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Bu Miin Huang - One of the best experts on this subject based on the ideXlab platform.
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Midazolam regulated caspase pathway endoplasmic reticulum stress autophagy and cell cycle to induce apoptosis in ma 10 mouse leydig tumor cells
OncoTargets and Therapy, 2016Co-Authors: Yung Chia Chen, Shu Chun Wang, Man Chi Huang, Meng Shao Lai, Bo Syong Pan, Fu Chi Kang, Bu Miin HuangAbstract:PURPOSE Midazolam is widely used as a sedative and anesthetic induction agent by modulating the different GABA receptors in the central nervous system. Studies have also shown that Midazolam has an anticancer effect on various tumors. In a previous study, we found that Midazolam could induce MA-10 mouse Leydig tumor cell apoptosis by activating caspase cascade. However, the detailed mechanism related to the upstream and downstream pathways of the caspase cascade, such as endoplasmic reticulum (ER) stress, autophagy, and p53 pathways plus cell cycle regulation in MA-10 mouse Leydig tumor cells, remains elusive. METHODS Flow cytometry assay and Western blot analyses were exploited. RESULTS Midazolam significantly decreased cell viability but increased sub-G1 phase cell numbers in MA-10 cells (P<0.05). Annexin V/propidium iodide double staining further confirmed that Midazolam induced apoptosis. In addition, expressions of Fas and Fas ligand could be detected in MA-10 cells with Midazolam treatments, and Bax translocation and cytochrome c release were also involved in Midazolam-induced MA-10 cell apoptosis. Moreover, the staining and expression of LC3-II proteins could be observed with Midazolam treatment, implying Midazolam could induce autophagy to control MA-10 cell apoptosis. Furthermore, the expressions of p-EIF2α, ATF4, ATF3, and CHOP could be induced by Midazolam, indicating that Midazolam could stimulate apoptosis through ER stress in MA-10 cells. Additionally, the expressions of cyclin A, cyclin B, and CDK1 could be inhibited by Midazolam, and the phosphorylation of p53, P27, and P21 could be adjusted by Midazolam, suggesting that Midazolam could manage cell cycle through the regulation of p53 pathway to induce apoptosis in MA-10 cells. CONCLUSION Midazolam could induce cell apoptosis through the activation of ER stress and the regulation of cell cycle through p53 pathway with the involvement of autophagy in MA-10 mouse Leydig tumor cells.
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Midazolam induces apoptosis in ma 10 mouse leydig tumor cells through caspase activation and the involvement of mapk signaling pathway
OncoTargets and Therapy, 2014Co-Authors: Yu Xuan Lin, Bo Syong Pan, Chi Hao Tseng, Ka Shun Cheng, Karlok Wong, Lyh Jyh Hao, Yang Kao Wang, Bu Miin HuangAbstract:PURPOSE The present study aims to investigate how Midazolam, a sedative drug for clinical use with cytotoxicity on neuronal and peripheral tissues, induced apoptosis in MA-10 mouse Leydig tumor cells. METHODS The apoptotic effect and underlying mechanism of Midazolam to MA-10 cells were investigated by flow cytometry assay and Western blotting methods. RESULTS Data showed that Midazolam induced the accumulation of the MA-10 cell population in the sub-G1 phase and a reduction in the G2/M phase in a time- and dose-dependent manner, suggesting an apoptotic phenomenon. Midazolam could also induce the activation of caspase-8, -9, and -3 and poly (ADP-ribose) polymerase proteins. There were no changes in the levels of Bax and cytochrome-c, whereas Bid was significantly decreased after Midazolam treatment. Moreover, Midazolam decreased both pAkt and Akt expression. In addition, Midazolam stimulated the phosphorylation of p38 and c-Jun NH2-terminal kinase but not extracellular signal-regulated kinase. CONCLUSION Midazolam could induce MA-10 cell apoptosis through the activation of caspase cascade, the inhibition of pAkt pathway, and the induction of p38 and c-Jun NH2-terminal kinase pathways.
