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Inhibitors Used (inhibitor + used)
Selected AbstractsOrlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight lossDIABETES OBESITY & METABOLISM, Issue 4 2009S. Jacob Background:, Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss,independent effects. Aim:, To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c)] are independent of weight loss. Methods:, This retrospective analysis of pooled data from seven multicentre, double-blind, placebo-controlled studies involved overweight or obese patients with type 2 diabetes (aged 18,70 years). Patients were required to have a body mass index of 27,43 kg/m2, HbA1c of 6.5 to <13%, and stable weight for ,3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. Results:, A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo-treated patients (,1.39 mmol/l vs. ,0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA1c compared with placebo (,0.74% vs. ,0.31%; p < 0.0001). For patients with minimal weight loss (,1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (,0.83 mmol/l vs. ±0.02 mmol/l; p = 0.0052) and HbA1c,0.29% vs. ±0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA1c) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. Conclusion:, Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non-esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon-like peptide-1 secretion in the lower small intestine. [source] Multiple effects of amprenavir against Candida albicansFEMS YEAST RESEARCH, Issue 2 2010Lys A. Braga-Silva Abstract Secreted aspartyl peptidases (Saps) are virulence attributes produced by Candida albicans that participate in multiple aspects of the fungal biology and pathogenesis. In the present paper, we have shown that amprenavir, a peptidase inhibitor used in HIV chemotherapy, inhibited Sap2 and growth of C. albicans and also promoted ultrastructural alterations. Esterase activity, sterol content, biofilm formation and the expression of surface mannose- and sialic acid-rich glycoconjugates were also reduced by amprenavir. [source] CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxineJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2006M. E. E. Shams PhD Summary Background:, Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O -desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N -desmethylvenlafaxine (NDV). Objectives:, The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. Method:, In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. Results:, There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1·8 and the 10th and 90th percentiles 0·3 and 5·2, respectively. Individuals with ODV/V ratios below 0·3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5·2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1·1 ± 0·8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4·8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0·3 had more side effects (P < 0·005) and reduced serum concentrations of sodium (P < 0·05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. Conclusion:, The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects. [source] Tadalafil as an in vitro sperm motility stimulantANDROLOGIA, Issue 1 2007T. Mostafa Summary Tadalafil (Cialis®) is a known oral selective phosphodiesterase-5 inhibitor used widely in the management of erectile dysfunction. To assess its ability on human sperm motility in vitro, 70 asthenozoospermic semen specimens delivered by masturbation were investigated. Semen samples were divided equally into four tubes, one as a control and to the others tadalafil dissolved solution was added in vitro in three different concentrations (4.0, 1.0, 0.5 mg ml,1 respectively). The tubes were incubated and were followed up for sperm motility per cent changes for 0.5, 1, 2, 3 h. It was found that the concentration used played an important role in the degree of sperm enhancement. Specimens treated with 4 mg ml,1 tadalafil solution demonstrated a significant decrease in sperm motility compared with the controls. Specimens treated with 1.0 mg ml,1 solution demonstrated significant increase in sperm progressive forward motility. Specimens treated with 0.5 mg ml,1 solution demonstrated significant increases in sperm motility but lower than that of 1 mg ml,1 concentration. It is concluded that in vitro use of tadalafil solution in special concentration has a significant stimulatory effect on asthenozoospermic sperm motility. [source] Capillary electrophoresis versus differential scanning calorimetry for the analysis of free enzyme versus enzyme-ligand complexes: In the search of the ligand-free status of cholinesterasesELECTROPHORESIS, Issue 2 2006Daniel Rochu Dr. Abstract Cholinesterases (ChEs) are highly efficient biocatalysts whose active site is buried in a deep, narrow gorge. The talent of CE to discover inhibitors in the gorge of highly purified preparations has fairly altered the meaning of a ChE ligand-free status. To attempt at a description of this one, we investigated the stability of Bungarus fasciatus acetylcholinesterase (AChE), alone or complexed with different inhibitors. Determination of midtransition temperature for thermal denaturation, using differential scanning calorimetry (DSC) and CE, provided conflicting results. Discrepancies strongly question the reality of a ligand-free AChE state. DSC allowed estimation of the stability of AChE-ligands complexes, and to rank the stabilizing effect of different inhibitors. CE acted as a detector of hidden ligands, provided that they were charged, reversibly bound, and thus dissociable upon action of electric fields. Then, CE allowed quantification of the stability of ligand-free AChE. CE and DSC providing each fractional and nonredundant information, cautious attention must be paid for actual estimation of the conformational stability of ChEs. Because inhibitors used in purification of ChEs by affinity chromatography are charged, CE remains a leading method to estimate enzyme stability and detect the presence of bound hidden ligands. [source] Haemophilia 2002: emerging risks of treatmentHAEMOPHILIA, Issue 3 2002B. L. EVATT Haemophilia care and treatment products have greatly improved over the past 2 decades. Transitions in treatment produced by these changes were accompanied by the emergence of unexpected risks and new complications. In order to provide the best comprehensive care to patients with haemophilia, healthcare providers periodically need to re-evaluate and adjust their management and therapeutic products to prevent or minimize the effects produced by the emerging issues. For example, reducing the effects of infectious agents