The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Gideon Koren - One of the best experts on this subject based on the ideXlab platform.
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Glyburide transport across the human placenta
Obstetrics & Gynecology, 2015Co-Authors: Rachelle A Schwartz, Barak Rosenn, Katarina Aleksa, Gideon KorenAbstract:OBJECTIVE:To estimate the magnitude of transplacental transfer of Glyburide in women with gestational diabetes mellitus (GDM).METHODS:A prospective, observational study was conducted on women with GDM on Glyburide therapy. On delivery admission, the Glyburide dose and time of last dose were recorded
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breast cancer resistance protein bcrp mediated Glyburide transport effect of the c421a q141k bcrp single nucleotide polymorphism
Drug Metabolism and Disposition, 2010Co-Authors: Erika K Pollex, Gideon Koren, Gregory J Anger, Janine R Hutson, Micheline PiquettemillerAbstract:The antidiabetic agent Glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP-binding cassette, subfamily G, member 2 (ABCG2) expressed in the placenta protects the fetus against the accumulation of Glyburide. A number of studies have investigated the significance of several single-nucleotide polymorphisms (SNPs) in the ABCG2 gene. Associations between the Q141K (C421A) SNP and ABCG2 protein expression, membrane surface translocation, efflux activity, or ATPase activity have been shown. Therefore, alterations in Glyburide transport across the placenta, resulting in increased fetal Glyburide exposure, may be seen in individuals carrying the C421A allele. The purpose of this study is to investigate whether the Q141K SNP causes alterations in ABCG2-mediated Glyburide transport. Glyburide accumulation assays were carried out with stably transfected human embryonic kidney (HEK)-293 cells expressing wild-type ABCG2 (Arg482) and polymorphic ABCG2 (Q141K). Glyburide kinetic parameters were determined for comparison of wild-type and SNP ABCG2 activity by simultaneously fitting data for ABCG2-expressing cells (saturable transport) and empty vector-expressing cells (nonsaturable transport) by nonlinear regression analysis. The apparent K t and V max values for the transfected HEK-293 cells expressing the polymorphic variant (Q141K) of ABCG2 were significantly higher than those values determined for the wild-type ABCG2-expressing cells ( p < 0.05). Our results indicate that the Q141K variant of ABCG2 may have the potential to alter the placental pharmacokinetics of Glyburide used in pregnancy.
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the role of placental breast cancer resistance protein in the efflux of Glyburide across the human placenta
Placenta, 2008Co-Authors: Erika K Pollex, Angelica Lubetsky, Gideon KorenAbstract:Gestational diabetes mellitus is a common medical complication in pregnancy. Recent findings demonstrate that Glyburide is effluxed against a concentration gradient from the fetal to the maternal circulation. However, the transport systems involved in the active efflux of Glyburide in the human placenta have not yet been identified. The ATP-binding cassette transporter, breast cancer resistance protein (BCRP), is highly expressed in placental syncytiotrophoblast suggesting it may play a role in protecting the fetus from drug toxicity. The objective of the present study was to determine whether BCRP participates in the transport of Glyburide across the human placenta. The placental transfer of Glyburide in the presence of specific BCRP inhibitor, nicardipine, was investigated using the ex vivo dual perfusion system of isolated human placental lobules. In a closed experiment, Glyburide was added (200 ng/mL) to the maternal and fetal circulations and the BCRP inhibitor (20 μM) was added to the maternal circulation. Samples were taken during pre-control, experimental, and post-control periods for measurement of Glyburide and markers of tissue viability. Results obtained from perfusions (n = 4) in the presence of the BCRP inhibitor show a significant increase in the mean fetal-to-maternal concentration ratio of Glyburide determined at 180 min, 0.56 ± 0.06, when compared to the mean ratio obtained in the absence of inhibitor, 0.32 ± 0.06 (p = 0.04). These data indicate that nicardipine partially blocked the transfer of Glyburide across the whole placenta through its inhibition of BCRP. This is the first ex vivo evidence that BCRP actively transports Glyburide.
