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Does intra-operative verapamil administration in kidney transplantation improve graft function.
Gupta, N, Caldas, M, Sharma, N, Bidnur, S, Ghosh, S, Todd, GT, Moore, RB
Clinical transplantation. 2019;(8):e13635
Abstract
The role of the calcium channel blocker (verapamil) in kidney transplant is controversial. Verapamil has been hypothesized to mitigate ischemia reperfusion injury (IRI) to the allograft. Herein, we evaluated the effect of intra-operative verapamil administration in a large cohort of kidney transplants. Total 684 transplants were performed during 2007-2017. Of these, 348 (50.9%) transplants received verapamil (2.5 mg) Ver (+), and 336 (49.1%) did not, Ver (-). Based on the donor type, the study was divided into three groups; living donor (LD) (N = 270), neurological determination of death (NDD) (N = 394), and donation after cardiac death (DCD) (N = 20). Ver (-) subgroup had more diabetic recipients as compared to Ver (+) subgroup in LD and NDD groups (P < 0.05). No significant difference was found for delayed graft function in any of the group (P > 0.05). Cold ischemia time and dialysis requirement were significantly higher in Ver (+) LD and NDD groups, respectively. Except for DCD group, there was no significant difference in eGFR (mL/min) immediately and 6 months after kidney transplant in any of the groups. Furthermore, univariate and multivariate logistic regression analysis was performed to account for potential confounders, but verapamil administration did not improve graft function in any of the groups (P > 0.05) after transplant.
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Minimal Physiologically Based Pharmacokinetic and Drug-Drug-Disease Interaction Model of Rivaroxaban and Verapamil in Healthy and Renally Impaired Subjects.
Ismail, M, Lee, VH, Chow, CR, Rubino, CM
Journal of clinical pharmacology. 2018;(4):541-548
Abstract
Current dosing recommendations for rivaroxaban advocate dosage reduction in patients with moderate to severe renal impairment and avoidance of concomitant strong inhibitors of CYP3A or P-glycoprotein. However, rivaroxaban dosing in patients with mild renal impairment taking concomitant moderate inhibitors of CYP3A and P-glycoprotein is not addressed. To quantify the impacts of concomitant verapamil administration and renal impairment on rivaroxaban pharmacokinetics, a minimal physiologically based pharmacokinetic model system was developed and used to evaluate potential increases in rivaroxaban exposure and the consequent increase in risk of major bleeding. Data from a phase 1, drug-drug interaction study were used to qualify the minimal physiologically based pharmacokinetic model system. Model-based simulations indicate that coadministration of rivaroxaban with verapamil substantially increases rivaroxaban exposure across all renal function categories, resulting in an exponential increase in bleeding risk. Reduction of the daily rivaroxaban dose to 10 to 15 mg reduces the major bleeding risk below the designated 4.5% threshold in the majority of patients with normal or mildly impaired renal function. A reduction to 10 mg daily in patients with moderate to severe renal impairment provides additional risk reduction so that 90% of those patients fall below the 4.5% threshold. A risk threshold of 4.5% was selected because it is the median predicted risk in patients treated concomitantly with ketoconazole, which is contraindicated for use with rivaroxaban. Patients taking both rivaroxaban and verapamil should take a reduced daily dose of rivaroxaban to minimize bleeding risk.
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Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies.
Martin, P, Gillen, M, Millson, D, Oliver, S, Brealey, C, Grossbard, EB, Baluom, M, Lau, D, Sweeny, D, Mant, T, et al
Drugs in R&D. 2016;(1):81-92
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Abstract
BACKGROUND Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of fostamatinib, R406, is primarily metabolized by CYP3A4. OBJECTIVES The aim of this study was to characterize hepatic microsomal metabolism of R406 and confirm the role of CYP3A4 in R406 metabolism, determining whether co-administration of CYP3A4 inhibitors (ketoconazole, verapamil) or inducers (rifampicin) affects R406 pharmacokinetics. METHODS R406 stability was determined using human hepatic microsomes. The CYP450 isoforms responsible for R406 metabolism in humans were identified using expressed CYP450 isoforms and specific chemical inhibitors. The ketoconazole interaction study (double-blind, randomized, placebo-controlled, two-period crossover) involved fostamatinib administration (single 80-mg dose), alone and with ketoconazole (200 mg twice daily). The verapamil and rifampicin interaction studies (open-label, two-period, fixed-sequence) involved fostamatinib administration (single 150-mg dose), alone and with immediate-release verapamil (80 mg three times daily) or rifampicin (600 mg once daily). Standard pharmacokinetic parameters were calculated in all studies. RESULTS/DISCUSSION Hepatic microsomes showed time-dependent loss of R406 and formation of para-O-demethylated R406. Microsomal metabolism of R406 was markedly inhibited by CYP3A4 inhibitors and, in the expressed CYP450 studies, the rate of R406 disappearance was greatest with CYP3A4. In the clinical studies, co-administration of ketoconazole caused a 2-fold (CI 1.77-2.30) increase in R406 exposure. Verapamil increased R406 exposure (39% increase, CI 8-80), whereas rifampicin co-administration decreased exposure by 75% (CI 68-81). Fostamatinib was well tolerated. CONCLUSION The oxidative metabolism of R406 is predominantly catalyzed by CYP3A4. In clinical studies, exposure to R406 is affected by concomitant administration of CYP3A4 inducers/inhibitors. These findings should be taken into account when considering co-prescription of fostamatinib with such agents.
