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Momir Mikov - One of the best experts on this subject based on the ideXlab platform.
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PAMPA model of Gliclazide permeability: The impact of probiotic bacteria and bile acids.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2020Co-Authors: Maja Đanić, Bojan Stanimirov, Nebojša Pavlović, Saša Vukmirović, Hani Al-salami, Slavica Lazarević, Momir MikovAbstract:Gut microbiota and bile acids possess the ability to modify absorption and pharmacokinetic profile of numerous drugs. Since the variability of Gliclazide response in patients cannot be explained only by genetic factors, the influence of gut microbiota and bile acids should be considered. The aim of this study was to determine the effects of probiotic bacteria and bile acids on the Gliclazide permeability. The permeability of Gliclazide with and without probiotic bacteria and bile acids (cholic acid, CA and deoxycholic acid, DCA) was tested using in vitro PAMPA model, at three different pH values (5.8, 6.5 and 7.4). Concentrations of Gliclazide were determined by HPLC analysis. The interactions of Gliclazide and bile acids were also investigated by molecular mechanics calculations (MM2). Probiotic bacteria significantly increased the permeability of Gliclazide across the PAMPA membrane at all observed pH values while the total amount of Gliclazide during incubation with bacteria was significantly reduced at pH 7.4, which could be a consequence of partial metabolism of the drug by enzymes of probiotic bacteria. Bile acids decreased the permeability of Gliclazide through PAMPA membrane, with more pronounced effects of DCA, by forming more stable complexes with Gliclazide. Given that probiotic bacteria and bile acids are naturally present in the gut and that each individual has a specific bacterial fingerprint, future research should extend the explanation of their effect on the Gliclazide bioavailability and therapy individualization in in vivo conditions.
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Transport and Biotransformation of Gliclazide and the Effect of Deoxycholic Acid in a Probiotic Bacteria Model.
Frontiers in Pharmacology, 2019Co-Authors: Maja Ðanić, Bojan Stanimirov, Nebojša Pavlović, Saša Vukmirović, Jelena Lazić, Hani Al-salami, Momir MikovAbstract:Introduction: Inter-individual differences in gut microflora composition may affect drug metabolism and overall therapeutic response. Gliclazide is a drug characterized by large inter-individual differences in therapeutic response; however, the causes of these differences are not fully explained and may be the outcome of microbial biotransformation. Recently, great attention has been paid to studies on bile acid (BA) interactions with gut microflora and the role of BAs in the modification of drug transport through biological membranes. The aim: Considering the assumption of Gliclazide-probiotic-BAs interactions, the aim of the study was to investigate the transport and biotransformation of Gliclazide in probiotic bacteria, as well as the effects of deoxycholic acid (DCA) on Gliclazide transport into bacterial cells. Materials and methods: Probiotics were incubated with Gliclazide with or without DCA for 24 hours at 37°C. The intracellular and extracellular concentrations of Gliclazide were determined at seven time points by high-performance liquid chromatography. Gliclazide biotransformation by the enzymatic activity of probiotic bacteria was examined using appropriate software packages. Results: During the 24 hour incubation with probiotic bacteria, significantly lower extracellular concentrations of Gliclazide were observed at all time points compared to controls, while in the group with DCA, the decrease in concentration was noticed only at 24 hours. The total concentration of Gliclazide throughout the whole period was significantly lower compared to control. Proposed pathways of Gliclazide biotransformation by probiotic bacteria involve reactions of hydrolysis and hydroxylation. Conclusion: Based on the results obtained, it can be concluded that there are interactions of Gliclazide-probiotics-DCA, at both the level of active and passive transport into the cells, and at the level of drug biotransformation by enzymatic activity of probiotic bacteria. The effect of these interactions on the final therapeutic response of Gliclazide should be further studied and confirmed in in vivo conditions.
