Third-generation Dihydropyridine Calcium Channel Blocker Research Articles

Azelnidipine treatment reduces the expression of Cav1.2 protein

AimsAzelnidipine, a third-generation dihydropyridine calcium channel blocker (DHP CCB), has a characteristic hypotensive effect that persists even after it has disappeared from the plasma, which is thought to be due to its high hydrophobicity. However, because azelnidipine is unique, it might have other unknown effects on L-type Cav1.2 channels that result in the long-lasting decrease of blood pressure. The aim of this study was to investigate the potential quantitative modification of Cav1.2 by azelnidipine. Main methodsHEK293 cells were used to express Cav1.2 channels. Immunocytochemical analysis was performed to detect changes in the surface expression of the pore-forming subunit of the Cav1.2 channel, Cav1.2α1c. Western blotting analysis was performed to evaluate changes in expression levels of total Cav1.2α1c and Cavβ2c. Key findingsThe surface expression of Cav1.2α1c was markedly reduced by treatment with azelnidipine, but not with other DHP CCBs (amlodipine and nicardipine). Results obtained with a dynamin inhibitor and an early endosome marker suggested that the reduction of surface Cav1.2α1c was not likely caused by internalization. Azelnidipine reduced the total amount of Cav1.2α1c protein in HEK293 cells and rat pulmonary artery smooth muscle cells. The reduction of Cav1.2α1c was rescued by inhibiting proteasome activity. In contrast, azelnidipine did not affect the amount of auxiliary Cavβ2c subunits that function as a chaperone of Cav1.2. SignificanceThis study is the first to demonstrate that azelnidipine reduces the expression of Cav1.2α1c, which might partly explain its long-lasting hypotensive effect.

Periodontal management of amlodipine-induced gingival hyperplasia in a hypertensive patient: A surgical approach

Background: Amlodipine is a third-generation dihydropyridine calcium channel blocker used to treat hypertension and angina. Gingival hyperplasia (GH) is an unwanted side effect associated with this therapy. It causes unsatisfactory esthetics, difficulty in maintaining good oral hygiene, abnormal tooth movement, and difficulty in mastication. GH can be managed by nonsurgical therapy alone or using a combination of nonsurgical and surgical therapy. Case Report: A 55-year-old female patient came to the clinical department of periodontology, University Hospital of Rabat, with a chief complaint of gingival enlargement. It was diagnosed and initially managed by nonsurgical periodontal treatment. Drug substitution and surgical intervention were executed. Regular supportive periodontal therapy showed a good and stable outcome over 2 years of follow-up. Conclusion: Amlodipine-induced GH can be managed using periodontal procedures combined with good oral hygiene and regular supportive periodontal therapy.

Lacidipine Attenuates Apoptosis via a Caspase-3 Dependent Pathway in Human Kidney Cells

Background: Acute kidney injury (AKI) is common in hospitalised patients and has a poor prognosis. Therefore, new therapeutic strategies are anticipated. Lacidipine, a novel third-generation dihydropyridine calcium channel blocker, has been demonstrated effective for hypertension. However, its potential effect on renal injury remains unknown. In the present study, an in vitro model of renal ischemia reperfusion (I/R) injury was used to investigate the protective effect and underlying mechanisms of lacidipine on human kidney cell (HKC) apoptosis. Methods: HKCs were subjected to adenosine triphosphate (ATP) depletion and recovery (0.01 µM AA, depletion for 2 h and recovery for 30 min), with or without lacidipine (1 µM and 10 µM, 24 h), then cell viability and apoptosis were determined using the cell counting kit-8 (CCK-8) assay and Annexin V flow cytometry. The expression of Bcl-2, Bax, and cytochrome c (cyt c) was examined by western blot. Results: Antimycin A (AA) was found to induce apoptosis of HKCs. The proportion of early apoptosis and activity of caspase-3 peaked at 30 min after ATP depletion and recovery and were attenuated by lacidipine. The expression of cyt c and Bax was decreased, while that of Bcl-2 was increased significantly in lacidipine treated group. Conclusion: We conclude that lacidipine protects HKCs against apoptosis induced by ATP depletion and recovery by regulating the caspase-3 pathway.