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The effectiveness of transdermal electromotive administration with verapamil and dexamethasone in the treatment of Peyronie's disease.
Tuygun, C, Ozok, UH, Gucuk, A, Bozkurt, IH, Imamoglu, MA
International urology and nephrology. 2009;(1):113-8
Abstract
AIM: To determine the effectiveness of transdermal electromotive administration (TEA) of verapamil and dexamethasone in the treatment of Peyronie's disease (PD). METHOD Totally, 51 patients with PD were prospectively included in the study. All patients were evaluated by history, subjective score scales, physical examination, photographs, and penile USG, before and after therapy. All patients were treated with TEA of the combination of verapamil and dexamethasone. The treatment plan included a total of 20 sessions (at 3-day intervals for a period of 2 months), each with a duration of 20 min. At the end of the study, improvements in penile plaques, penile deviation, pain on erection, and erectile dysfunction were determined. RESULTS The findings in 41 of the 51 patients were eligible to present. Median patient age was 52 years. Median duration of disease at presentation was 8 months. Remarkable reduction in palpable plaques and in penile angulation was observed in 10 patients (24%) and 11 (26%) patients, respectively. There were significant decreases in median plaque volume from 72 mm(2) to 45 mm(2) (P < 0.001), and in median penile angulation from 25 degrees to 15 degrees (P < 0.001). Impaired sexual activity and pain on erection had completely resolved in 11 (55%) patients and in 16 (80%), respectively. CONCLUSION The results of our study have shown that TEA of the combination of verapamil and dexamethasone is a more effective therapy for improving subjective symptoms rather than objective symptoms. Therefore, we think that this treatment can be individualized according to the clinical features of PD patients.
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Effects of verapamil on anterior ST segment and ventricular fibrillation cycle length in patients with Brugada syndrome.
Chinushi, M, Iijima, K, Tagawa, M, Komura, S, Furushima, H, Aizawa, Y
Journal of electrocardiology. 2009;(4):367-73
Abstract
PURPOSE This study examined the effects of verapamil (5-10 mg intravenous) on the cardiac electrical activity of 10 Brugada syndrome (BS) patients having vasospastic angina, atrial fibrillation, and/or hypertension. RESULTS Verapamil showed no significant change in the ST-segment elevation. Likewise, there was no significant change in the lengths of QRS complex, HV and corrected QT intervals, or effective refractory period at the right ventricle. The conduction time between right ventricular apex and outflow tract, measured at 400-millisecond pacing, was mildly prolonged by verapamil. At baseline, induced ventricular fibrillation (VF) was terminated by a 200-J shock in all patients. After verapamil, VF was reinduced in 7, was noninducible in 2, and self-terminated in 1 patient. Mean F-F interval was shorter after than before verapamil, and a 360-J shock was required in 2 of the 7 patients. CONCLUSION In some BS patients, calcium channel blockade may modify the electrical characteristics of VF.
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The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates.