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PP208—Deoxycholic Acid as a Modifier of the Blood Brain Barrier Permeation in Rat
Clinical Therapeutics, 2013Co-Authors: Mladena Lalic-popovic, Svetlana Goločorbin-kon, Boris Milijašević, Velibor Vasovic, Momir MikovAbstract:2013 e83 PP208—Deoxycholic AciD As A MoDifier of the BlooD BrAin BArrier PerMeAtion in rAt M. Lalic-Popovic; S. Golocorbin-Kon; V. Vasovic; B. Milijasevic; and M. Mikov Department of Pharmacy, Faculty of Medicine, Novi Sad, Serbia; Faculty of Pharmacy, University of Montenegro, Podgorica, Montenegro; and Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, Novi Sad, Serbia Introduction: Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as prooters of drug penetration across biological membranes. Aim: The aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of Gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Patients (or Materials) and Methods: Twenty-four male Wistar rats were randomly allocated to 4 groups, of which 2 were given alloxan intraperitoneally (100 mg/kg) to induce diabetes. One diabetic group and 1 healthy group were given a bolus Gliclazide intra-arterially (20 mg/kg), while the other 2 groups apart from Gliclazide got deoxycholic acid (4 mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised, and blood glucose and Gliclazide concentrations were measured. Results: Penetration of Gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared with healthy animals. Also in both, healthy and diabetic animals, deoxycholic acid increased the permeation of Gliclazide through that in BBB. Deoxycholic acid pretreatment also changed the pattern of blood glucose level increase after Gliclazide application in diabetic as well as in healthy animals. Conclusion: Deoxycholic acid promotes Gliclazide penetration across BBB in diabetic and in healthy animals. In addition, deoxycholic acid alters some pharmacokinetic properties of Gliclazide in both healthy and diabetic rats. Thus, deoxycholic acid should be more investigated in the treatment of diabetes mellitus and as permeation promoter of lipophilic molecules through BBB as well as other biological membranes. Financial Source: This work has been supported by Ministry of Science and Technology development of Serbia N041012.
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deoxycholic acid as a modifier of the permeation of Gliclazide through the blood brain barrier of a rat
Experimental Diabetes Research, 2013Co-Authors: Mladena Lalicpopovic, Boris Milijašević, Svetlana Golocorbinkon, Hani Alsalami, Velibor Vasovic, Momir MikovAbstract:Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as promoters of drug penetration across biological membranes. Accordingly, the aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of Gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Twenty-four male Wistar rats were randomly allocated to four groups, of which, two were given alloxan intraperitoneally (100 mg/kg) to induce diabetes. One diabetic group and one healthy group were given a bolus Gliclazide intra-arterially (20 mg/kg), while the other two groups apart from Gliclazide got deoxycholic acid (4 mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised and blood glucose and Gliclazide concentrations were measured. Penetration of Gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared to healthy animals. Also in both, the healthy and diabetic animals, deoxycholic acid increased the permeation of Gliclazide through that in BBB.
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probiotics decreased the bioavailability of the bile acid analog monoketocholic acid when coadministered with Gliclazide in healthy but not diabetic rats
European Journal of Drug Metabolism and Pharmacokinetics, 2012Co-Authors: Hani Alsalami, Svetlana Golocorbinkon, Grant Butt, Ian G Tucker, Momir MikovAbstract:In recent studies we showed that Gliclazide has no hypoglycemic effect on type 1 diabetic (T1D) rats while MKC does, and their combination exerted a better hypoglycemic effect than MKC alone. We also showed that the most hypoglycemic effect was noticed when T1D rats were treated with probiotics then gavaged with MKC + Gliclazide (blood glucose decreased from 24 ± 3 to 10 ± 2 mmol/l). The aim of this study is to investigate the influence of probiotics on MKC pharmacokinetics when coadministered with Gliclazide, in T1D rats. 80 male Wistar rats (weight 350 ± 50 g) were randomly allocated into 8 groups (10 rats/group), 4 of which were injected with alloxan (30 mg/kg) to induce T1D. Group 1 was healthy and group 2 was diabetic. Groups 3 (healthy) and 4 (diabetic) were gavaged with probiotics (75 mg/kg) every 12 h for 3 days and 12 h later all groups received a single oral dose of MKC + Gliclazide (4 and 20 mg/kg respectively). The remaining 4 groups were treated in the same way but administered MKC + Gliclazide via the i.v. route. Blood samples collected from T1D rats prior to MKC + Gliclazide revealed that probiotic treatment alone reduced blood glucose levels twofold. When coadministered with Gliclazide, the bioavailability of MKC was reduced in healthy rats treated with probiotics but remained the same in diabetic pretreated rats. The decrease in MKC bioavailability, when administered with Gliclazide, caused by probiotic treatment in healthy but not diabetic rats suggests that probiotic treatment induced MKC metabolism or impaired its absorption, only in healthy animals. The different MKC bioavailability in healthy and diabetic rats could be explained by different induction of presystemic elimination of MKC in the gut by probiotic treatment.