Comparison of Pharmacokinetic Characteristics and the Safety between Amlodipine Maleate Tablet 5 mg and Amlodipine Besylate Tablet 5 mg

1 Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Korea, University of Ulsan College of Medicine, School of Military Medicine, The First Republic of Korea Army, Department of Clinical Pharmacology and Therapeutics, Inje University Pusan Paik Hospital, Pusan, Korea, 5 Division of Clinical Pharmacology, Clinical Trials Center, Pusan National University Hospital, Division of Clinical Pharmacology, Clinical Trial Center, Samsung Medical Center, Technical research center, CKD research institute, Chong Kun Dang Pharmaceutical Co, Ltd Background: Amlodipine is a third-generation dihydropyridine calcium channel blocker for treating hypertension. Though marketed primarily as a besylate salt, there have been some efforts to find other comparable salts. Among them, maleate is the salt that has been considered favorable for many drugs. The aim of this study was to compare the pharmacokinetics, as well as safety and tolerability of amlodipine maleate with amlodipine besylate. Methods: This study was open, randomized, two-period crossover design investigated in twelve healthy male volunteers over a 144 h period after administrating two forms of amlodipine 5 mg, respectively. Each period was separated with 2 weeks. Plasma concentrations of amlodipine were determined by liquid chromatography-tandem mass spectrometry. Safety profiles were assessed by vital signs, physical examinations, electrocardiograms, laboratory testing and adverse events monitoring. Results: All subjects were completed this study. Geometric mean ratios (GMRs) of amlodipine maleate/amlodipine besylate of Cmax and AUClast for amlodipine were 0.92 (90 % confidence interval, 0.81 ∼ 1.05) and 1.05 (0.96 ∼ 1.16), respectively. No serious adverse events were reported, and no clinically relevant changes were observed in safety profiles during this trial. Conclusion: Pharmacokinetics, tolerability and the safety were comparable between amlodipine maleate and amlodipine besylate in healthy individuals.

Comparative study on antioxidant effects and vascular matrix metalloproteinase-2 downregulation by dihydropyridines in renovascular hypertension

The vascular remodeling associated with hypertension involves oxidative stress and enhanced matrix metalloproteinases (MMPs) expression/activity, especially MMP-2. While previous work showed that lercanidipine, a third-generation dihydropyridine calcium channel blocker (CCB), attenuated the oxidative stress and increased MMP-2 expression/activity in two-kidney, one-clip (2K1C) hypertension, no previous study has examined whether first- or second-generation dihydropyridines produce similar effects. We compared the effects of nifedipine, nimodipine, and amlodipine on 2K1C hypertension-induced changes in systolic blood pressure (SBP), vascular remodeling, oxidative stress, and MMPs levels/activity. Sham-operated and 2K1C rats were treated with water, nifedipine 10 mg/kg/day, nimodipine 15 mg/kg/day, or amlodipine 10 mg/kg/day by gavage, starting 3 weeks after hypertension was induced. SBP was monitored weekly. After 6 weeks of treatment, quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin-stained sections. Aortic and systemic reactive oxygen species levels were measured by using dihydroethidine and thiobarbituric acid-reactive substances (TBARs), respectively. Aortic MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Nifedipine, nimodipine, or amlodipine attenuated the increases in SBP in hypertensive rats by approximately 17% (P < 0.05) and prevented vascular hypertrophy (P < 0.05). These CCBs blunted 2K1C-induced increases in vascular oxidative stress and plasma TBARs concentrations (P < 0.05). All dihydropyridines attenuated the increases in aortic MMP-2 levels and activity associated with 2K1C hypertension. These findings suggest lack of superiority of one particular dihydropyridine, at least with respect to antioxidant effects, MMPs downregulation, and inhibition of vascular remodeling in hypertension.