Lemma, GL, Wang, Z, Hamman, MA, Zaheer, NA, Gorski, JC, Hall, SD
Clinical pharmacology and therapeutics. 2006;(3):218-30
Abstract
BACKGROUND Verapamil has the capability to inhibit and induce cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), but the relative extent and time course of these events in vivo are unclear. The effect of verapamil on CYP3A and P-gp activity was determined by examining its effect on its own disposition and on the disposition of fexofenadine, respectively. METHODS Twelve healthy volunteers received 60 mg fexofenadine alone or after administration of 240 mg verapamil for 1, 10, and 38 days. The concentrations of verapamil and norverapamil, as well as their enantiomers, were quantified in serum by chiral HPLC. The concentrations of fexofenadine and its metabolite, azacyclonol, were quantified in serum and urine by liquid chromatography-mass spectrometry. RESULTS The mean +/- SD maximum serum concentration (Cmax) and the area under the serum concentration-time curve of S-verapamil increased significantly on days 10 (40 +/- 21 ng/mL [P = .00044] and 433 +/- 316 ng.h.mL(-1) [P = .00047], respectively) and 38 (42 +/- 27 ng/mL [P = .019] and 433 +/- 256 ng.h.mL(-1) [P = .0081], respectively) compared with day 1 (21 +/- 12 ng/mL and 222 +/- 156 ng.h.mL(-1), respectively). The oral clearance (CLoral) of S-verapamil decreased significantly from 702 +/- 304 L/h on day 1 to 377 +/- 210 L/h on day 10 (P = .0029) and 449 +/- 419 L/h on day 38 (P = .05). Similar trends were observed for the Cmax and area under the serum concentration-time curve of R-verapamil and R- and S-norverapamil. All subjects showed a significant decrease in the CLoral of fexofenadine after a single dose (98 +/- 54 L/h, P = .00105) and 10-day dosing (102 +/- 40 L/h, P = .0011) of verapamil compared with the control value (156 +/- 69 L/h). The Cmax of fexofenadine was significantly increased by a single dose (165 +/- 42 ng/mL, P = .0005) and 10-day dosing (148 +/- 39 ng/mL, P = .0008) of verapamil compared with the control value (114 +/- 45 ng/mL). No significant difference in fexofenadine Cmax (P = .37) and CLoral (P = .43) was observed between the control values and values at 38 days of verapamil treatment. CONCLUSION Verapamil inhibited CYP3A activity, with a maximum effect occurring within 10 days. Short-term administration of verapamil caused net inhibition of intestinal P-gp, whereas long-term administration of verapamil induced P-gp activity.
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Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics.
Yasui-Furukori, N, Uno, T, Sugawara, K, Tateishi, T
Clinical pharmacology and therapeutics. 2005;(1):17-23
Abstract
OBJECTIVE Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics. METHODS Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing. RESULTS Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of fexofenadine by 2.5-fold (95% CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-infinity) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%-58%) but not during verapamil treatment. CONCLUSION This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters.
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Global differences in blood pressure control and clinical outcomes in the INternational VErapamil SR-Trandolapril STudy (INVEST).
Zineh, I, Cooper-Dehoff, RM, Wessel, TR, Arant, CB, Sleight, P, Geiser, EA, Pepine, CJ
Clinical cardiology. 2005;(7):321-8
Abstract
BACKGROUND The INternational VErapamil SR-Trandolapril Study (INVEST), a prospective, randomized, antihypertensive trial, found that two different medication regimens produced similar blood pressure (BP) control with equivalent cardiovascular (CV) outcomes (death from any cause, nonfatal myocardial infarction [MI], or nonfatal stroke). HYPOTHESIS The study was undertaken to investigate whether differences exist by global regions in demographics, treatment, and outcomes in the INVEST trial. METHODS Data were analyzed for 22,576 patients with stable coronary artery disease (CAD) enrolled in INVEST. We investigated differences in patient characteristics, treatment approaches, BP control, and clinical outcomes by creating three global regions based on geographical location: Northern Americas (NA), Caribbean (CA), and Eurasia (EA). RESULTS We observed significant regional differences in patient characteristics, treatment patterns, BP control, and CV outcomes. At baseline, patients from NA were older and had greater body mass index, higher rates of diabetes, peripheral vascular disease, and coronary revascularization, but lower rates of MI or left ventricular hypertrophy than patients in CA and EA. At 24 months, there were regional differences in both study and nonstudy antihypertensive drug use. Despite having higher mean baseline BP, patients from CA and EA achieved lower mean systolic BP throughout study follow-up. Furthermore, patients from both CA and EA had lower rates of all-cause mortality, fatal or nonfatal MI, fatal or nonfatal stroke, and newly diagnosed diabetes than patients from NA. CONCLUSIONS In INVEST, regional differences in medication utilization, BP control, and CV outcomes were identified. These disparities warrant further investigation to define appropriate care for patients with hypertension and stable CAD from an international public health perspective.
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Comparative study of angiotensin converting enzyme inhibitor and calcium channel blocker in the treatment of steroid-resistant idiopathic nephrotic syndrome.
