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Total Suppression (total + suppression)
Selected AbstractsAntidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulationDIABETES OBESITY & METABOLISM, Issue 11 2008R. R Ortiz-Andrade Aim:, The present investigation was designed to determine the in vivo antidiabetic effect of naringenin (NG) in normoglycaemic and diabetic rat models through blood glucose (GLU) measurements following acute and subchronic time periods. Possible modes of action of NG were investigated and its acute toxicity determined. Methods:, Normoglycaemic and non-insulin-dependent diabetes mellitus (NIDDM) rat models were treated for acute and subchronic (5 days) time periods with 50 mg/kg/day of NG. Blood biochemical profiles were determined after 5 days of the treatment in normoglycaemic and NIDDM rats using commercial kits for GLU, triglycerides (TG), total cholesterol (CHOL) and high-density lipoprotein (HDL). In order to elucidate its antidiabetic mode of action, NG was administered intragastrically and an oral glucose tolerance test performed using GLU and sucrose (2 g/kg) as substrates. The inhibitory effect of a single concentration of NG (10 ,M) on 11,-hydroxysteroid dehydrogenase type 1 (11,-HSD1) activity in vitro was determined. Finally, the preclinical safety and tolerability of NG was determined by toxicological evaluation in mice and rats using Organization for Economic Cooperation and Development (OECD) protocols. Results:, Intragastrically administered NG (50 mg/kg) induced a significant decrease in plasma GLU in normoglycaemic and NIDDM rat models (p < 0.05) following acute and subchronic time periods. After 5 days of administration, NG produced significant diminished blood GLU and TG levels in streptozotocin,nicotinamide,induced diabetic rats. The administration of NG to normal rats significantly increased the levels of TG, CHOL and HDL (p < 0.05). NG (5 and 50 mg/kg) induced a total suppression in the increase of plasma GLU levels after administration of substrates (p < 0.01), but NG did not produce inhibition of ,-glucosidase activity in vitro. However, NG (10 ,M) was shown to inhibit 11,-HSD1 activity by 39.49% in a cellular enzyme assay. Finally, NG showed a Medium Lethal Dose LD50 > 5000 mg/kg and ranking at level five based on OECD protocols. Conclusion:, Our findings suggest that NG may exert its antidiabetic effect by extra-pancreatic action and by suppressing carbohydrate absorption from intestine, thereby reducing the postprandial increase in blood GLU levels. [source] The phosphate site of trehalose phosphorylase from Schizophyllum commune probed by site-directed mutagenesis and chemical rescue studiesFEBS JOURNAL, Issue 5 2008Christiane Goedl Schizophyllum commune,,,-trehalose phosphorylase utilizes a glycosyltransferase-like catalytic mechanism to convert its disaccharide substrate into ,- d -glucose 1-phosphate and ,- d -glucose. Recruitment of phosphate by the free enzyme induces ,,,-trehalose binding recognition and promotes the catalytic steps. Like the structurally related glycogen phosphorylase and other retaining glycosyltransferases of fold family GT-B, the trehalose phosphorylase contains an Arg507-XXXX-Lys512 consensus motif (where X is any amino acid) comprising key residues of its putative phosphate-binding sub-site. Loss of wild-type catalytic efficiency for reaction with phosphate (kcat/Km = 21 000 m,1·s,1) was dramatic (,107 -fold) in purified Arg507,Ala (R507A) and Lys512,Ala (K512A) enzymes, reflecting a corresponding change of comparable magnitude in kcat (Arg507) and Km (Lys512). External amine and guanidine derivatives selectively enhanced the activity of the K512A mutant and the R507A mutant respectively. Analysis of the pH dependence of chemical rescue of the K512A mutant by propargylamine suggested that unprotonated amine in combination with H2PO4,, the protonic form of phosphate presumably utilized in enzymatic catalysis, caused restoration of activity. Transition state-like inhibition of the wild-type enzyme A by vanadate in combination with ,,,-trehalose (Ki = 0.4 ,m) was completely disrupted in the R507A mutant but only weakened in the K512A mutant (Ki = 300 ,m). Phosphate (50 mm) enhanced the basal hydrolase activity of the K512A mutant toward ,,,-trehalose by 60% but caused its total suppression in wild-type and R507A