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breast cancer resistance protein mediating the trans placental transfer of Glyburide across the human placenta
Placenta, 2008Co-Authors: C Gedeon, Micheline Piquettemiller, Gregory J Anger, Gideon KorenAbstract:Abstract Members of the ATP-binding cassette (ABC) efflux transporter family, including P-glycoprotein (PGP), the multidrug resistance-associated proteins (MRPs) and the breast cancer resistance protein (BCRP) have been shown to be highly expressed in the human placenta. Recent studies documented that the oral hypoglycemic Glyburide does not cross the human placenta to an appreciable extent. Furthermore, the trans-placental transfer of Glyburide has been shown not to be affected by either the presence of PGP inhibitor, verapamil or MRP inhibitor, indomethacin. Therefore, our objective was to identify other human placental ABC transporters potentially involved in limiting the trans-placental transfer of Glyburide to the fetus. [ 3 H]-Glyburide transport was examined in brush border human placental vesicles in the presence or absence of specific inhibitors. Prepared vesicles were 70% oriented right-side-out and demonstrated 25–27 fold enrichment as compared to whole placenta. Functional studies demonstrated significant increases in the intra-vesicular accumulation of [ 3 H]-Glyburide in vesicles treated with the BCRP inhibitor, novobiocin. In contrast, PGP inhibition as well as MRP inhibition did not affect [ 3 H]-Glyburide accumulation. This is the first evidence to clearly indicate that Glyburide is preferentially transported by BCRP, in the brush border of the human placenta. Our study also indicates that BCRP likely effluxes substrates in the fetal to maternal direction in the human placenta.
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transport of Glyburide by placental abc transporters implications in fetal drug exposure
Placenta, 2006Co-Authors: C Gedeon, Gideon Koren, Javad Behravan, Micheline PiquettemillerAbstract:Much evidence has demonstrated that a number of ATP-binding cassette (ABC) efflux transporters including P-glycoprotein (PGP), the multidrug resistance-associated proteins (MRPs) and the breast cancer resistance protein (BCRP) are highly expressed in placental tissues and are believed to profoundly limit the passage of therapeutic or toxic xenobiotics to the fetus. Recent studies indicate that the oral hypoglycemic Glyburide does not cross the human placenta to an appreciable extent. Our objective was to identify placental transporters potentially involved in limiting the transplacental transfer of Glyburide to the fetus. Thus, [3H]-Glyburide transport was examined in BCRP, PGP, MRP1, MRP2 and MRP3 over-expressing cell lines in the presence or absence of specific inhibitors. Our results demonstrated significant increases in the intracellular accumulation of [3H]-Glyburide in BCRP and MRP3 over-expressing cells in the presence of the inhibitors novobiocin and indomethacin, respectively. PGP inhibition with verapamil or MRP inhibition with indomethacin did not affect [3H]-Glyburide accumulation in the PGP or MRP2 over-expressing cell lines and only limited changes were seen in the MRP1 over-expressing cell line. On the other hand, Glyburide was found to significantly inhibit MRP1-, MRP2- and MRP3-mediated efflux of 5-carboxyfluorescein diacetate and PGP-mediated transport of rhodamine 123. Our evidence is the first to clearly indicate that Glyburide is preferentially transported by BCRP and MRP3.
Taylor W Kimberly - One of the best experts on this subject based on the ideXlab platform.
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effect of iv Glyburide on adjudicated edema endpoints in the games rp trial
Neurology, 2018Co-Authors: Taylor W Kimberly, Matthew B Bevers, Rudiger Von Kummer, Andrew M Demchuk, Javier Romero, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, Kevin N ShethAbstract:Objective In this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV Glyburide on adjudicated, edema-related endpoints. Methods Blinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV Glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined. Results In the per-protocol sample, 41 patients received Glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 [58.5%] in IV Glyburide vs n = 23 [63.9%] in placebo, p = 0.91) or the incidence of malignant edema (n = 19 [46%] in IV Glyburide vs n = 17 [47%] in placebo, p = 0.94). However, treatment with IV Glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 [2.4%] with IV Glyburide vs n = 8 [22.2%] with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV Glyburide had less midline shift ( p p p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 [58%] vs n = 15 [94%], p = 0.016). Conclusion IV Glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV Glyburide in large hemispheric infarction are warranted to corroborate these findings. ClinicalTrials.gov identifier NCT01794182. Level of evidence This study provides Class II evidence that for patients with large hemispheric infarction, IV Glyburide improves some edema-related endpoints.
