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1.
Effect of Lisinopril and Verapamil on Angiopoietin 2 and Endostatin in Hypertensive Diabetic Patients with Nephropathy: A Randomized Trial.
Salem, M, Sallam, AM, Abdel-Aleem, E, El-Mesallamy, HO
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2021;(7):470-477
Abstract
Angiogenesis is a multistep process implicated in the pathophysiology and progression of diabetic nephropathy (DN). Angiotensin-converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) have an important role in DN. We performed a randomized-controlled trial of lisinopril alone (an ACEI) or in combination with verapamil (a CCB) as a therapy for DN in type 2 diabetes mellitus (T2DM) patients with hypertension (HTN) and urinary albumin creatinine ratio (UACR) (30-300 mg/g) also to evaluate their effect on UACR, the angiogenic proteins: Angiopoietin 2 (Ang-2) and Endostatin (EST). Forty T2DM patients with microalbuminuria, aged 45-65 years were included. Patients were randomly assigned into group 1 receiving oral lisinopril and group 2 receiving oral lisinopril and verapamil once daily. After 3 months follow-up fasting blood glucose (FPG), HbA1c, lipid profile, UACR, serum urea and creatinine levels were assessed. EST and Ang-2 were measured using ELISA technique. Baseline Ang-2 and EST levels were elevated in both groups compared with controls (p<0.001). After follow-up, group 2 had significantly decreased FPG, HbA1c, UACR, EST and Ang-2 compared with their baseline levels (p<0.001 for all comparisons) and with group 1 (p<0.001). No adverse reactions were reported. Baseline EST and Ang-2 were positively correlated to UACR (r=0.753, p<0.001) (r=0.685, p<0.001). Lisinopril/verapamil combination enhanced glycemic control and kidney function via diminishing EST and Ang-2. This combination can be considered as a safe and effective approach for early stage nephropathy therapy in T2DM.
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2.
Effects of L-type voltage-gated Ca2+ channel blockade on cholinergic and thermal sweating in habitually trained and untrained men.
Amano, T, Fujii, N, Kenny, GP, Okamoto, Y, Inoue, Y, Kondo, N
American journal of physiology. Regulatory, integrative and comparative physiology. 2020;(5):R584-R591
Abstract
We evaluated the hypothesis that the activation of L-type voltage-gated Ca2+ channels contributes to exercise training-induced augmentation in cholinergic sweating. On separate days, 10 habitually trained and 10 untrained men participated in two experimental protocols. Prior to each protocol, we administered 1% verapamil (Verapamil, L-type voltage-gated Ca2+ channel blocker) and saline (Control) at forearm skin sites on both arms via transdermal iontophoresis. In protocol 1, we administered low (0.001%) and high (1%) doses of pilocarpine at both the verapamil-treated and verapamil-untreated forearm sites. In protocol 2, participants were passively heated by immersing their limbs in hot water (43°C) until rectal temperature increased by 1.0°C above baseline resting levels. Sweat rate at all forearm sites was continuously measured throughout both protocols. Pilocarpine-induced sweating in Control was higher in trained than in untrained men for both the concentrations of pilocarpine (both P ≤ 0.001). Pilocarpine-induced sweating at the low-dose site was attenuated at the Verapamil versus the Control site in both the groups (both P ≤ 0.004), albeit the reduction was greater in trained as compared with in untrained men (P = 0.005). The verapamil-mediated reduction in sweating remained intact at the high-dose pilocarpine site in the untrained men (P = 0.004) but not the trained men (P = 0.180). Sweating did not differ between Control and Verapamil sites with increases in rectal temperature in both groups (interaction, P = 0.571). We show that activation of L-type voltage-gated Ca2+ channels modulates sweat production in habitually trained men induced by a low dose of pilocarpine. However, no effect on sweating was observed during passive heating in either group.
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3.
Therapeutic effects of nebulized verapamil on chronic obstructive pulmonary disease: A randomized and double-blind clinical trial.