Kumar, NS, Singh, AK, Mishra, RN, Prakash, J
The Journal of the Association of Physicians of India. 2004;:454-8
Abstract
BACKGROUND The aim of this study was to evaluate and compare the anti-proteinuric effect of ramipril and verapamil in patients with steroid-resistant idiopathic nephrotic syndrome. Twenty one (21) cases of steroid-resistant idiopathic nephrotic syndrome were randomized to receive ramipril (11) and verapamil (10) and were followed up for 12 months; monthly for the 1st 3 months and then every 3 months for the remaining study period. The degree of reduction of proteinuria, blood pressure, serum creatinine, serum albumin and side effects were noted between the two groups. The comparison within the groups over different time periods was made using paired 't' test and between the groups for specific time period by unpaired 't' test. The level of significance was taken as 5% or below. RESULTS Seventeen patients (nine in the ramipril group and eight in the verapamil group) completed the study. The mean age of the patients, duration of illness, 24 hours urinary excretion of protein, mean arterial pressure, serum creatinine, cholesterol and albumin were similar in both the groups at time of randomization. The 24 hours urinary protein excretion decreased from 6319.44 +/- 1971.70 mg/day to 1852.44 +/- 1813.74 mg/day in patients receiving ramipril and from 5332.87 +/- 1947.47 mg /day to 2759.37 +/- 1929.6 mg/day in patients treated with verapamil after 12 months. There was no statistically significant difference in the reduction of proteinuria between the two groups. However, reduction in proteinuria was statistically significant from 2nd month onwards in Ramipril group and reduction was sustained throughout the study period. Reduction in mean arterial pressure was better achieved in Ramipril groups. The change in the serum potassium, creatinine, cholesterol and albumin were similar in either group of patients. Cough (2), hypotension (1) and reversible rise in serum creatinine (1) were observed with ramipril and no side effect was noted with verapamil. CONCLUSION Both ramipril and verapamil can reduce proteinuria in patients suffering from steroid-resistant idiopathic nephrotic syndrome. However, ramipril had a better and sustained reduction in proteinuria with well-controlled mean arterial pressure. Verapamil can be considered as an alternative to ramipril when the use of the latter is not tolerated because of side effects and/or worsening of renal function in patients with chronic renal insufficiency.
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Evaluation of the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention: the randomized, double-blind, placebo-controlled, multicenter Verapamil Slow-Release for Prevention of Cardiovascular Events After Angioplasty (VESPA) Trial.
Bestehorn, HP, Neumann, FJ, Büttner, HJ, Betz, P, Stürzenhofecker, P, von Hodenberg, E, Verdun, A, Levai, L, Monassier, JP, Roskamm, H
Journal of the American College of Cardiology. 2004;(12):2160-5
Abstract
OBJECTIVES We investigated the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention (PCI). BACKGROUND Thus far, there is no established systemic pharmacologic approach for the prevention of restenosis after PCIs. Five small studies reported encouraging results for calcium channel blockers. METHODS Our randomized double-blind trial included 700 consecutive patients with successful PCI of a native coronary artery. Patients received the calcium channel blocker verapamil, 240 mg twice daily for six months, or placebo. Primary clinical end point was the composite rate of death, myocardial infarction, and target vessel revascularization (TVR) during one-year follow-up; the angiographic end point was late lumen loss at the six-month follow-up angiography. RESULTS We obtained complete clinical follow-up in 95% of the patients, and scheduled angiography was performed in 94%. The proportion of patients treated with stents was 83%. The primary clinical end point was reached in 67 (19.3%) patients on verapamil and in 103 (29.3%) patients on placebo (relative risk [RR] 0.66 [95% confidence interval (CI) 0.48 to 0.89]; p = 0.002). This difference between the groups was driven by TVR (17.5% with verapamil vs. 26.2% with placebo; RR 0.67 [95% CI 0.49 to 0.93]; p = 0.006). Late lumen loss was 0.74 +/- 0.70 mm with verapamil and 0.81 +/- 0.75 mm with placebo (p = 0.11). Compared with placebo, verapamil reduced the rate of restenosis > or =75% (7.8% vs. 13.7%; RR 0.57 [95% CI 0.35 to 0.92]; p = 0.014). CONCLUSIONS Verapamil compared with placebo improves long-term clinical outcome after PCI of native coronary arteries by reducing the need for TVR. This was caused by a reduction in the rate of high-grade restenosis.