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Chemical Compound Review

Posicor     [(1S,2S)-2-[2-[3-(1H- benzoimidazol-2...

Synonyms: Mibefradil, Lopac-M-5441, CHEMBL45816, SureCN39551, CS-1218, ...
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Disease relevance of Mibefradil


High impact information on Mibefradil

  • DTNB alone and in combination with mibefradil induces thermal analgesia [2].
  • Lung histology showed neutrophil sequestration without ALI with LPS pretreatment/saline or D.0 plasma perfusion, but ALI with LPS pretreatment/D.42 plasma perfusion, and inhibition of D.42 plasma induced ALI with WEB 2170 or mibefradil [4].
  • T-Type and tetrodotoxin-sensitive Ca(2+) currents coexist in guinea pig ventricular myocytes and are both blocked by mibefradil [5].
  • The alpha1H channel is sensitive to mibefradil, a nondihydropyridine Ca2+ channel blocker, with an IC50 of 1.4 micromol/L, consistent with the reported potency of mibefradil for T-type Ca2+ channels [6].
  • The T-type Ca(2+) channel blocker mibefradil inhibited Ca(2+) spikes and waves on cells and, in parallel, inhibited cell motility and invasion in a dose-dependent manner [7].

Chemical compound and disease context of Mibefradil

  • The higher dose of both mibefradil and verapamil was antiarrhythmic during ischemia, at the cost of depressed contractile activity [8].
  • The purpose of this study was to evaluate the effects of mibefradil (Ro 40-5967) on the frequency and duration of episodes of asymptomatic ischemia in patients with stable angina pectoris and to determine the most efficient single therapeutic dose of this drug [9].
  • Proliferation of glioma C6 cells, which show little T-channel expression, is less sensitive to these drugs (IC(50) = 8 and 5 microM for pimozide and mibefradil, respectively) [10].
  • She developed ankle edema, and nifedipine was replaced by mibefradil [11].
  • CONCLUSIONS: Whereas the selective T-type Ca(2+)-channel blocker mibefradil protects against atrial remodeling caused by 7-day atrial tachycardia, the selective L-type blocker diltiazem is without effect [12].

Biological context of Mibefradil


Anatomical context of Mibefradil


Associations of Mibefradil with other chemical compounds


Gene context of Mibefradil

  • Additionally, the effect of mibefradil on CYP3A was assessed using human liver microsomes [23].
  • Since mibefradil is a potent mechanism-based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug-drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A-mediated pathways [24].
  • These data suggest that the severity of drug interactions seen with mibefradil use is due to the dual inhibition of both P-gp and CYP3A [23].
  • METHODS: Metabolism of the above five statins (0.5, 5 or 10 microM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1-50 microM) [24].
  • Among the calcium channel blockers tested, aranidipine and efonidipine increased ABCA1 protein expression without an increase in ABCA1 mRNA expression, whereas other calcium channel blockers (eg, nifedipine, amlodipine, and nicardipine) or T-type calcium channel blockers (eg, mibefradil and nickel chloride) failed to upregulate ABCA1 expression [25].

Analytical, diagnostic and therapeutic context of Mibefradil

  • METHODS: Mibefradil (Ro 40-5967, 1 mg/kg body weight intravenously [i.v.]) was given as a bolus 30 min before anterior descending coronary artery ligation, followed by 2 mg/kg per h i.v. during 20 min of ischemia and 25 min of reperfusion in open chest pigs [8].
  • METHODS: We performed an open label study, examining the effects of two intravenous doses of mibefradil, selected to produce plasma levels comparable to those measured after oral administration of 50 mg (dose 1: 400 ng/ml) or 100 mg (dose 2: 800 ng/ml) of the drug [26].
  • Compared with placebo, mibefradil was associated with significantly less ischemia as manifested during ambulatory ECG monitoring [9].
  • The renal protective effects of mibefradil were at least equivalent to those of an ACE inhibitor in this animal model of chronic renal failure [27].
  • Mibefradil and nickel were, respectively, 162-fold and 300-fold more potent in inhibiting myogenic tone compared with K(+)-induced constriction [log(IC(50), M): mibefradil, basal -7.3 +/- 0.2 (n = 9) and K(+) -5.1 +/- 0.1 (n = 5); nickel, basal -4.1 +/- 0.2 (n = 5) and K(+) -1.6 +/- 0.5 (n = 5); means +/- SE] [28].