Bozorgmehr, R, Edalatifard, M, Safavi, E, Rahimi, B, Ghorbani, F, Abtahi, H, Amini, S, Pourdowlat, G
The clinical respiratory journal. 2020;(4):370-381
Abstract
OBJECTIVES In this study, we assessed the clinical effect of inhaled verapamil on hospitalized COPD patients in a randomized and double-blind study. METHOD COPD patients randomly received 10 mg of inhaled verapamil or 4 cc nebulized distilled water (DW) as placebo. RESULTS Twenty patients enrolled in each group with no difference in baseline characteristics. Mean age was 64.95 ± 8.9 and 66.9 ± 10.74 years in verapamil and control group; respectively, (P > 0.05). The mean dyspnea score was 6.4 ± 1.2 and 6.2 ± 1.8 in the verapamil and control group, respectively and decreased to 4.9 ± 1.3 and 5.7 ± 1.8 after the intervention. The mean change in the verapamil group was significantly higher, (22.43% ± 10.6% vs 8.7% ± 12.1%), P = 0.00. Unlike the control group, the FEV1 value in the verapamil group significantly increased and reached to 1.17 ± 0.4 L from 1.03 ± 0.4. There was a significant decrease in airway resistance in both groups after intervention. However, neither total lung capacity and residual volume nor forced vital capacity changed significantly. Moreover, oxygen saturation in the verapamil group changed 4.8% ± 2.5% and this improvement in the control group was 1.8 ± 1 (P = 0.00). Smoker subjects, ones with PAP more than 35 mm Hg and obese patients benefit from verapamil. CONCLUSION The beneficial impact of inhaled verapamil on the diminishing of dyspnea score along with its bronchodilatory effect would make this selective calcium blocker agent a therapeutic option in COPD.
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4.
A Prospective Noninterventional, Observational Study to Describe the Effectiveness and Safety of Trandolapril and Verapamil Single-Pill Combination in the Management of Patients with Hypertension and Type 2 Diabetes Mellitus: A Harvest TR Study.
Atalar, E, Eskin, F, Tugtekin, HB, Karabulut, A, Kanyilmaz, S, Kirbiyik, H, Ozyildiz, AG
BioMed research international. 2020;:2123601
Abstract
Maintaining regular blood pressure control usually requires multidrug regimens rather than monotherapy. The objective of this study was to describe the effectiveness and safety of an angiotensin-converting enzyme inhibitor and a nondihydropyridine calcium channel blocker in a single-tablet combination in patients with hypertension, a heart rate higher than 70 beats/min, and type 2 diabetes mellitus (T2DM). This study was conducted in Turkey as a prospective, noninterventional, observational study. At 22 clinical sites, the data of 200 patients with hypertension were used for efficacy analysis; however, 262 patients received at least one dose of trandolapril/verapamil fixed-dose combination at two dose strengths. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, PR interval, glycated haemoglobin (HbA1c), and albumin/creatinine ratios were recorded during 8 weeks of treatment. With treatment, the mean (±SD) SBP that was recorded as 162.8 (±14.642) mm Hg at baseline was reduced to 131.7 ± 11.1 mm Hg at week 8 (p < 0.05). Similarly, the mean DBP was reduced from 93.76 ± 9.16 mm Hg to 77.6 ± 7.6 mm Hg (p < 0.001). Following 8 weeks of treatment, SBP and DBP values were reduced below 140 mm Hg and 90 mm Hg in most patients (81.5%), respectively. The mean heart rate as evaluated using electrocardiography measurements was reduced to 78.25 beats/min at week 8 as compared with baseline during trandolapril/verapamil single-pill combination treatment (p < 0.001). Treatment with trandolapril and verapamil was well tolerated over 8 weeks with no unexpected safety signals. In conclusion, the single-pill combination of trandolapril and verapamil was considered effective in reducing and controlling blood pressure in patients with hypertension and T2DM. There was a significant improvement in HbA1c and ACR levels in a smaller subgroup of the patient cohort. The trandolapril/verapamil combination was evaluated as being safe and well-tolerated following a treatment period of 8 weeks. This trial was registered with NCT02298556.