David J Greenblatt - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics cannot explain the increased effective dose requirement for morphine and Midazolam in rats during their extended administration alone or in combination
Journal of Pharmacy and Pharmacology, 2017Co-Authors: David J Greenblatt, Stefan J Schaller, Saad M Alam, Jianren Mao, Yanli Zhao, M Blobner, J Jeevendra A MartynAbstract:Objectives Chronic administration of morphine and Midazolam, alone or in combination, can induce tolerance to their effects. Data showed that co-administration of morphine and Midazolam increased effective dose requirement of morphine, exceeding that observed with morphine alone. Methods To elucidate the pharmacokinetic component to the tolerance, we administered Midazolam (2 mg/kg) and morphine (10 mg/kg) alone or their combination daily to rats for 12 days followed by a pharmacokinetic study on day 13. On the study day, each animal received a single bolus dose of 5 mg/kg morphine, and 2 mg/kg of Midazolam 30 s later. Multiple blood samples were obtained for 6 h. Plasma drug concentrations were assayed by mass spectrometry optimized for small samples. Key findings Mean morphine clearance was as follows: 22.2, 27.2, 26.0 and 23.4 l/h per kg in the saline–saline, saline–Midazolam, saline–morphine and Midazolam–morphine groups, respectively. Corresponding Midazolam clearances were 32.8, 23.0, 22.2 and 31.1 l/h per kg. ANOVA indicated no significant differences among the four groups in the clearances, half-lives, and volumes of distribution. Morphine and Midazolam clearances were significantly correlated (R2 = 0.48, P < 0.001). Conclusions This animal model suggests that altered pharmacokinetics cannot explain tolerance evidenced as increased dose requirement for morphine or Midazolam, when administered alone or combination, for extended periods.
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differentiation of intestinal and hepatic cytochrome p450 3a activity with use of Midazolam as an in vivo probe effect of ketoconazole
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Rebecca L Velez, Shirley M Tsunoda, Lisa L Von Moltke, David J GreenblattAbstract:Background The cytochrome P450 3A (CYP3A) isoforms are responsible for the metabolism of a majority of therapeutic compounds, and they are abundant in the intestine and liver. CYP3A activity is highly variable, causing difficulty in the therapeutic use of CYP3A substrates. A practical in vivo probe method that characterizes both intestinal and hepatic CYP3A activity would be useful. Objectives To determine the intestinal and hepatic contribution to the bioavailability of Midazolam with use of the CYP3A inhibitor ketoconazole. Methods The pharmacokinetics of Midazolam was assessed in nine (six men and three women) healthy individuals after single doses of 2 mg intravenous and 6 mg oral Midazolam (phase I). These pharmacokinetic values were compared with those obtained after single doses of 2 mg intravenous and 6 mg oral Midazolam and three doses of 200 mg oral ketoconazole (phase II). Results After ketoconazole therapy, area under the concentration versus time curve of Midazolam increased 5-fold after intravenous Midazolam administration (P ≤ .001) and 16-fold after oral Midazolam administration (P ≤ .001). Intrinsic clearance decreased by 84% (P = .003). Total bioavailability increased from 25% to 80% (P < .001). The intestinal component of Midazolam bioavailability increased to a greater extent than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P ≤ .001], respectively). In the control phase, female subjects had greater Midazolam clearance values than the male subjects. Conclusions Ketoconazole caused marked inhibition of CYP3A activity that was greater in the intestine than the liver. Administration of single doses of oral and intravenous Midazolam with and without oral ketoconazole exemplifies a practical method for differentiating intestinal and hepatic CYP3A activity. Clinical Pharmacology & Therapeutics (1999) 66, 461–471; doi:
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Midazolam hydroxylation by human liver microsomes in vitro inhibition by fluoxetine norfluoxetine and by azole antifungal agents