  1. Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers. Mullins, M.E., Horowitz, B.Z., Linden, D.H., Smith, G.W., Norton, R.L., Stump, J. JAMA (1998) [Pubmed]
  2. Redox modulation of T-type calcium channels in rat peripheral nociceptors. Todorovic, S.M., Jevtovic-Todorovic, V., Meyenburg, A., Mennerick, S., Perez-Reyes, E., Romano, C., Olney, J.W., Zorumski, C.F. Neuron (2001) [Pubmed]
  3. Efficacy of mibefradil compared with amlodipine in suppressing exercise-induced and daily silent ischemia: results of a multicenter, placebo-controlled trial. Tzivoni, D., Kadr, H., Braat, S., Rutsch, W., Ramires, J.A., Kobrin, I. Circulation (1997) [Pubmed]
  4. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. Silliman, C.C., Voelkel, N.F., Allard, J.D., Elzi, D.J., Tuder, R.M., Johnson, J.L., Ambruso, D.R. J. Clin. Invest. (1998) [Pubmed]
  5. T-Type and tetrodotoxin-sensitive Ca(2+) currents coexist in guinea pig ventricular myocytes and are both blocked by mibefradil. Heubach, J.F., Köhler, A., Wettwer, E., Ravens, U. Circ. Res. (2000) [Pubmed]
  6. Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Cribbs, L.L., Lee, J.H., Yang, J., Satin, J., Zhang, Y., Daud, A., Barclay, J., Williamson, M.P., Fox, M., Rees, M., Perez-Reyes, E. Circ. Res. (1998) [Pubmed]
  7. Identification of channels promoting calcium spikes and waves in HT1080 tumor cells: their apparent roles in cell motility and invasion. Huang, J.B., Kindzelskii, A.L., Clark, A.J., Petty, H.R. Cancer Res. (2004) [Pubmed]
  8. Effects of mibefradil, a novel calcium channel blocking agent with T-type activity, in acute experimental myocardial ischemia: maintenance of ventricular fibrillation threshold without inotropic compromise. Muller, C.A., Opie, L.H., McCarthy, J., Hofmann, D., Pineda, C.A., Peisach, M. J. Am. Coll. Cardiol. (1998) [Pubmed]
  9. Effects of a new calcium antagonist, mibefradil (Ro 40-5967), on silent ischemia in patients with stable chronic angina pectoris: a multicenter placebo-controlled study. The Mibefradil International Study Group. Braun, S., van der Wall, E.E., Emanuelsson, H., Kobrin, I. J. Am. Coll. Cardiol. (1996) [Pubmed]
  10. The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms. Bertolesi, G.E., Shi, C., Elbaum, L., Jollimore, C., Rozenberg, G., Barnes, S., Kelly, M.E. Mol. Pharmacol. (2002) [Pubmed]
  11. Serious interaction between mibefradil and tacrolimus. Krähenbühl, S., Menafoglio, A., Giostra, E., Gallino, A. Transplantation (1998) [Pubmed]
  12. Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs. Fareh, S., Bénardeau, A., Nattel, S. Cardiovasc. Res. (2001) [Pubmed]
  13. Effects of an angiotensin-converting enzyme inhibitor, a calcium antagonist, and an endothelin receptor antagonist on renal afferent arteriolar structure. Skov, K., Fenger-Grøn, J., Mulvany, M.J. Hypertension (1996) [Pubmed]
  14. Nonlinear kinetics and pharmacologic response to mibefradil. du Souich, P., Besner, J.G., Clozel, J.P., Welker, H.A., Lefebvre, M., Caillé, G. Clin. Pharmacol. Ther. (2000) [Pubmed]
  15. Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam. Backman, J.T., Wang, J.S., Wen, X., Kivistö, K.T., Neuvonen, P.J. Clin. Pharmacol. Ther. (1999) [Pubmed]
  16. Mibefradil prevents neointima formation after vascular injury in rats. Possible role of the blockade of the T-type voltage-operated calcium channel. Schmitt, R., Clozel, J.P., Iberg, N., Bühler, F.R. Arterioscler. Thromb. Vasc. Biol. (1995) [Pubmed]
  17. Mibefradil potently blocks ATP-activated K(+) channels in adrenal cells. Gomora, J.C., Enyeart, J.A., Enyeart, J.J. Mol. Pharmacol. (1999) [Pubmed]
  18. Zinc and mercuric ions distinguish TRESK from the other two-pore-domain K+ channels. Czirják, G., Enyedi, P. Mol. Pharmacol. (2006) [Pubmed]
  19. HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers. Chouabe, C., Drici, M.D., Romey, G., Barhanin, J., Lazdunski, M. Mol. Pharmacol. (1998) [Pubmed]
  20. An ACTH- and ATP-regulated background K+ channel in adrenocortical cells is TREK-1. Enyeart, J.J., Xu, L., Danthi, S., Enyeart, J.A. J. Biol. Chem. (2002) [Pubmed]
  21. The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon. Beltrame, J.F., Turner, S.P., Leslie, S.L., Solomon, P., Freedman, S.B., Horowitz, J.D. J. Am. Coll. Cardiol. (2004) [Pubmed]
  22. Differential effects of T- and L-type calcium antagonists on glomerular dynamics in spontaneously hypertensive rats. Nakamura, Y., Ono, H., Frohlich, E.D. Hypertension (1999) [Pubmed]
  23. Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro. Wandel, C., Kim, R.B., Guengerich, F.P., Wood, A.J. Drug Metab. Dispos. (2000) [Pubmed]
  24. Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations. Prueksaritanont, T., Ma, B., Tang, C., Meng, Y., Assang, C., Lu, P., Reider, P.J., Lin, J.H., Baillie, T.A. British journal of clinical pharmacology. (1999) [Pubmed]
  25. Divergent action of calcium channel blockers on ATP-binding cassette protein expression. Hasegawa, K., Wakino, S., Kanda, T., Yoshioka, K., Tatematsu, S., Homma, K., Takamatsu, I., Sugano, N., Hayashi, K. J. Cardiovasc. Pharmacol. (2005) [Pubmed]
  26. Hemodynamic and cardiac effects of the selective T-type and L-type calcium channel blocking agent mibefradil in patients with varying degrees of left ventricular systolic dysfunction. Rousseau, M.F., Hayashida, W., van Eyll, C., Hess, O.M., Benedict, C.R., Ahn, S., Chapelle, F., Kobrin, I., Pouleur, H. J. Am. Coll. Cardiol. (1996) [Pubmed]
  27. Mibefradil prevents L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats. Qiu, C., Bruneval, P., Roeckel, A., Heudes, D., Duong Van Huyen, J.P., Roux, S. J. Hypertens. (1999) [Pubmed]
  28. Role of T-type calcium channels in myogenic tone of skeletal muscle resistance arteries. VanBavel, E., Sorop, O., Andreasen, D., Pfaffendorf, M., Jensen, B.L. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
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