Clevidipine: A new intravenous option for the management of acute hypertension

The pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and place in therapy of clevidipine are reviewed. Clevidipine is a new lipophilic, short-acting, third-generation dihydropyridine calcium channel blocker (CCB) approved for use in the management of acute hypertension when oral agents are not feasible. It exerts its hemodynamic effects through selective arterial vasodilation without effects on the venous circulation. Clevidipine has a half-life of approximately two minutes after i.v. administration, resulting in very rapid onset and offset of antihypertensive action. Unlike many current i.v. antihypertensive agents that are metabolized by the kidneys or liver, clevidipine is metabolized in the blood and tissues and does not accumulate in the body. Clevidipine does not appear to inhibit or induce cytochrome P-450 isoenzymes. Several Phase III clinical trials have reported the clinical efficacy and safety of clevidipine in patients with severe hypertension and in cardiac surgical patients with perioperative hypertension. The most frequent adverse events reported in clinical trials of clevidipine were headache, nausea, and vomiting. Risk of rebound hypertension, especially in patients not transitioned from clevidipine to oral antihypertensive therapy after prolonged infusions, should be monitored for at least eight hours after the drug is discontinued. Clevidipine, a novel third-generation dihydropyridine CCB, has demonstrated efficacy and safety in patients with acute hypertension and preoperative, perioperative, and postoperative hypertension. While its short duration of action and short half-life are appropriate for use in acute settings, more information on its safety is needed to assess its appropriate use in therapy.

New Drug Approvals: Clevidipine: An Ultra Short-Acting Calcium Channel Antagonist for Acute Hypertension

To review the safety, efficacy, and pharmacologic characteristics of clevidipine, a new ultra short-acting intravenous antihypertensive agent for the treatment of moderate-to-severe hypertension. A literature search was conducted through MEDLINE (1966-March 2009), International Pharmaceutical Abstracts (1970-March 2009), and EMBASE (1988-March 2009) using the search terms clevidipine, H324/38, hypertension, and hypertensive crisis. Available studies, abstracts, and review articles published in English that evaluated the pharmacology, pharmacokinetics, safety, and clinical efficacy of clevidipine were reviewed and critically evaluated. Clevidipine is a new third-generation dihydropyridine calcium-channel blocker available for intravenous management of moderate-to-severe hypertension. Clevidipine is an ultra short-acting, selective arteriolar vasodilator that acts similar to other L-type dihydropyridine calcium-channel blockers by inhibiting influx of extracellular calcium into the vascular smooth muscle. Its safety and efficacy have been primarily evaluated in the perioperative setting in patients undergoing cardiac surgery requiring management of elevated blood pressure. In comparison to most other intravenous antihypertensives, clevidipine has a rapid onset of action, is ultra short-acting, easily titratable with a predictable dose response, and is void of drug-drug interactions and need for dose adjustment in patients with hepatic or renal insufficiency, thus making it a valuable antihypertensive in both the intraoperative and critical care settings. In clinical trials, clevidipine was well tolerated at infusion rates from 2-32 mg per hour, for up to 72 hours. Clevidipine is the first intravenous antihypertensive approved by the Food and Drug Administration in nearly a decade. Based on available published clinical trials, clevidipine appears to be safe and effective in the acute management of moderate-to-severe elevations in blood pressure and a viable alternative to other agents such as nitroglycerin, sodium nitroprusside, and nicardipine.