Nanne Kleefstra - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of Gliclazide as treatment for type 2 diabetes a systematic review and meta analysis of randomized trials
PLOS ONE, 2014Co-Authors: Gijs W D Landman, Geertruide H De Bock, Kornelis J J Van Hateren, Peter R Van Dijk, Klaas H Groenier, Rijk O B Gans, S T Houweling, Henk J G Bilo, Nanne KleefstraAbstract:Objective and Design Gliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of Gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156) Data Sources Medline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database. Selection Included were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing Gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used. Results Nineteen trials were included; 3,083 patients treated with Gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin, Gliclazide was slightly more effective (−0.13% (95%CI: −0.25, −0.02, I2 55%)). One out of 2,387 Gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 Gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I2 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes. Conclusions The methodological quality of randomized trials comparing Gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and Gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.
Guntram Schernthaner - One of the best experts on this subject based on the ideXlab platform.
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a long term comparison of pioglitazone and Gliclazide in patients with type 2 diabetes mellitus a randomized double blind parallel group comparison trial
Diabetic Medicine, 2005Co-Authors: B Charbonnel, Guntram Schernthaner, D R Matthews, M Hanefeld, P BrunettiAbstract:Aims This study compared the effects of pioglitazone and Gliclazide on metabolic control in drug-naive patients with Type 2 diabetes mellitus. Methods A total of 1270 patients with Type 2 diabetes were randomized in a parallel-group, double-dummy, double-blind study. Patients with poorly controlled Type 2 diabetes (HbA1c 7.5–11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or Gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C-peptide and pro-insulin levels were measured. Results Mean HbA1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: −1.4%; Gliclazide: −1.4%; (90% CI: −0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the Gliclazide group [2.0 mmol/l; treatment difference −0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: −0.7 to −0.1)]. Improvements in high-density lipoprotein cholesterol (HDL-C) and total cholesterol/HDL-C were greater with pioglitazone than with Gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for Gliclazide, whereas twice as many patients reported oedema with pioglitazone than with Gliclazide. Conclusions Pioglitazone monotherapy was equivalent to Gliclazide in reducing HbA1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.
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Gliclazide modified release a critical review of pharmacodynamic metabolic and vasoprotective effects
Metabolism-clinical and Experimental, 2003Co-Authors: Guntram SchernthanerAbstract:Abstract Gliclazide modified release (MR) is a new formulation of the drug Gliclazide and is given once daily. The specifically designed hydrophilic matrix of Gliclazide MR leads to a progressive drug release that parallels the 24-hour glycemic profile in type 2 diabetic patients. Development studies showed a sustained efficacy over 2 years coupled with a very good acceptability. Gliclazide MR acts selectively on adenosine triphosphate-dependent potassium (K ATP ) channels of the pancreatic β cell. No interaction with cardiovascular K ATP channels has been shown, indicating that the drug can be safely used in patients with ischemic heart disease. In addition, Gliclazide MR shows the ability to inhibit key mechanisms in diabetic angiopathy, independently of glycemic control.
Amit X Garg - One of the best experts on this subject based on the ideXlab platform.
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the hypoglycemic risk of glyburide glibenclamide compared with modified release Gliclazide
Canadian Journal of Diabetes, 2015Co-Authors: Kristin K Clemens, Jamie L Fleet, Stephanie N. Dixon, Eric Mcarthur, Irene Hramiak, Amit X GargAbstract:Abstract Objectives The risk for hypoglycemia when taking glyburide compared with modified-release Gliclazide remains to be established in older adults in routine care. We investigated the risk of a hospital encounter with hypoglycemia following a new prescription for glyburide compared with modified-release Gliclazide. Methods In 2 population-based matched retrospective cohort studies in Ontario, Canada, between 2002 and 2011, we examined older adults who were newly prescribed glyburide or Gliclazide as monotherapy or in the presence of metformin. Our primary outcome was a hospital encounter with hypoglycemia assessed within 90 days. Results The baseline characteristics between matched groups were similar. Initiating glyburide vs. Gliclazide as monotherapy was associated with a higher risk for a hospital encounter with hypoglycemia (69 patients of 4374 taking glyburide [1.58%] vs. 8 patients of 4374 taking Gliclazide [0.18%], absolute risk increase 1.40% [95% CI 1.01% to 1.79%], number needed to harm 71 [55 to 99], odds ratio 8.63 [95% CI 4.15 to 17.93], p Conclusions Glyburide was associated with a higher risk for hypoglycemia than modified-release Gliclazide. The results of our studies may help to convince healthcare professionals who use glyburide to consider modified-release Gliclazide as a safer alternative.