The Journal of Clinical Pharmacology, 1996Co-Authors: Lisa L Von Moltke, David J Greenblatt, Jurgen Schmider, Su Xiang Duan, Eugene C Wright, Jerold S Harmatz, Richard I ShaderAbstract:Biotransformation of the imidazobenzodiazepine Midazolam to its alpha-hydroxy and 4-hydroxy metabolites was studied in vitro using human liver microsomal preparations. Formation of alpha-hydroxy-Midazolam was a high-affinity (Km = 3.3 mumol/L) Michaelis-Menten process coupled with substrate inhibition at high concentrations of Midazolam. Formation of 4-hydroxy-Midazolam had much lower apparent affinity (57 mumol/L), with minimal evidence of substrate inhibition. Based on comparison of Vmax/Km ratios for the two pathways, alpha-hydroxy-Midazolam formation was estimated to account for 95% of net intrinsic clearance. Three azole antifungal agents were inhibitors of Midazolam metabolism in vitro, with inhibition being largely consistent with a competitive mechanism. Mean competitive inhibition constants (Ki) versus alpha-hydroxy-Midazolam formation were 0.0037 mumol/L for ketoconazole, 0.27 mumol/L for itraconazole, and 1.27 mumol/L for fluconazole. An in vitro-in vivo scaling model predicted inhibition of oral Midazolam clearance due to coadministration of ketoconazole or itraconazole; the predicted inhibition was consistent with observed interactions in clinical pharmacokinetic studies. The selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine and its principal metabolite, norfluoxetine, also were inhibitors of both pathways of Midazolam biotransformation, with norfluoxetine being a much more potent inhibitor than was fluoxetine itself. This finding is consistent with results of other in vitro studies and of clinical studies, indicating that fluoxetine, largely via its metabolite norfluoxetine, may impair clearance of P450-3A substrates.
Joseph S Bertino - One of the best experts on this subject based on the ideXlab platform.
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duration of pleconaril effect on cytochrome p450 3a activity in healthy adults using the oral biomarker Midazolam
Drug Metabolism and Disposition, 2006Co-Authors: Joseph D, Anne N Nafziger, Gerry Rhodes, Joseph S BertinoAbstract:The objective of this study was to evaluate the duration of oral pleconaril (a picornavirus inhibitor) effect on intestinal and hepatic cytochrome P450 (P450) 3A activity as assessed by oral Midazolam. Healthy adults received oral Midazolam (0.075 mg/kg) on days 1 (baseline), 7, 9, 13, 20, 27, and 34. Oral pleconaril (400 mg) three times daily for 15 doses was administered on days 2 through 7. Blood samples were collected during each day of Midazolam dosing to determine plasma Midazolam concentrations. On days 5, 6, and 7, blood samples were collected to determine plasma pleconaril concentrations. Midazolam pharmacokinetics were determined by noncompartmental analyses, with bioequivalence assessed by least-squares geometric mean ratios (LS-GMR) and 90% confidence intervals (90% CI). Eighteen subjects completed the study. Midazolam Cmax (LS-GMR; 90% CI) decreased 24% on day 7 (0.76; 0.66–0.87). Midazolam oral clearance increased 53% on day 7 (1.53; 1.38–1.69). Midazolam oral clearance remained different on days 9 (1.38; 1.25–1.52) and 13 (1.19; 1.07–1.31) versus day 1. Midazolam volume of distribution (1.82; 1.57–2.11) and elimination half-life (1.19; 1.03–1.38) were also different on day 7 in comparison with day 1. Oral pleconaril increased intestinal and hepatic CYP3A activity. The duration of increased CYP3A activity by pleconaril was at least 6 days (but no longer than 13 days) after pleconaril discontinuation.
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the effect of oral pleconaril on hepatic cytochrome p450 3a activity in healthy adults using intravenous Midazolam as a probe
The Journal of Clinical Pharmacology, 2006Co-Authors: Joseph D, Anne N Nafziger, Gerry Rhodes, Anne M Gartung, Joseph S BertinoAbstract:Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) Midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single-dose, IV Midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS-GMR) with 90% confidence intervals (90% CIs) for the measured Midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased Midazolam AUC0-∞ 28% and increased systemic clearance 39%. LS-GMR (90% CI) were 0.718 (0.674–0.765) and 1.392 (1.307–1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in Midazolam AUC0-∞ and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.