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5.
The β-cell effect of verapamil-based treatment in patients with type 2 diabetes: a systematic review.
Carnovale, C, Dassano, A, Mosini, G, Mazhar, F, D'Addio, F, Pozzi, M, Radice, S, Fiorina, P, Clementi, E
Acta diabetologica. 2020;(2):117-131
Abstract
AIMS: The possibility that verapamil has new beneficial effects in diabetic patients in terms of an improvement in glycometabolic control has been put forward recently in several studies. However, to date the issue is still under debate. We conducted the first systematic review examining the impact of verapamil-based treatment on glycometabolic outcomes, in type 2 diabetes (T2D) patients. METHODS We searched the PubMed, MEDLINE, Embase, Cochrane and ClinicalTrials.gov up to 9 October 2018, for all studies evaluating whether verapamil-based treatment is associated with changes in glycated haemoglobin (HbA1c), fasting plasma glucose levels, glucose and C-peptide areas from baseline in humans, without restrictions for study type. RESULTS Plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (mean change - 13 ± 5.29; P = 0.049); HbA1c values were instead not affected by the drug (mean change - 0.10 ± 0.12; P = 0.453). In five studies, groups exposed to verapamil achieved lower value of glycometabolic outcomes: comparison with values recorded in control groups showed a significant difference, in terms of both HbA1c and plasma glucose levels. CONCLUSIONS Despite the fact that plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (the HbA1c values were not affected by the drug), the clinical significance of the glycometabolic response induced by verapamil-based treatment remains unclear due to the high variety of sample size and type of studies presently available. Further experimental and clinical trials are needed to clarify unambiguously the role of verapamil in metabolic control.
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6.
Phenylalkylamines in calcium channels: computational analysis of experimental structures.
Tikhonov, DB, Lin, L, Yang, DSC, Yuchi, Z, Zhorov, BS
Journal of computer-aided molecular design. 2020;(11):1157-1169
Abstract
Experimental 3D structures of calcium channels with phenylalkylamines (PAAs) provide basis for further analysis of atomic mechanisms of these important cardiovascular drugs. In the crystal structure of the engineered calcium channel CavAb with Br-verapamil and in the cryo-EM structure of the Cav1.1 channel with verapamil, the ligands bind in the inner pore. However, there are significant differences between these structures. In the crystal structure the ligand ammonium group is much closer to the ion in the selectivity-filter region Site 3, which is most proximal to the inner pore, than in the cryo-EM structure. Here we used Monte Carlo energy minimizations to dock PAAs in calcium channels. Our computations suggest that in the crystal structure Site 3 is occupied by a water molecule rather than by a calcium ion. Analysis of the published electron density map does not rule out this possibility. In the cryo-EM structures the ammonium group of verapamil is shifted from the calcium ion in Site 3 either along the pore axis, towards the cytoplasm or away from the axis. Our unbiased docking reproduced these binding modes. However, in the cryo-EM structures detergent and lipid molecules interact with verapamil. When we removed these molecules, the nitrile group of verapamil bound to the calcium ion in Site 3. Models of Cav1.2 with different PAAs suggest similar binding modes and direct contacts of the ligands electronegative atoms with the calcium ion in Site 3. Such interactions explain paradoxes in structure-activity relationships of PAAs.
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7.
The Safety and Efficacy of Intralesional Verapamil Versus Intralesional Triamcinolone Acetonide for Keloids and Hypertrophic Scars: A Systematic Review and Meta-analysis.