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long term outcomes in patients aged 70 years with intravenous Glyburide from the phase ii games rp study of large hemispheric infarction an exploratory analysis
Stroke, 2018Co-Authors: Kevin N Sheth, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, Nils H Petersen, Ken Cheung, Lauren A Beslow, Taylor W KimberlyAbstract:Background and Purpose— We aimed to determine whether subjects aged ≤70 years who were treated with intravenous Glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. Methods— GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke–Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82–300 cm 3 ) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated with intravenous Glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous Glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood–brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift). Results— Participants ≤70 years of age treated with intravenous Glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P =0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous Glyburide-treated subjects at 90 days (odds ratio, 2.31; P =0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous Glyburide on the Barthel Index ( P =0.03) and EuroQol group 5-dimension ( P =0.05). Participants treated with intravenous Glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P P Conclusions— In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous Glyburide. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.
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safety and efficacy of intravenous Glyburide on brain swelling after large hemispheric infarction games rp a randomised double blind placebo controlled phase 2 trial
Lancet Neurology, 2016Co-Authors: Kevin N Sheth, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, Lauren A Beslow, Ann Christin Ostwaldt, Gregory J Del Zoppo, Sven Jacobson, Taylor W KimberlyAbstract:Summary Background Preclinical models of stroke have shown that intravenous Glyburide reduces brain swelling and improves survival. We assessed whether intravenous Glyburide (RP-1127; glibenclamide) would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction. Methods For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18–80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82–300 cm 3 on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous Glyburide group. Intravenous Glyburide was given as a 0·13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0·16 mg/h for the first 6 h and then 0·11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov, number NCT01794182. Findings Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous Glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous Glyburide group and 14 (39%) in the placebo group had an mRS score of 0–4 at 90 days without decompressive craniectomy (adjusted odds ratio 0·87, 95% CI 0·32–2·32; p=0·77). Ten (23%) of 44 participants in the intravenous Glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0·76), and four of 20 had serious adverse events (two in the intravenous Glyburide group and two in the placebo group, p=1·00). One cardiac death occurred in each group (p=1·00). Interpretation Intravenous Glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous Glyburide. Funding Remedy Pharmaceuticals.
L Blonde - One of the best experts on this subject based on the ideXlab platform.
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greater reductions in a1c in type 2 diabetic patients new to therapy with Glyburide metformin tablets as compared to Glyburide co administered with metformin
Diabetes Obesity and Metabolism, 2003Co-Authors: L Blonde, J Wogen, C Kreilick, A A SeymourAbstract:Background: A cohort of patients with type 2 diabetes, prescribed Glyburide/metformin tablets, experienced significantly greater improvements in glycaemic control compared to patients receiving Glyburide co-administered with metformin. Aim: To compare the change in A1C for type 2 diabetic patients new to combination therapy with fixed-dose Glyburide/metformin tablets vs. Glyburide co-administered with metformin in a usual-care setting. Methods: This retrospective cohort study analysed medication usage via an administrative pharmacy claims database and the patients' corresponding laboratory results. Patients were new to antidiabetic combination therapy with Glyburide/metformin tablets or Glyburide co-administered with metformin between August 2000 and July 2001 and had A1C measurements at baseline and within 76–194 days of initiating combination therapy. The change from baseline in A1C was analysed using statistical regression to adjust for significant covariates (baseline A1C and dosage). Adherence with therapy was also compared. Results: The cohort consisted of 950 patients who received Glyburide/metformin tablets and 471 taking Glyburide co-administered with metformin. Glyburide/metformin patients were younger (mean age = 56 vs. 60 years, p < 0.0001) and received lower doses of each drug than patients taking Glyburide co-administered with metformin (Glyburide mean final dose = 6 vs. 10 mg/day, p < 0.0001; metformin = 893 vs. 1297 mg/day, p < 0.0001). The mean decrease from baseline A1C, adjusted for baseline A1C and dosage, of 2.02% for Glyburide/metformin tablets was significantly (p < 0.0001) greater than the decrease of 1.49% for Glyburide co-administered with metformin. Glyburide/metformin patients with baseline A1C ≥ 8 experienced a significantly (p < 0.0001) greater decrease in A1C of 2.93% compared to 1.92% for Glyburide co-administered with metformin. For patients with baseline A1C < 8%, the difference between the A1C responses remained significant, even though the reductions in A1C were smaller for both Glyburide/metformin tablets and Glyburide co-administered with metformin (0.54% and 0.23%, p = 0.0017). Patients were more adherent with Glyburide/metformin tablets (84% vs. 76%, p < 0.0001), though regression analysis indicated that adherence was not a significant predictor of change in A1C. Conclusions: The lower medication doses delivered by Glyburide/metformin tablets provided a significantly greater reduction in A1C than did Glyburide co-administered with metformin in patients with type 2 diabetes, especially when baseline A1C ≥ 8%.
