethanol strains suggests that the cell size, cell cycle and adaptation to ethanol are thought to be closely correlated

Stress-induced c-Fos expression is differentially modulated by dexamethasone, diazepam and imipramine

Immobilization stress upregulates c-Fos expression in several CNS areas. Repeated stress or the use of drugs can modulate stress-induced c-Fos expression. Here, we investigated in 40 different areas of the rat brain the effects of dexamethasone (SDX, a synthetic glucocorticoid), diazepam (SBDZ, a benzodiazepine), and imipramine (IMI, an antidepressant) on the c-Fos expression induced by restraint stress. Wistar rats were divided into four groups and submitted to 20 days of daily injection of saline (three first groups) or imipramine, 15 mg/kg, i.p. On day 21, animals were submitted to injections of saline (somatosensory, SS), SDX (1 mg/kg, i.p.), SBDZ (5 mg/kg, i.p.), or IMI (15 mg/kg, i.p.) before being submitted to restraint. Immediately after stress, the animals were perfused and their brains processed with immunohistochemistry for c-Fos (Ab-5 Oncogene Science). Dexamethasone reduced stress- induced c-Fos expression in SS cortex, hippocampus, paraventricular nucleus of the hypothalamus (PVH), and locus coeruleus (LC), whereas diazepam reduced c-Fos staining in the SS cortex, hippocampus, bed nucleus of stria terminalis, septal area, and hypothalamus (preoptic area and supramammillary nucleus). Chronic administration of imipramine decreased staining in the hippocampus, PVH, and LC, while increasing it in the nucleus raphe pallidus. We conclude that dexamethasone, diazepam and imipramine differentially modulate stress-induced Fos expression. the present study provides an important comparative background that may help in the further understanding of the effects of these compounds and on the brain activation as well as on the behavioral, neuroendocrine, and autonomic responses to stress.UFRRJ, Dept Physiol Sci, BR-23890000 Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilWeb of Scienc

Fanconi anaemia with bilateral diffuse pulmonary arterio venous fistulae: a case report

<p>Abstract</p> <p>Background</p> <p>We report a patient with cytogenetically confirmed Fanconi anaemia with associated diffuse bilateral pulmonary arterio-venous fistulae. This is only the second reported case of diffuse pulmonary arterio-venous fistulae with Fanconi anaemia.</p> <p>Case Presentation</p> <p>A 16 year old Sri Lankan boy, with a cytogenetically confirmed Fanconi anaemia was admitted to University Medical Unit, National Hospital of Sri Lanka for further assessment and treatment. Both central and peripheral cyanosis plus clubbing were noted on examination. The peripheral saturation was persistently low on room air and did not improve with supplementary Oxygen. Contrast echocardiography failed to demonstrate an intra cardiac shunt but showed early crossover of contrast, suggesting the possibility of pulmonary arterio-venous fistulae. Computed tomography pulmonary angiogram was inconclusive. Subsequent right heart catheterisation revealed bilateral diffuse arterio-venous fistulae not amenable for device closure or surgical intervention.</p> <p>Conclusion</p> <p>To our knowledge, this is the second reported patient with diffuse pulmonary arterio-venous fistulae associated with Fanconi anaemia. We report this case to create awareness among clinicians regarding this elusive association. We recommend screening patients with Fanconi anaemia using contrast echocardiography at the time of assessment with transthoracic echocardiogram. Though universal screening may be impossible given the cost constraints, such screening should at least be performed in patients with clinical evidence of desaturation or when a therapeutic option such as haematopoietic stem cell transplantation is considered. Treatment of pulmonary arteriovenous fistulae would improve patient outcome as desaturation by shunting worsens the anaemic symptoms by reducing the oxygen carrying capacity of blood.</p

Reexamining the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality

BACKGROUND: Low birth weight (<2,500 g) is a strong predictor of infant mortality. Yet low birth weight, in isolation, is uninformative since it is comprised of two intertwined components: preterm delivery and reduced fetal growth. Through nonparametric logistic regression models, we examine the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality. METHODS: We derived data on over 10 million singleton live births delivered at ≥ 24 weeks from the 1998–2000 U.S. natality data files. Nonparametric multivariable logistic regression based on generalized additive models was used to examine neonatal mortality (deaths within the first 28 days) in relation to fetal growth (gestational age-specific standardized birth weight), gestational age, and number of cigarettes smoked per day. All analyses were further adjusted for the confounding effects due to maternal age and gravidity. RESULTS: The relationship between standardized birth weight and neonatal mortality is nonlinear; mortality is high at low z-score birth weights, drops precipitously with increasing z-score birth weight, and begins to flatten for heavier infants. Gestational age is also strongly associated with mortality, with patterns similar to those of z-score birth weight. Although the direct effect of smoking on neonatal mortality is weak, its effects (on mortality) appear to be largely mediated through reduced fetal growth and, to a lesser extent, through shortened gestation. In fact, the association between smoking and reduced fetal growth gets stronger as pregnancies approach term. CONCLUSIONS: Our study provides important insights regarding the combined effects of fetal growth, gestational age, and smoking on neonatal mortality. The findings suggest that the effect of maternal smoking on neonatal mortality is largely mediated through reduced fetal growth

Phase I study of the combination of losoxantrone and cyclophosphamide in patients with refractory solid tumours

Losoxantrone is a DNA intercalator that was developed with the potential to replace anthracyclines. The recommended single agent dose of losoxantrone is 50 mg m−2 every 3 weeks. We conducted a phase I study of losoxantrone and a fixed dose of cyclophosphamide on a q3 weekly schedule. Forty-nine patients were enrolled, of which 46 were evaluable for toxicity. The dose-limiting toxicity was neutropenia at the maximum tolerable losoxantrone dose of 45 mg m−2. With granulocyte colony-stimulating factor support, significant further dose escalation of losoxantrone was achieved. Cardiotoxicity was seen with cumulative dosing. Pharmacokinetics of losoxantrone revealed linear kinetics and triphasic clearance, with significant interpatient variability. No objective responses were seen in this study. Neutropenia was dose-limiting in this combination with or without granulocyte colony-stimulating factor support. The recommended dose for further testing is cyclophosphamide 500 mg m−2 followed by losoxantrone 95 mg m−2 with granulocyte colony-stimulating factor support