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The Hypoglycemic Risk of Glyburide (Glibenclamide) Compared with Modified-Release Gliclazide.
Canadian journal of diabetes, 2015Co-Authors: Kristin K Clemens, Jamie L Fleet, Stephanie N. Dixon, Eric Mcarthur, Irene Hramiak, Amit X GargAbstract:The risk for hypoglycemia when taking glyburide compared with modified-release Gliclazide remains to be established in older adults in routine care. We investigated the risk of a hospital encounter with hypoglycemia following a new prescription for glyburide compared with modified-release Gliclazide. In 2 population-based matched retrospective cohort studies in Ontario, Canada, between 2002 and 2011, we examined older adults who were newly prescribed glyburide or Gliclazide as monotherapy or in the presence of metformin. Our primary outcome was a hospital encounter with hypoglycemia assessed within 90 days. The baseline characteristics between matched groups were similar. Initiating glyburide vs. Gliclazide as monotherapy was associated with a higher risk for a hospital encounter with hypoglycemia (69 patients of 4374 taking glyburide [1.58%] vs. 8 patients of 4374 taking Gliclazide [0.18%], absolute risk increase 1.40% [95% CI 1.01% to 1.79%], number needed to harm 71 [55 to 99], odds ratio 8.63 [95% CI 4.15 to 17.93], p<0.0001). Similar findings were noted when glyburide vs. Gliclazide was initiated in the presence of metformin (110 patients of 8038 taking glyburide [1.37%] vs. 19 patients of 8038 taking Gliclazide [0.24%], absolute risk increase 1.13% [95% CI 0.86% to 1.40%], number needed to harm 77 [71 to 116], odds ratio 6.06 [95% CI 3.68 to 9.97], p<0.0001). Glyburide was associated with a higher risk for hypoglycemia than modified-release Gliclazide. The results of our studies may help to convince healthcare professionals who use glyburide to consider modified-release Gliclazide as a safer alternative. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
Liu Zhi-min - One of the best experts on this subject based on the ideXlab platform.
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Comparison of efficacy and safety between domestic slow-released Gliclazide and Gliclazide in the treatment of Chinese patients with type 2 diabetes mellitus
Chinese Journal of Diabetes, 2005Co-Authors: Liu Zhi-minAbstract:Objective To compare the clinical efficacy and safety of once-daily 60 mg of slow-(released) Gliclazide(China Associate Pharmaceutical Co.LTD) with twice-daily of Gliclazide((160 mg/d)) in the treatment of Chinese patients with type 2 diabetes mellitus(T2DM).Methods 234 Chinese patients with T2DM meeting 1997 WHO diagnostic criteria were recruited from 4 clinical centers.The patients were assigned to slow-released Gliclazide(117 case) or Gliclazide(117 cases) treatment group in a ramdomized,double blinded,multicentre clinical trial.The trial consisted of 2-weeks wash followed by 12-week treatment period.Results Compared with the baseline,HbA_1c,fasting and postprandial plasma glucose levels were significantly reduced in two groups after 12-week treatment.In slow-released Gliclazide group,the mean reductions of blood HbA_1c,fasting and postprandial plasma glucose levels were 0.81%,1.91 mmol/L and 2.41mmol/L respectively;in Gliclazide group,the mean reductions of blood HbA_1c,fasting and postprandial plasma glucose levels were 0.76%,1.97mmol/L and 2.13 mmol/L respectively.The differences in the reduction rates of fasting and postprandial plasma glucose levels between the two groups were not statistically significant.No serious adverse events in two groups were found;no laboratory-proved hypoglycemia(plasma glucose≤2.78 mmol/L) was observed.Conclusion Oncedaily 60 mg of slow-released Gliclazide provides an effective control of plasma glucose levels for Chinese T2DM patients.Compared with twice-daily of Gliclazide(160 mg/day),slow-released Gliclazide is equally well safe and effective.