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Greater reductions in A1C in type 2 diabetic patients new to therapy with Glyburide/metformin tablets as compared to Glyburide co‐administered with metformin
Diabetes Obesity and Metabolism, 2003Co-Authors: L Blonde, J Wogen, C Kreilick, A A SeymourAbstract:Background: A cohort of patients with type 2 diabetes, prescribed Glyburide/metformin tablets, experienced significantly greater improvements in glycaemic control compared to patients receiving Glyburide co-administered with metformin. Aim: To compare the change in A1C for type 2 diabetic patients new to combination therapy with fixed-dose Glyburide/metformin tablets vs. Glyburide co-administered with metformin in a usual-care setting. Methods: This retrospective cohort study analysed medication usage via an administrative pharmacy claims database and the patients' corresponding laboratory results. Patients were new to antidiabetic combination therapy with Glyburide/metformin tablets or Glyburide co-administered with metformin between August 2000 and July 2001 and had A1C measurements at baseline and within 76–194 days of initiating combination therapy. The change from baseline in A1C was analysed using statistical regression to adjust for significant covariates (baseline A1C and dosage). Adherence with therapy was also compared. Results: The cohort consisted of 950 patients who received Glyburide/metformin tablets and 471 taking Glyburide co-administered with metformin. Glyburide/metformin patients were younger (mean age = 56 vs. 60 years, p
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Glyburide metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylurea therapy
Diabetes Obesity and Metabolism, 2002Co-Authors: L Blonde, Julio Rosenstock, A D Mooradian, B A Piper, David HenryAbstract:Aim: To compare the efficacy, safety and tolerability of a fixed combination Glyburide/metformin preparation with those of Glyburide or metformin alone in patients with type 2 diabetes inadequately controlled by sulphonylurea, diet and exercise. Methods: In this 16-week, randomized, double-blind, parallel group study, 639 patients with inadequate glycaemic control on at least half-maximal dose of sulphonylurea were randomly assigned to: Glyburide 10 mg b.i.d. (n = 164); metformin 500 mg (n = 153); Glyburide/metformin 2.5 mg/500 mg (n = 160); or Glyburide/metformin 5 mg/500 mg (n = 162). Titration was allowed to maximum doses of 2000 mg for metformin or 10 mg/2000 mg and 20 mg/2000 mg for Glyburide/metformin 2.5 mg/500 mg and 5 mg/500 mg respectively. The primary outcome measure was HbA1c level after 16 weeks; secondary end-points included fasting and 2-h post-prandial plasma glucose. Adverse events (AEs) were recorded and summarized by treatment group. Results: Both strengths of Glyburide/metformin equally reduced mean HbA1c by 1.7% more than did Glyburide alone (p < 0.001), and by 1.9% more than did metformin alone (p < 0.001). Final mean fasting plasma glucose concentrations were also lower in both Glyburide/metformin groups than in the Glyburide (−2.8 mmol/l, −51.3 mg/dl; p < 0.001) and metformin groups (−3.6 mmol/l, −64.2 mg/dl; p < 0.001). Safety and tolerability were similar across all treatment groups, except for a higher incidence of gastrointestinal AEs in the metformin monotherapy group, and more patients reporting mild or moderate symptoms of hypoglycaemia while taking Glyburide/metformin. Conclusions: Both Glyburide/metformin tablet strengths produced, with equal efficacy, significantly better glycaemic control than monotherapy with either agent. These data also confirm that glycaemic efficacy does not require maximal sulphonylurea doses in combination with metformin.
Micheline Piquettemiller - One of the best experts on this subject based on the ideXlab platform.
