Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new verapamil research articles will be listed here shortly after becoming available to us.
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Medical research on verapamil
Phytother Res. 2008 Dec 2;
Chung SY, Han AR, Sung MK, Jung HJ, Nam JW, Seo EK, Lee HJ
Five phenylbutenoid derivatives from the rhizomes of Zingiber cassumunar Roxb. (Zingiberaceae) were evaluated for their P-glycoprotein (P-gp) inhibitory effects in a P-gp over-expressing multidrug resistant (MDR) human breast cancer cell line, MCF-7/ADR. As a result, a phenylbutenoid dimer, (+/-)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene (1), exhibited highly potent P-gp inhibitory activity, decreasing the IC(50) value of daunomycin (DNM) to 4.31 +/- 0.40 microm in the cells (DNM IC(50) = 37.1 +/- 0.59 microm). The positive control, verapamil decreased the IC(50) value of DNM to 6.94 +/- 0.40 microm. Three phenylbutenoid monomers, 2-4 from this plant, also resulted in a significant decrease in the IC(50) values of DNM compared with the control. In particular, compound 1 markedly enhanced [(3)H]-DNM accumulation and significantly reduced [(3)H]-DNM efflux compared with the control, and this effect was more potent than that of verapamil, a well-known P-gp inhibitor. These results suggest that compound 1 of Z. cassumunar can be developed as a potent chemo-sensitizing agent that reverses P-gp-mediated MDR in human cancer chemotherapy. Copyright (c) 2008 John Wiley & Sons, Ltd.
Rhythmic contractility in the hepatic portal "corkscrew" vein of the rat snake.
Comp Biochem Physiol A Mol Integr Physiol. 2008 Nov 21;
Conklin DJ, Lillywhite HB, Bishop B, Hargens AR, Olson KR
Terrestrial, but not aquatic, species of snakes have hepatic portal veins with a corkscrew morphology immediately posterior of the liver. Relatively large volumes of venous blood are associated with this region, and the corkscrew vein has been proposed to function as a bidirectional valve that impedes gravitational shifts of intravascular volume. To better understand the functional significance of the corkscrew anatomy, we investigated the histology and contractile mechanisms in isolated corkscrew segments of the hepatic portal vein of a yellow rat snake (Pantherophis obsoletus). Morphologically, the corkscrew portal vein is here shown to have two distinct layers of smooth muscle - an inner circular layer, and an outer longitudinal layer, separated by a layer of collagen, - whereas only a single circular layer of smooth muscle is present in the adjacent posterior caval vein. Low frequency (~0.3 cycles min(-1)) spontaneous and catecholamine-induced rhythms were observed in 11% and 89% of portal vein segments, respectively, but neither spontaneous nor agonist-induced cycling was observed in adjacent posterior (non-corkscrew) caval veins. Catecholamines, angiotensin II, or stretch increased the amplitude and/or frequency of contractile cycles. Ouabain, verapamil or indomethacin, but not tetrodotoxin, alpha-, or ss-adrenergic receptor antagonists, inhibited cyclical contractions indicating a dependence of these cycles on Na(+)/K(+) ATPase, extracellular Ca(2+) and prostanoid(s). These data suggest that the rhythmic contractility of the corkscrew segment of the ophidian portal vein may act in conjunction with its morphological features to improve venous return and to prevent retrograde shifts of blood that might otherwise pool in posterior veins.
Pharm Res. 2008 Dec 2;
Dahan A, Amidon GL
PURPOSE: To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate. METHODS: Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP-BL and BL-AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6'-7'-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum. RESULTS: Colchicine exhibited 20-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP-BL permeability was increased and BL-AP was decreased by GFJ in a concentration-dependent manner (IC(50) values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6'-7'-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL-AP secretion (IC(50) values of 90, 592 and 11.6 muM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability. CONCLUSION: The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.
Microbiology. 2008 Dec; 154(Pt 12): 3775-81
Teng J, Goto R, Iida K, Kojima I, Iida H
The Cch1 protein of the yeast Saccharomyces cerevisiae is a homologue of the pore-forming alpha(1) subunit of mammalian voltage-gated Ca(2+) channels (VGCCs), and it constitutes a high-affinity Ca(2+)-influx system with the Mid1 protein in this organism. Here, we characterized the kinetic property of a putative Cch1-Mid1 Ca(2+) channel overexpressed in S. cerevisiae cells, and showed that the L-type VGCC blockers nifedipine and verapamil partially inhibited Cch1-Mid1 activity, but typical P/Q-, N-, R- and T-type VGCC blockers did not inhibit activity. In contrast, a third L-type VGCC blocker, diltiazem, increased Cch1-Mid1 activity. Diltiazem did not increase Ca(2+) uptake in the cch1Delta and mid1Delta single mutants and the cch1Delta mid1Delta double mutant, indicating that the diltiazem-induced increase in Ca(2+) uptake is completely dependent on Cch1-Mid1. These results suggest that Cch1 is pharmacologically similar to L-type VGCCs, but the interactions between Cch1 and the L-type VGCC blockers are more complicated than expected.