enzymes. The results portray differential roles for the side chains of Lys512 and Arg507 in trehalose phosphorylase catalysis, reactant state binding of phosphate and selective stabilization of the transition state respectively. [source] Arrhythmic Storm Responsive to Quinidine in a Patient with Brugada Syndrome and Vasovagal SyncopePACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 8 2005MANLIO F. MÁRQUEZ A 37-year-old man with Brugada syndrome (BrS) and arrhythmic storm is described. One month after implantation of a cardioverter-defibrillator he presented with recurrent appropriate shocks for spontaneous ventricular fibrillation (VF). Because of this arrhythmic storm, quinidine therapy was initiated with total suppression of all spontaneous arrhythmias. He had remained free of arrhythmias for 22 months since quinidine initiation. Two episodes of VF occurred after the patient stopped taking the medication. The patient resumed quinidine and has been free of VF for the last 3 months. This response to quinidine in a patient with symptomatic BrS supports its role in the prophylaxis of arrhythmic events in BrS. [source] Emamectin, a novel insecticide for controlling field crop pests,PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 11 2002Isaac Ishaaya Abstract Emamectin is a macrocyclic lactone insecticide with low toxicity to non-target organisms and the environment, and is considered an important component in pest-management programmes for controlling field crop pests. It is a powerful compound for controlling the cotton bollworm Helicoverpa armigera (Hübner). A spray concentration of 25,mg AI litre,1 in a cotton field resulted in over 90% suppression of H armigera larvae up to day 28 after treatment, while similar mortality of the Egyptian cotton leafworm Spodoptera littoralis Boisduval, under the same conditions, was maintained for 3 days only. Emamectin is a potent compound for controlling the western flower thrips Frankliniella occidentalis (Pergande) under both laboratory and field conditions and its activity on adults was over 10-fold greater than that of abamectin. Spray concentrations of 10 and 50,mg AI litre,1 in Ageratum houstonianum Mill flowers resulted in total suppression of adults up to day 11 and of larvae up to day 20 after treatment. Under standard laboratory conditions, emamectin exhibits a considerable activity on the whitefly Bemisia tabaci (Gennadius) and the leafminer Liriomyza huidobrensis (Blanchard). Further studies are required to evaluate its potential activity on the latter pests under field conditions. © 2002 Society of Chemical Industry [source] Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patientACTA PAEDIATRICA, Issue 9 2002KM Main Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more widespread in chronic lung diseases. A considerable number of patients is concomitantly treated with topical or systemic glucocorticoids for anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such as CYP3A isoforms, they may compromise the metabolic clearance of glucocorticoids, thereby causing serious adverse effects. A patient with cystic fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term treatment with daily doses of 800 mg itraconazole and 1600 ,g budesonide. The patient experienced symptoms of striae, moon-face, increased facial hair growth, mood swings, headaches, weight gain, irregular menstruation despite oral contraceptives and increasing insulin requirement for diabetes mellitus. Endocrine investigations revealed total suppression of spontaneous and stimulated plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an improvement in clinical symptoms and recovery of the pituitary-adrenal axis after 3 mo. Conclusion: This observation suggests that the metabolic clearance of budesonide was compromised by itraconazole's inhibition of cytochrome P450 enzymes, especially the CYP3A isoforms, causing an elevation in systemic budesonide concentration. This provoked a complete suppression of the endogenous adrenal function, as well as iatrogenic Cushing's syndrome. Patients on combination therapy of itraconazole and budesonide inhalation should be monitored regularly for adrenal insufficiency. This may be the first indicator of increased systemic exogenous steroid concentration, before clinical signs of Cushing's syndrome emerge. [source] | |||||||||||||