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breast cancer resistance protein bcrp mediated Glyburide transport effect of the c421a q141k bcrp single nucleotide polymorphism
Drug Metabolism and Disposition, 2010Co-Authors: Erika K Pollex, Gideon Koren, Gregory J Anger, Janine R Hutson, Micheline PiquettemillerAbstract:The antidiabetic agent Glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP-binding cassette, subfamily G, member 2 (ABCG2) expressed in the placenta protects the fetus against the accumulation of Glyburide. A number of studies have investigated the significance of several single-nucleotide polymorphisms (SNPs) in the ABCG2 gene. Associations between the Q141K (C421A) SNP and ABCG2 protein expression, membrane surface translocation, efflux activity, or ATPase activity have been shown. Therefore, alterations in Glyburide transport across the placenta, resulting in increased fetal Glyburide exposure, may be seen in individuals carrying the C421A allele. The purpose of this study is to investigate whether the Q141K SNP causes alterations in ABCG2-mediated Glyburide transport. Glyburide accumulation assays were carried out with stably transfected human embryonic kidney (HEK)-293 cells expressing wild-type ABCG2 (Arg482) and polymorphic ABCG2 (Q141K). Glyburide kinetic parameters were determined for comparison of wild-type and SNP ABCG2 activity by simultaneously fitting data for ABCG2-expressing cells (saturable transport) and empty vector-expressing cells (nonsaturable transport) by nonlinear regression analysis. The apparent K t and V max values for the transfected HEK-293 cells expressing the polymorphic variant (Q141K) of ABCG2 were significantly higher than those values determined for the wild-type ABCG2-expressing cells ( p < 0.05). Our results indicate that the Q141K variant of ABCG2 may have the potential to alter the placental pharmacokinetics of Glyburide used in pregnancy.
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breast cancer resistance protein mediating the trans placental transfer of Glyburide across the human placenta
Placenta, 2008Co-Authors: C Gedeon, Micheline Piquettemiller, Gregory J Anger, Gideon KorenAbstract:Abstract Members of the ATP-binding cassette (ABC) efflux transporter family, including P-glycoprotein (PGP), the multidrug resistance-associated proteins (MRPs) and the breast cancer resistance protein (BCRP) have been shown to be highly expressed in the human placenta. Recent studies documented that the oral hypoglycemic Glyburide does not cross the human placenta to an appreciable extent. Furthermore, the trans-placental transfer of Glyburide has been shown not to be affected by either the presence of PGP inhibitor, verapamil or MRP inhibitor, indomethacin. Therefore, our objective was to identify other human placental ABC transporters potentially involved in limiting the trans-placental transfer of Glyburide to the fetus. [ 3 H]-Glyburide transport was examined in brush border human placental vesicles in the presence or absence of specific inhibitors. Prepared vesicles were 70% oriented right-side-out and demonstrated 25–27 fold enrichment as compared to whole placenta. Functional studies demonstrated significant increases in the intra-vesicular accumulation of [ 3 H]-Glyburide in vesicles treated with the BCRP inhibitor, novobiocin. In contrast, PGP inhibition as well as MRP inhibition did not affect [ 3 H]-Glyburide accumulation. This is the first evidence to clearly indicate that Glyburide is preferentially transported by BCRP, in the brush border of the human placenta. Our study also indicates that BCRP likely effluxes substrates in the fetal to maternal direction in the human placenta.
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transport of Glyburide by placental abc transporters implications in fetal drug exposure
Placenta, 2006Co-Authors: C Gedeon, Gideon Koren, Javad Behravan, Micheline PiquettemillerAbstract:Much evidence has demonstrated that a number of ATP-binding cassette (ABC) efflux transporters including P-glycoprotein (PGP), the multidrug resistance-associated proteins (MRPs) and the breast cancer resistance protein (BCRP) are highly expressed in placental tissues and are believed to profoundly limit the passage of therapeutic or toxic xenobiotics to the fetus. Recent studies indicate that the oral hypoglycemic Glyburide does not cross the human placenta to an appreciable extent. Our objective was to identify placental transporters potentially involved in limiting the transplacental transfer of Glyburide to the fetus. Thus, [3H]-Glyburide transport was examined in BCRP, PGP, MRP1, MRP2 and MRP3 over-expressing cell lines in the presence or absence of specific inhibitors. Our results demonstrated significant increases in the intracellular accumulation of [3H]-Glyburide in BCRP and MRP3 over-expressing cells in the presence of the inhibitors novobiocin and indomethacin, respectively. PGP inhibition with verapamil or MRP inhibition with indomethacin did not affect [3H]-Glyburide accumulation in the PGP or MRP2 over-expressing cell lines and only limited changes were seen in the MRP1 over-expressing cell line. On the other hand, Glyburide was found to significantly inhibit MRP1-, MRP2- and MRP3-mediated efflux of 5-carboxyfluorescein diacetate and PGP-mediated transport of rhodamine 123. Our evidence is the first to clearly indicate that Glyburide is preferentially transported by BCRP and MRP3.