Drug Metab Dispos. 2008 Dec 1;
Syvanen S, Lindhe O, Palner M, Kornum BR, Rahman O, Langstrom B, Knudsen GM, Hammarlund-Udenaes M
Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabelled P-glycoprotein (P-gp) substrates across species using Positron Emission Tomography (PET). Brain concentrations and brain-to-plasma ratios were compared; [(11)C]verapamil in rats, guinea pigs and monkeys, [(11)C]GR205171 in rats, guinea pigs, monkeys and humans, and [(18)F]altanserin in rats, minipigs and humans. The fraction of the unbound radioligand in plasma was studied along with its metabolism. The effect of P-gp inhibition was investigated by administering cyclosporin A (CsA). Pronounced species differences were found in the brain and brain-to-plasma concentrations of [(11)C]verapamil, [(11)C]GR205171 and [(18)F]altanserin with higher brain distribution in humans, monkeys and minipigs than in rats and guinea pigs. For example, the brain-to-plasma ratio of [(11)C]GR205171 was almost 9-fold higher in humans compared to rats. The species differences were still present after P-gp inhibition although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.
Evidence that Resistance to Nilotinib May Be Due to BCR-ABL, Pgp, or Src Kinase Overexpression.
Cancer Res. 2008 Dec 1; 68(23): 9809-16
Mahon FX, Hayette S, Lagarde V, Belloc F, Turcq B, Nicolini F, Belanger C, Manley PW, Leroy C, Etienne G, Roche S, Pasquet JM
Targeting the tyrosine kinase activity of Bcr-Abl is an attractive therapeutic strategy in chronic myeloid leukemia (CML) and in Bcr-Abl-positive acute lymphoblastic leukemia. Whereas imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, is now used in frontline therapy for CML, second-generation inhibitors of Bcr-Abl tyrosine kinase such as nilotinib or dasatinib have been developed for the treatment of imatinib-resistant or imatinib-intolerant disease. In the current study, we generated nilotinib-resistant cell lines and investigated their mechanism of resistance. Overexpression of BCR-ABL and multidrug resistance gene (MDR-1) were found among the investigated mechanisms. We showed that nilotinib is a substrate of the multidrug resistance gene product, P-glycoprotein, using verapamil or PSC833 to block binding. Up-regulated expression of p53/56 Lyn kinase, both at the mRNA and protein level, was found in one of the resistant cell lines and Lyn silencing by small interfering RNA restored sensitivity to nilotinib. Moreover, failure of nilotinib treatment was accompanied by an increase of Lyn mRNA expression in patients with resistant CML. Two Src kinase inhibitors (PP1 and PP2) partially removed resistance but did not significantly inhibit Bcr-Abl tyrosine kinase activity. In contrast, dasatinib, a dual Bcr-Abl and Src kinase inhibitor, inhibited the phosphorylation of both BCR-ABL and Lyn, and induced apoptosis of the Bcr-Abl cell line overexpressing p53/56 Lyn. Such mechanisms of resistance are close to those observed in imatinib-resistant cell lines and emphasize the critical role of Lyn in nilotinib resistance. [Cancer Res 2008;68(23):9809-16].
J Ethnopharmacol. 2008 Nov 8;
Gilani AH, Shah AJ, Zubair A, Khalid S, Kiani J, Ahmed A, Rasheed M, Ahmad VU
AIM OF THE STUDY: The study was aimed to investigate the chemical composition and pharmacological basis for traditional use of essential oil of Nepeta cataria L. (Limiaceae) (Nc.Oil) in gastrointestinal and respiratory disorders. MATERIALS AND METHODS: Chemical analysis was carried out through GC-EIMS, (13)C NMR and Kovats Retention Indices while pharmacological study was carried out in isolated tissues preparations. RESULTS: Four major components; 1,8-cineol (21.00%), alpha-humulene (14.44%), alpha-pinene (10.43%) and geranyl acetate (8.21%) were identified among the 27 compounds in Nc.Oil. In isolated rabbit jejunum, Nc.Oil, papaverine and verapamil inhibited spontaneous and high K(+)(80mM) precontractions, as well as shifted the Ca(++) concentration-response curves (CRCs) to right, indicating calcium channel blocking activity. In isolated guinea-pig trachea, Nc.Oil and papaverine inhibited carbachol (1muM) and K(+) precontractions with similar potency, while verapamil was more potent against K(+). Nc.Oil also potentiated isoprenaline inhibitory CRCs, similar to papaverine, indicating papaverine-like PDE inhibitor activity. In isolated guinea-pig atria, Nc.Oil caused cardiodepression at around 25-80 times higher concentrations, similar to papaverine. CONCLUSIONS: These data indicate that Nepeta cataria possesses spasmolytic and myorelaxant activities mediated possibly through dual inhibition of calcium channels and PDE, which may explain its traditional use in colic, diarrhea, cough and asthma.