Bo Syong Pan - One of the best experts on this subject based on the ideXlab platform.
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Midazolam regulated caspase pathway endoplasmic reticulum stress autophagy and cell cycle to induce apoptosis in ma 10 mouse leydig tumor cells
OncoTargets and Therapy, 2016Co-Authors: Yung Chia Chen, Shu Chun Wang, Man Chi Huang, Meng Shao Lai, Bo Syong Pan, Fu Chi Kang, Bu Miin HuangAbstract:PURPOSE Midazolam is widely used as a sedative and anesthetic induction agent by modulating the different GABA receptors in the central nervous system. Studies have also shown that Midazolam has an anticancer effect on various tumors. In a previous study, we found that Midazolam could induce MA-10 mouse Leydig tumor cell apoptosis by activating caspase cascade. However, the detailed mechanism related to the upstream and downstream pathways of the caspase cascade, such as endoplasmic reticulum (ER) stress, autophagy, and p53 pathways plus cell cycle regulation in MA-10 mouse Leydig tumor cells, remains elusive. METHODS Flow cytometry assay and Western blot analyses were exploited. RESULTS Midazolam significantly decreased cell viability but increased sub-G1 phase cell numbers in MA-10 cells (P<0.05). Annexin V/propidium iodide double staining further confirmed that Midazolam induced apoptosis. In addition, expressions of Fas and Fas ligand could be detected in MA-10 cells with Midazolam treatments, and Bax translocation and cytochrome c release were also involved in Midazolam-induced MA-10 cell apoptosis. Moreover, the staining and expression of LC3-II proteins could be observed with Midazolam treatment, implying Midazolam could induce autophagy to control MA-10 cell apoptosis. Furthermore, the expressions of p-EIF2α, ATF4, ATF3, and CHOP could be induced by Midazolam, indicating that Midazolam could stimulate apoptosis through ER stress in MA-10 cells. Additionally, the expressions of cyclin A, cyclin B, and CDK1 could be inhibited by Midazolam, and the phosphorylation of p53, P27, and P21 could be adjusted by Midazolam, suggesting that Midazolam could manage cell cycle through the regulation of p53 pathway to induce apoptosis in MA-10 cells. CONCLUSION Midazolam could induce cell apoptosis through the activation of ER stress and the regulation of cell cycle through p53 pathway with the involvement of autophagy in MA-10 mouse Leydig tumor cells.
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Midazolam induces apoptosis in ma 10 mouse leydig tumor cells through caspase activation and the involvement of mapk signaling pathway
OncoTargets and Therapy, 2014Co-Authors: Yu Xuan Lin, Bo Syong Pan, Chi Hao Tseng, Ka Shun Cheng, Karlok Wong, Lyh Jyh Hao, Yang Kao Wang, Bu Miin HuangAbstract:PURPOSE The present study aims to investigate how Midazolam, a sedative drug for clinical use with cytotoxicity on neuronal and peripheral tissues, induced apoptosis in MA-10 mouse Leydig tumor cells. METHODS The apoptotic effect and underlying mechanism of Midazolam to MA-10 cells were investigated by flow cytometry assay and Western blotting methods. RESULTS Data showed that Midazolam induced the accumulation of the MA-10 cell population in the sub-G1 phase and a reduction in the G2/M phase in a time- and dose-dependent manner, suggesting an apoptotic phenomenon. Midazolam could also induce the activation of caspase-8, -9, and -3 and poly (ADP-ribose) polymerase proteins. There were no changes in the levels of Bax and cytochrome-c, whereas Bid was significantly decreased after Midazolam treatment. Moreover, Midazolam decreased both pAkt and Akt expression. In addition, Midazolam stimulated the phosphorylation of p38 and c-Jun NH2-terminal kinase but not extracellular signal-regulated kinase. CONCLUSION Midazolam could induce MA-10 cell apoptosis through the activation of caspase cascade, the inhibition of pAkt pathway, and the induction of p38 and c-Jun NH2-terminal kinase pathways.
Joseph D - One of the best experts on this subject based on the ideXlab platform.