Kevin N Sheth - One of the best experts on this subject based on the ideXlab platform.
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effect of iv Glyburide on adjudicated edema endpoints in the games rp trial
Neurology, 2018Co-Authors: Taylor W Kimberly, Matthew B Bevers, Rudiger Von Kummer, Andrew M Demchuk, Javier Romero, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, Kevin N ShethAbstract:Objective In this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV Glyburide on adjudicated, edema-related endpoints. Methods Blinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV Glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined. Results In the per-protocol sample, 41 patients received Glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 [58.5%] in IV Glyburide vs n = 23 [63.9%] in placebo, p = 0.91) or the incidence of malignant edema (n = 19 [46%] in IV Glyburide vs n = 17 [47%] in placebo, p = 0.94). However, treatment with IV Glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 [2.4%] with IV Glyburide vs n = 8 [22.2%] with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV Glyburide had less midline shift ( p p p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 [58%] vs n = 15 [94%], p = 0.016). Conclusion IV Glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV Glyburide in large hemispheric infarction are warranted to corroborate these findings. ClinicalTrials.gov identifier NCT01794182. Level of evidence This study provides Class II evidence that for patients with large hemispheric infarction, IV Glyburide improves some edema-related endpoints.
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long term outcomes in patients aged 70 years with intravenous Glyburide from the phase ii games rp study of large hemispheric infarction an exploratory analysis
Stroke, 2018Co-Authors: Kevin N Sheth, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, Nils H Petersen, Ken Cheung, Lauren A Beslow, Taylor W KimberlyAbstract:Background and Purpose— We aimed to determine whether subjects aged ≤70 years who were treated with intravenous Glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. Methods— GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke–Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82–300 cm 3 ) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated with intravenous Glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous Glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood–brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift). Results— Participants ≤70 years of age treated with intravenous Glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P =0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous Glyburide-treated subjects at 90 days (odds ratio, 2.31; P =0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous Glyburide on the Barthel Index ( P =0.03) and EuroQol group 5-dimension ( P =0.05). Participants treated with intravenous Glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P P Conclusions— In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous Glyburide. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.
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safety and efficacy of intravenous Glyburide on brain swelling after large hemispheric infarction games rp a randomised double blind placebo controlled phase 2 trial
Lancet Neurology, 2016Co-Authors: Kevin N Sheth, Holly E Hinson, Bradley J Molyneaux, Marc J Simard, Lauren A Beslow, Ann Christin Ostwaldt, Gregory J Del Zoppo, Sven Jacobson, Taylor W KimberlyAbstract:Summary Background Preclinical models of stroke have shown that intravenous Glyburide reduces brain swelling and improves survival. We assessed whether intravenous Glyburide (RP-1127; glibenclamide) would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction. Methods For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18–80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82–300 cm 3 on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous Glyburide group. Intravenous Glyburide was given as a 0·13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0·16 mg/h for the first 6 h and then 0·11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov, number NCT01794182. Findings Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous Glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous Glyburide group and 14 (39%) in the placebo group had an mRS score of 0–4 at 90 days without decompressive craniectomy (adjusted odds ratio 0·87, 95% CI 0·32–2·32; p=0·77). Ten (23%) of 44 participants in the intravenous Glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0·76), and four of 20 had serious adverse events (two in the intravenous Glyburide group and two in the placebo group, p=1·00). One cardiac death occurred in each group (p=1·00). Interpretation Intravenous Glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous Glyburide. Funding Remedy Pharmaceuticals.