Treatment of Acute Postoperative Hypertension in Cardiac Surgery Patients: An Efficacy Study of Clevidipine Assessing Its Postoperative Antihypertensive Effect in Cardiac Surgery-2 (ESCAPE-2), a Randomized, Double-Blind, Placebo-Controlled Trial

Acute postoperative hypertension is a well-known complication of cardiac surgery and is associated with postoperative morbidity. Clevidipine, an ultrashort-acting, third-generation dihydropyridine calcium channel blocker, exerts vascular-selective, arterial-specific vasodilation to decrease arterial blood pressure without negatively impacting cardiac function. In this double-blind, placebo-controlled trial, we examined the efficacy and safety of clevidipine in treating postoperative hypertension in cardiac surgery patients. Two hundred six patients undergoing cardiac surgery were randomized preoperatively. Of these, 110 met postrandomization inclusion criteria for the study [systolic blood pressure (SBP) >or=140 mm Hg within 4 h of admission to a postoperative setting, and clinically assessed as needing SBP reduction by >or=15% from baseline]. Patients received an infusion of either clevidipine (0.4-8.0 microg kg(-1) min(-1)) or 20% lipid emulsion (placebo) for 30 min to a maximum of 1 h unless treatment failure occurred sooner. The primary end point was the incidence of treatment failure, defined as the inability to decrease SBP by >or=15% from baseline, or the discontinuation of study treatment for any reason within the 30-min period after study drug initiation. Clevidipine-treated patients had a significantly lower incidence of treatment failure than placebo patients [8.2% (5 of 61) vs 79.6% (39 of 49), P < 0.0001]. Treatment success was achieved in 91.8% of clevidipine-treated patients. Median time to target SBP with clevidipine was 5.3 min (95% confidence interval, 4-7 min). No clinically significant increase in heart rate from baseline was observed. Adverse event rates were similar for both treatment groups. Clevidipine is effective and safe in the rapid treatment of acute postoperative hypertension after cardiac surgery.

Clinical perspectives in the prevention and treatment of chronic nephropathy, including an overview of the DEMAND Study

Background: The prevalence of chronic renal disease is increasing: 1.8 million people worldwide are affected by end-stage renal disease (ESRD) and need dialysis. Preventing the progression of renal disease is therefore important, particularly in patients with type 2 diabetes mellitus (DM), since the number of diabetic patients requiring dialysis--as well as the relative costs of such treatment--are increasing rapidly. Objective: The goal of this article was to provide a summary of how effective control of systemic blood pressure and proteinuria can slow the progression of ESRD. An overview of the design of the ongoing Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) study is also given. Methods: A literature search of MEDLINE was conducted for the period 1992 through 2005, using the following search terms: diabetes, microalbuminuria, ESRD, hypertension, manidipine, and proteinuria control. Results: Optimal blood pressure and proteinuria control, as well as glycemic and lipid control, are of utmost importance in minimizing the incidence and progression of nephropathy and cardiovascular diseases in patients with type 2 DM. Once overt nephropathy occurs, renal function will decline linearly with time until the patient needs renal replacement therapy, either dialysis or renal transplantation. It should be noted, however, that all patients do not lose renal function at the same rate. Therefore, the aim of treatment is to modify the rate of disease progression from a rapid pattern to a very slow one. The effects of angiotensin-converting enzyme (ACE) inhibitor therapy on proteinuria and the progressive decline in glomerular filtration rate (GFR) in diabetic and nondiabetic patients have been addressed in several trials, including the Ramipril Efficacy in Nephropathy core study. This study showed that at comparable levels of blood pressure control, ACE inhibitors were more effective than conventional antihypertensive treatment at reducing proteinuria, slowing the rate of GFR decline, and limiting the progression of ESRD. The goal of the DEMAND study is to assess the efficacy of the third-generation dihydropyridine calcium channel blocker manidipine, given in association with delapril, an ACE inhibitor, in the treatment of diabetic nephropathy. The results are expected in 2008. Conclusions: The nephroprotective treatment of diabetic patients should start before they develop proteinuria, both to avoid ESRD and to prevent cardiovascular disease. In this respect, the goal of the DEMAND study is to determine if the combined therapy between delapril, an ACE inhibitor, and manidipine, a dihydropyridine calcium channel blocker, slows the rate of GFR decline more effectively than conventional antihypertensive therapy in hypertensive type 2 diabetic patients with normo- or microalbuminuria.