remains the highest priority for the haemophilia community because of the high level of morbidity and mortality that has resulted from earlier therapeutic agents. In many countries, the goal has been to achieve absolute zero risk for infectious agents. In some instances, the screening procedures to achieve these goals reduced the availability of plasma needed for manufactured derivatives and produced another emerging risk, shortages of clotting factor preparations. Similarly, better diagnostic methods identified other potential agents that were not inactivated by current technology. Likewise, immune tolerance regimens and the prophylactic management of haemophilia introduced different therapeutic delivery systems with their own risks. The drugs used to manage diseases such as human immunodeficiency virus (HIV), which were transmitted by products manufactured before mid-1980, create their own set of risks for this community. Topical emerging risks of treatment, including variant Creutzfeldt,Jakob disease, an assessment of its risks and impact, the complications of using indwelling catheters, and the role of protease inhibitors used to treat HIV may have on bleeding complications of haemophilia are discussed. [source] Monoamine Metabolism and Behavioral Responses to Ethanol in Mitochondrial Aldehyde Dehydrogenase Knockout MiceALCOHOLISM, Issue 10 2006Elizabeth Fernandez Background: It is widely accepted that, in addition to removing acetaldehyde produced during the metabolism of ethanol, mitochondrial aldehyde dehydrogenase (ALDH2) functions in the pathway by which aldehyde metabolites of the monoamines dopamine (DA) and serotonin (5-HT) are converted to their acidic metabolites. Moreover, studies of ALDH2 inhibitors used for treating alcoholism suggest that their antidipsotropic effects may be related to inhibition of monoamine metabolism. Therefore, we examined the hypothesis that altered brain monoamine metabolism is related to the influence of ALDH2 on behavioral responses to ethanol. Methods: Mice were generated with a gene-trap mutation of the ALDH2 gene. ALDH2 mRNA was absent in ALDH2,/, mice. Western blot analysis of liver mitochondria confirmed the absence of ALDH2 protein in the ALDH2,/, mice. Wild-type and ALDH2-deficient mice were tested for the effects of different doses of ethanol on locomotor activity, ataxia, and a 2-bottle ethanol,water preference test. Results: Wild-type and ALDH2+/, mice preferred ethanol to water. However, ALDH2,/, mice drank significantly less ethanol than wild-type or ALDH2+/, mice. Locomotor activity and ataxia were significantly more affected by ethanol in ALDH2,/, mice than in wild-type or ALDH2+/, mice. There was no effect of genotype on levels of 5-HT, DA, or their precursors or metabolites in several brain regions, as measured by HPLCec. Conclusions: The results indicate that: (1) the effect of the mutant genotype on behavioral responses to ethanol is unrelated to altered brain monoamine metabolism and (2) ALDH2 is not required for the metabolism of brain monoamines in vivo. [source] Reversible inhibitors of TAFIa can both promote and inhibit fibrinolysisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2003M. Schneider Summary., The plasma carboxypeptidase activated thrombin-activable fibrinolysis inhibitor (TAFIa), is thermally unstable at 37 °C, with a half-life of 8 or 15 min depending on the isoform. The arginine analog, 2-guanidinoethylmercaptosuccinate (GEMSA), not only inhibits TAFIa but also slows the spontaneous inactivation of the enzyme, thereby reducing the activity of TAFIa, while extending its apparent half-life. Because, as shown in previous work, the ability of TAFIa to prolong clot lysis can be more dependent on its half-life than its concentration, in this study we determined whether reversible inhibitors of TAFIa could paradoxically prolong clot lysis. Potato tuber carboxypeptidase inhibitor (PTCI) or GEMSA were titrated into normal pooled human plasma, in the presence of soluble thrombomodulin. Both inhibitors mediate a biphasic antifibrinolytic effect, prolonging clot lysis at lower concentrations and enhancing clot lysis at higher concentrations. The antifibrinolytic effect of GEMSA is maximized at 1 mmol L,1, increasing clot lysis time from 100 min to 350 min. The antifibrinolytic effect of PTCI is maximized at 100 nmol L,1, increasing clot lysis time from 100 min to 240 min. To further characterize the nature of this biphasic effect, TAFI at various concentrations was added to TAFI-immunodepleted human plasma in the presence of PTCI or GEMSA. The magnitude of the effect depends on the concentration of TAFIa, the concentration of inhibitor, and the potency of the inhibitor. We propose that the biphasic antifibrinolytic effect is mediated by the dynamic equilibrium of free TAFIa that inactivates quickly, and TAFIa bound to inhibitor that inactivates slowly. TAFIa inhibitors used as therapeutic agents might not only enhance lysis at higher concentrations, but also stabilize fibrin clots at intermediate concentrations. [source] 5-HYDROXYTRYPTAMINE IN THE CARDIOVASCULAR SYSTEM: FOCUS ON THE SEROTONIN TRANSPORTER (SERT)CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2006Wei Ni SUMMARY 1The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression. 2The aim of the present review is to discuss our current knowledge of 5-HT and SERT in the cardiovascular (CV) system, as well as their function in physiological and pathophysiological states. 3The SERT protein has been located in multiple CV tissues, including the heart, blood vessels, brain, platelets, adrenal gland and kidney. Modification of SERT function occurs at both transcriptional and translational levels. The functions of SERT in these tissues is largely unexplored, but includes modulation of cardiac and smooth muscle contractility, platelet aggregation, cellular mitogenesis, modulating neuronal activity and urinary excretion. 4Recent studies have uncovered potential relationships between the expression of SERT gene promoter variants (long (l) or short (s)) with CV diseases. Specifically, the risk of myocardial infarction and pulmonary hypertension is increased with expression of the ll promoter, a variant associated with increased expression and function of SERT. The relationship between promoter variants and other CV diseases has not been investigated. 5Newly available experimental tools, such as pharmacological compounds and genetically altered mice, should prove useful in the investigation of the function of SERT in the CV system. 6In summary, the function of SERT in the CV system is just beginning to be revealed. [source] | |||||||||||||