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1.
Dihydropyridine Calcium Channel Blockers and the Risk of Severe COVID-19.
Mendez, SR, Frank, RC, Stevenson, EK, Chung, M, Silverman, MG
Chest. 2021;(1):89-93
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2.
Treatment effect of lacidipine and amlodipine on clinic and ambulatory blood pressure and arteria stiffness in a randomised double-blind trial.
Wang, Y, Li, Y, Huo, Y, Wang, JG
Blood pressure. 2021;(2):108-117
Abstract
PURPOSE In a randomised, double-blind trial, we investigated effects of lacidipine on clinic and ambulatory blood pressure (BP) and arterial stiffness in patients with mild-to-moderate hypertension, as compared with amlodipine. MATERIALS AND METHODS Previously untreated and treated patients (n = 269, 50-80 years of age) with clinic hypertension (a clinic systolic/diastolic BP 140-180/<110 mmHg and <160/100 mmHg, respectively) were randomly assigned to double-dummy treatment with lacidipine (4-6 mg/day) or amlodipine (5-7.5 mg/day) for 20 weeks. The primary efficacy variable was the change in 24-h ambulatory systolic BP at 20 weeks of treatment. Arterial stiffness was measured as brachial-ankle pulse wave velocity (PWV). RESULTS After 20 weeks of treatment, 24-h systolic BP decreased from 141.3 ± 14.0 and 138.3 ± 12.8 mmHg at baseline, respectively, in the lacidipine (n = 134) and amlodipine groups (n = 135), by a least square mean (±SE) change of 15.2 ± 1.3 and 15.5 ± 1.3 mmHg, respectively, with a between-group difference (95% confidence interval [CI]) of 0.3 mmHg (-3.4 to 4.1, p = 0.86). Similar results were observed for other ambulatory BP components and clinic BP. Clinic and ambulatory pulse rate did not significantly change in either group (p ≥ 0.21). PWV decreased significantly (p < 0.001) from baseline in both groups, with a non-significant between-group difference of 0.24 m/s (p = 0.45). The incidence rate of adverse events was 30.3% (n = 40) and 27.5% (n = 36) in the lacidipine and amlodipine groups, respectively (p = 0.61). No serious adverse event occurred in the trial. CONCLUSIONS Lacidipine effectively lowers clinic and ambulatory BP in patients with mild-to-moderate hypertension and significantly improves arterial stiffness, similarly as amlodipine.
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3.
The effect of an L/N-type calcium channel blocker on intradialytic blood pressure in intradialytic hypertensive patients.
Ito, T, Fujimoto, N, Ishikawa, E, Dohi, K, Fujimoto, M, Murata, T, Kiyohara, M, Takeuchi, H, Koyabu, S, Nishimura, H, et al
Clinical and experimental hypertension (New York, N.Y. : 1993). 2019;(1):92-99
Abstract
BACKGROUND Intradialytic hypertension (HTN), which is one of the poor prognostic markers in patients undergoing hemodialysis, may be associated with sympathetic overactivity. The L/N-type calcium channel blocker, cilnidipine, has been reported to suppress sympathetic nerves activity in vivo. Therefore, we hypothesized that cilnidipine could attenuate intradialytic systolic blood pressure (SBP) elevation. METHODS Fifty-one patients on chronic hemodialysis who had intradialytic-HTN (SBP elevation ≥10 mmHg during hemodialysis) and no fluid overload were prospectively randomized into two groups: control and cilnidipine groups. Cilnidipine group patients took cilnidipine (10 mg/day) for 12 weeks. The primary endpoint was the change in the intradialytic SBP elevation before and after the 12-week intervention. RESULTS Before the intervention, no differences were observed in age, sex or pre-dialytic SBP (148.5 ± 12.9 vs. 148.3 ± 19.3 mmHg) between the two groups. Intradialytic SBP elevation was unchanged in the control group. Cilnidipine significantly lowered the post-dialytic SBP with an attenuation of the intradialytic SBP elevation from 12.0 ± 15.4 mmHg to 4.8 ± 10.1 mmHg. However, the observed difference in the intradialytic SBP elevation by cilnidipine did not reach statistical significance (group×time interaction effect p = 0.25). Cathecolamine levels were unaffected by the intervention in both groups. CONCLUSION Cilnidipine lowers both the pre- and post-dialytic SBP and might attenuate intradialytic SBP elevation. Therefore, cilnidipine may be effective in lowering SBP during HD in patients with intradialytic-HTN.
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4.
Bactericidal and immunomodulatory properties of magnetic nanoparticles functionalized by 1,4-dihydropyridines.