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assessment of oral Midazolam limited sampling strategies to predict area under the concentration time curve auc during cytochrome p450 cyp 3a baseline inhibition and induction or activation
Principles and Practice of Constraint Programming, 2010Co-Authors: Joseph D, Shirley M Tsunoda, E T Nguyen, Howard E Greenberg, J C Gorski, Scott R PenzakAbstract:UNLABELLED: A previous study reported a 2- and 3-timepoint limited sampling strategy (LSS) model accurately predicted oral Midazolam area under the concentration time curve (AUC), and thus cytochrome P450 (CYP) 3A activity. OBJECTIVE: This study evaluated whether the LSS models predict Midazolam AUC during CYP3A baseline, inhibition and induction/activation. MATERIALS AND METHODS: Plasma Midazolam concentrations from 106 healthy adults from 6 published studies were obtained where oral Midazolam was co-administered alone or with ketoconazole, double-strength grapefruit juice, Ginkgo biloba extract, pleconaril, or rifampin. Observed and predicted Midazolam AUCs were determined. Bias and precision of the LSS models were determined. RESULTS: Contrasting results were observed for the 2- and 3-timepoint LSS models in accurately predicting Midazolam AUC during baseline CYP3A conditions. With the exception of 1 study (single dose, double-strength grapefruit juice), the 2- and 3-timepoint LSS models did not accurately predict Midazolam AUC during conditions of CYP3A inhibition and induction/activation. CONCLUSION: The previously reported 2- and 3-timepoint oral Midazolam LSS models are not applicable to the evaluated conditions of CYP3A baseline, inhibition, and induction/ activation.
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duration of pleconaril effect on cytochrome p450 3a activity in healthy adults using the oral biomarker Midazolam
Drug Metabolism and Disposition, 2006Co-Authors: Joseph D, Anne N Nafziger, Gerry Rhodes, Joseph S BertinoAbstract:The objective of this study was to evaluate the duration of oral pleconaril (a picornavirus inhibitor) effect on intestinal and hepatic cytochrome P450 (P450) 3A activity as assessed by oral Midazolam. Healthy adults received oral Midazolam (0.075 mg/kg) on days 1 (baseline), 7, 9, 13, 20, 27, and 34. Oral pleconaril (400 mg) three times daily for 15 doses was administered on days 2 through 7. Blood samples were collected during each day of Midazolam dosing to determine plasma Midazolam concentrations. On days 5, 6, and 7, blood samples were collected to determine plasma pleconaril concentrations. Midazolam pharmacokinetics were determined by noncompartmental analyses, with bioequivalence assessed by least-squares geometric mean ratios (LS-GMR) and 90% confidence intervals (90% CI). Eighteen subjects completed the study. Midazolam Cmax (LS-GMR; 90% CI) decreased 24% on day 7 (0.76; 0.66–0.87). Midazolam oral clearance increased 53% on day 7 (1.53; 1.38–1.69). Midazolam oral clearance remained different on days 9 (1.38; 1.25–1.52) and 13 (1.19; 1.07–1.31) versus day 1. Midazolam volume of distribution (1.82; 1.57–2.11) and elimination half-life (1.19; 1.03–1.38) were also different on day 7 in comparison with day 1. Oral pleconaril increased intestinal and hepatic CYP3A activity. The duration of increased CYP3A activity by pleconaril was at least 6 days (but no longer than 13 days) after pleconaril discontinuation.
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the effect of oral pleconaril on hepatic cytochrome p450 3a activity in healthy adults using intravenous Midazolam as a probe
The Journal of Clinical Pharmacology, 2006Co-Authors: Joseph D, Anne N Nafziger, Gerry Rhodes, Anne M Gartung, Joseph S BertinoAbstract:Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) Midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single-dose, IV Midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS-GMR) with 90% confidence intervals (90% CIs) for the measured Midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased Midazolam AUC0-∞ 28% and increased systemic clearance 39%. LS-GMR (90% CI) were 0.718 (0.674–0.765) and 1.392 (1.307–1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in Midazolam AUC0-∞ and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.