Jiang, ZY, Liao, XC, Liu, MZ, Fu, ZH, Min, DH, Guo, GH
Advances in skin & wound care. 2020;(4):1-7
Abstract
BACKGROUND Keloids and hypertrophic scars often result after skin trauma. Currently, intralesional triamcinolone acetonide (TAC) is the criterion standard in nonsurgical management of keloids and hypertrophic scars. Intralesional verapamil may be an effective alternative modality, but it has been insufficiently studied. Accordingly, the study authors conducted a systematic review and meta-analysis of randomized controlled trials to compare the efficacy and safety of the two drugs. METHODS The study authors systematically searched the MEDLINE, EMBASE, Cochrane Library, and China National Knowledge Infrastructure databases for relevant trials published in any language through September 2018. RESULTS According to the four studies included in this review, TAC improved scar pliability and vascularity more than verapamil after 3 weeks (P < .05). For scar height and scar pigmentation, no statistical difference was observed between the treatments (P > .05). The difference in effects on symptoms was not statistically significant (P = .89). For pain and telangiectasia, no statistical difference was observed (P > .05). Verapamil resulted in fewer cases of skin atrophy (P < .05). CONCLUSIONS It appears that TAC is more effective than verapamil for improving scar pliability and vascularity in keloids and hypertrophic scars after 3 weeks of treatment. However, verapamil has fewer adverse drug reactions than TAC, which allows for a longer treatment period and the possibility that it might be effective for patients who cannot receive TAC.
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8.
Preventing spasm of the radial artery conduit during coronary artery bypass grafting: Nicardipine versus verapamil.
Özdemir, HI, van Dijk, CHB, Özdemir, AB, van Straten, BHM, Haanschoten, M, Soliman-Hamad, MA
Journal of cardiac surgery. 2019;(12):1505-1510
Abstract
BACKGROUND AND AIM OF THE STUDY In vitro studies have shown a reduction in radial artery spasm with the use of calcium antagonists. The purpose of this study was to evaluate the efficacy of topical treatment of the radial artery conduit using either verapamil or nicardipine before the anastomoses. METHODS This prospective randomized study included 131 patients, who underwent coronary artery bypass grafting surgery with the use of the radial artery as a conduit. In 65 patients, the harvested radial artery was topically treated with verapamil and in 66 patients with nicardipine. After harvesting the radial artery, the direct flow through the conduit was measured in vitro before 5-minute incubation in nicardipine or verapamil and measured again after incubation. The flow before and after incubation was compared. Postincubation flow was also compared in the two groups. After performing the anastomosis, the flow through the radial artery was measured in vivo. RESULTS The mean flow after NaCl incubation was 19.93 ± 12.66 mL/min and after incubation in the Ca+ channel blocker 47.16 ± 14.58 mL/min (P < .001). No significant difference in postincubation free flow was found between verapamil (46.29 ± 15.43 mL/min) and nicardipine (48.01 ± 13.77 mL/min; P = .503). CONCLUSION Topical treatment with Ca+ channel blockers reduces radial artery spasm and significantly increases the free flow through the radial artery conduit. Nicardipine is a safe and effective alternative of verapamil in preventing spasm of radial artery conduit.
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9.
How CaV1.2-bound verapamil blocks Ca2+ influx into cardiomyocyte: Atomic level views.
Li, W, Shi, G
Pharmacological research. 2019;:153-157
Abstract
The first clinically used antiarrhythmic, antianginal and anti-hypertensive phenylalkylamine, verapamil's cardiovascular activity is inextricably linked to its ability to antagonize Ca2+ overload via blocking CaV1.2, a cardiac L-type Ca2+ channel of undisputed physiological and pharmacological importance in cardiovascular disorders such as myocardial ischemia-reperfusion injury. From a structural point of view, however, the action mechanism of verapamil is still elusive. Therefore, incorporating previous findings for verapamil and CaV1.2, this review article puts forward two experimental data-derived and -supported 3D structure models for CaV1.2's α1 subunit and its verapamil-bound form. Furthermore, this article suggests three biophysical mechanisms, namely competitive binding, steric hindrance and electrostatic repulsion, towards an atomic level understanding of how verapamil blocks the L-type Ca2+ current mediated by CaV1.2 in reality, which can be useful for the design and development of next-generation Ca2+ antagonists to provide safer and more effective treatment of cardiovascular diseases.
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10.
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.