Niemirowicz-Laskowska, K, Głuszek, K, Piktel, E, Pajuste, K, Durnaś, B, Król, G, Wilczewska, AZ, Janmey, PA, Plotniece, A, Bucki, R
International journal of nanomedicine. 2018;:3411-3424
Abstract
BACKGROUND 1,4-Dihydropyridine (1,4-DHP) and its derivatives are well-known calcium channel blockers with antiarrhythmic and antihypertensive activities. These compounds exhibit pleiotropic effects including antimicrobial activities that rely on their positive charge and amphipathic nature. Use of magnetic nanoparticles (MNPs) as carriers of 1,4-DHP modulates their properties and enables improved formulations with higher efficacy and less toxicity. METHODS In this study, the antimicrobial and immunomodulatory activities of novel 1,4-DHP derivatives in free form and immobilized on MNPs were determined by evaluating pathogen outgrowth and proinflammatory cytokine release in experimental settings that involve incubation of various 1,4-DHPs with clinical isolates of bacteria or fungi as well as mammalian cell culture models. RESULTS Conventional immobilization of 1,4-DHP on aminosilane-coated MNPs markedly enhances their antimicrobial activity compared to nonimmobilized molecules, in part because of the higher affinity of these nanosystems for bacterial cell wall components in the presence of human body fluids. CONCLUSION Optimized nanosystems are characterized by improved biocompatibility and higher anti-inflammatory properties that provide new opportunities for the therapy of infectious diseases.
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5.
Reduction in microalbuminuria by calcium channel blockers in patients with type 2 diabetes mellitus and hypertension-A randomized, open-label, active-controlled, superiority, parallel-group clinical trial.
Hwang, YC, Yoon, KH, Cha, BS, Lee, KW, Jang, HC, Min, KW, Chung, CH, Lee, MK
International journal of clinical practice. 2017;(9)
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Abstract
BACKGROUND It has been suggested that renoprotection with calcium channel blockers (CCBs) may differ. This study aimed to compare the anti-proteinuric effect of different CCBs in patients with type 2 diabetes (T2D). METHODS A multicentre, randomized, open-label, active-controlled study was performed in seven centres in Korea. A total of 74 patients with T2D and microalbuminuria treated with renin-angiotensin system (RAS) blockers were randomized to a cilnidipine 10 mg treatment (n=38) or amlodipine 5 mg treatment (n=36). RESULTS Urine albumin to creatinine ratio (ACR) reduction was similar between the two groups at 12 weeks (-53.0±123.2 mg/g in cilnidipine group and -35.7±83.6 mg/g in amlodipine group, P=.29) or 24 weeks (-57.3±106.9 mg/g in cilnidipine group and -20.0±110.4 mg/g in amlodipine group, P=.24). In a subgroup analysis, cilnidipine treatment showed a larger ACR reduction than amlodipine treatment at 12 weeks (-84.7±106.8 mg/g in cilnidipine group and -9.5±79.2 mg/g in amlodipine group, P=.01) and 24 weeks (-84.0±111.7 mg/g in cilnidipine group and 14.6±119.4 mg/g in amlodipine group, P=.008), particularly in patients with a longer duration of diabetes more than 10 years. CONCLUSIONS Cilnidipine did not show any additional anti-albuminuric effect compared with amlodipine in patients with T2D and microalbuminuria treated with an RAS blocker. However, the anti-albuminuric effect of cilnidipine might differ according to the duration of diabetes.
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Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial.
Xue, C, Zhou, C, Yang, B, Lv, J, Dai, B, Yu, S, Wang, Y, Zhao, G, Mei, C
BMJ open. 2017;(2):e013672
Abstract
INTRODUCTION Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS AND ANALYSIS This study will be a multicentred, prospective, double-blind, randomised parallel controlled trial for hypertensive CKD patients in China. Patients will be randomised to one of two treatment groups: a combination of benidipine 4-8 mg/day and fosinopril 20 mg/day; or a combination of HCTZ 12.5-25 mg/day and fosinopril 20 mg/day. Patients will be followed up for 24 months after a month's fosinopril run-in. There will be dose-titration after 1 and 2 months. The primary endpoint is changes in estimated glomerular filtration rate (eGFR) from baseline to month 24. Secondary endpoints include changes in home blood pressure (BP), ambulatory BP, proteinuria, urinary albumin/creatinine ratio, and composite renal events in 24 months. Inclusion criteria are: age 18-80 years, non-dialysis CKD patients with eGFR >30 mL/min/1.73 m2, home BP >130 mm Hg systolic or BP >80 mm Hg diastolic at the screening and randomisation, and 24 hour proteinuria <3.5 g. Principal exclusions are hypertensive crisis, transplantation, cancer, severe diabetes complications, hyperkalaemia and severe allergy. The required sample size was 511 patients for detecting a difference in the change of eGFR (one sided α=0.025, power 1-β=0.90). ETHICS AND DISSEMINATION BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT02646397.