Clin Exp Immunol. 2008 Nov 24;
Odening KE, Li W, Rutz R, Laufs S, Fruehauf S, Fishelson Z, Kirschfink M
Multi-drug resistance (MDR) is a major obstacle in cancer chemotherapy. There are contrasting data on a possible correlation between the level of expression of the drug transporter P-glycoprotein (P-gp) and susceptibility to complement-dependent cytotoxicity (CDC). We therefore investigated the sensitivity of human ovarian carcinoma cells and their P-gp expressing MDR variants to complement. Chemoselected P-gp expressing MDR cells showed increased resistance to CDC associated with overexpression of membrane-bound complement regulatory proteins (mCRP) and increased release of the soluble inhibitors C1 inhibitor and factor I. MDR1 gene transfection alone did not alter the susceptibility of P-gp expressing A2780-MDR and SKOV3-MDR cells to CDC. However, subsequent vincristine treatment conferred an even higher resistance to complement to these cells, again associated with increased expression of mCRP. Blocking the function of P-gp with verapamil, cyclosporine A or the anti-P-gp-antibody MRK16 had no impact on their complement resistance, whereas blocking of mCRP enhanced their susceptibility to complement. These results suggest that enhanced resistance of chemoselected MDR ovarian carcinoma cells to CDC is not conferred by P-gp, but is due at least partly to overexpression of mCRP, probably induced by treatment with the chemotherapeutic agents.
Bull Exp Biol Med. 2008 Mar; 145(3): 291-4
Tkachenko EY, Gonzalez EV, Kozaruk VP, Kozyreva TV
Ionophoretic application of alpha1- and beta-adrenoceptor blockers into the skin produces no effect on the parameters of thermal homeostasis under thermoneutral conditions. alpha1-Adrenoblocker verapamil inhibits cold shivering during fast and slow cold exposure; it elevates the temperature threshold and moderates the vasoconstrictor response during rapid cooling. These changes are accompanied by a compensatory decrease in the threshold and stimulation of non-shivering thermogenesis. Application of non-selective beta-blocker propranolol had no effect on the temperature thresholds of the thermoregulatory reactions, but augmented the maximum amplitude of shivering during both cooling protocols, thereby compensating the decrease in non-shivering thermogenesis. In the whole organism, block of one type adrenoceptors during cold exposure is accompanied by activation of the compensatory mechanisms mediated by adrenoceptors of the other type.
Toxicol In Vitro. 2008 Nov 13;
Treijtel N, Eijkeren JC, Nijmeijer S, de Greef-van der Sandt IC, Freidig AP
The metabolism and active transport of ritonavir and saquinavir were studied using sandwich-cultured rat hepatoyctes and rat liver microsomes. For ritonavir four comparable metabolites were observed in the sandwich-culture and in microsomes. For saquinavir eight metabolites were observed in sandwich-culture and 14 different metabolites in microsomes. Ketoconazole did not affect the metabolism of ritonavir in sandwich-culture or microsomes and slightly inhibited the metabolism of saquinavir in sandwich-culture. This inhibition resulted in a different metabolite profile for saquinavir in microsomes. Ritonavir had a pronounced inhibiting effect on the metabolism of saquinavir and affected the hydroxylation of 6beta-testosterone negatively. In the active transport studies, cyclosporin A and PSC833 enhanced the metabolism of ritonavir, suggesting that ritonavir is normally excreted into the bile canaliculi. Verapamil, showed no effect on the metabolism of ritonavir. The intrinsic clearance was estimated at 1.65 and 67.5mul/min/1x10(6) cells and the hepatic metabolism clearance at 0.017 and 6.83ml/min/SRW for ritonavir and saquinavir respectively. In conclusion, for saquinavir the metabolism rate and the amount of metabolites produced was higher than for ritonavir. Ritonavir had a strong inhibitory effect on the metabolism of saquinavir and seemed to be excreted into the bile.