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Calcium channel blockade blunts the renal effects of acute nitric oxide synthase inhibition in healthy humans.
Montanari, A, Lazzeroni, D, Pelà, G, Crocamo, A, Lytvyn, Y, Musiari, L, Cabassi, A, Cherney, DZI
American journal of physiology. Renal physiology. 2017;(5):F870-F878
Abstract
Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 μg·kg-1·min-1 NG-nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP (P < 0.005 vs. baseline), -10% GFR, -20% RBF, -49% UNaV (P < 0.001), and +120% U8-iso-PGF2αV (P < 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME (P > 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA, P > 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (-6%), RBF (-12%), and UNaV (-34%) were blunted vs. PL + l-NAME and LOS + l-NAME (P < 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%, P > 0.05 vs. baseline; P < 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability.
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Treatment of hypertensive patients with diabetes: beyond blood pressure control and focus on manidipine.
Saiz Satjes, M, Martinez-Martin, FJ
Future cardiology. 2016;(4):435-47
Abstract
Renin-angiotensin system inhibitors should be considered as the first-line therapy in the treatment of patients with hypertension and diabetes. However, most of the diabetic subjects with hypertension require at least two drugs to achieve blood pressure targets. The ACCOMPLISH trial suggested that the best combination in the treatment of high-risk hypertensive patients should include a renin-angiotensin system inhibitor and a dihydropyridine. However, not all dihydropyridines block the same receptors. Those dihydropyridines that block T-type calcium channel blockers may provide additional advantages. A number of studies suggest that compared with amlodipine, manidipine have the same antihypertensive efficacy, but with a lesser risk of ankle edema. In addition, manidipine, but not amlodipine, significantly reduces urinary albumin excretion rates.
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Comparative effect of fixed-dose combination tablets of candesartan cilexetil/amlodipine versus olmesartan medoxomil/azelnidipine on laboratory parameters in patients with hypertension: a retrospective cohort study.
Susa, N, Nishida, Y, Yada, Y, Nakayama, T, Asai, S, Takahashi, Y
Clinical and experimental hypertension (New York, N.Y. : 1993). 2016;(2):173-9
Abstract
We conducted a retrospective cohort study to evaluate and compare the long-term effects of two single-pill fixed-dose combinations (FDCs), candesartan/amlodipine and olmesartan/azelnidipine, on laboratory parameters in patients in routine clinical practice. We identified an equal number of new users (n = 182) of a candesartan/amlodipine (8/5 mg/day) FDC tablet (CAN/AML users) and a propensity-score matched cohort (n = 182) receiving an olmesartan/azelnidipine (20/16 mg/day) FDC tablet (OLM/AZ users). Generalized estimating equations were used to estimate and compare the effects of the drugs on serum levels of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid, sodium, potassium, aspartate aminotransferase, and alanine aminotransferase levels up to 12 months after the start of study drug administration. There was a significant increase of serum creatinine level and a significant decrease of eGFR from the baseline period to during the exposure period in both CAN/AML and OLM/AZ users, and a significant increase of BUN level in CAN/AML users. However, there were no significant differences in the mean changes of laboratory parameters between CAN/AML and OLM/AZ users. Our findings suggested that the effects of CAN/AML and OLM/AZ on laboratory parameters, including an unfavorable effect on renal function, were similar at least during 1 year of administration.
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10.
Binding mechanisms of 1,4-dihydropyridine derivatives to L-type calcium channel Cav1.2: a molecular modeling study.
Xu, L, Li, D, Tao, L, Yang, Y, Li, Y, Hou, T
Molecular bioSystems. 2016;(2):379-90
Abstract
L-type Ca(2+) channels (LTCCs), the heteromultimeric proteins, are associated with electrical signaling and provide the key link between electrical signals and non-electrical processes. 1,4-Dihydropyridine (DHP) derivatives are a major class of blockers for LTCCs, and have experienced widespread use in the treatment of cardiovascular diseases. However, the precise knowledge of the binding mechanism of these ligands to LTCCs at the atomic level has remained unknown because of the unavailability of the crystal structures of LTCCs. In this study, homology modeling, molecular docking, molecular dynamics (MD) simulations, free energy calculations and decomposition were employed to explore the structural requirement of the binding of DHP derivatives to human Cav1.2, a member of LTCCs. The binding conformations of the DHPs in the active site of Cav1.2 were predicted, and the rank of the binding free energies of Cav1.2/DHPs is generally consistent with the experimental data. The structural analysis shows that most studied ligands fit into a hydrophobic pocket formed by Phe1129, Ile1173, Phe1176, Met1177 and Met1509, and form aryl-aryl interaction with Phe1129 or Tyr1508. The consistency between the predictions and experimental data suggest that the developed model is reliable and can be used as a valuable platform for the structure-based design of new potent ligands of Cav1.2.