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Cilnidipine, a dual L-/N-type calcium channel blocker, dilates both efferent and afferent arterioles and is renoprotective. Our multi-center, open-labeled, and randomized trial compared the antiproteinuric effect of cilnidipine with that of amlodipine in hypertensive patients with kidney disease. A group of 339 patients, already receiving renin–angiotensin system inhibitor treatment, were randomly assigned to cilnidipine or amlodipine. The primary endpoint was a decrease in the urinary protein to creatinine ratio. After 1-year of treatment, systolic and diastolic blood pressures were significantly reduced in both groups which did not differ between them. The urinary protein to creatinine ratio significantly decreased in the cilnidipine compared to the amlodipine group. Cilnidipine exerted a greater antiproteinuric effect than amlodipine even in the subgroup whose blood pressure fell below the target level. This study suggests that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients when coupled with a renin–angiotensin system inhibitor.

This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension. In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups. Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period. Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension. UMIN 000006081.

Background Essential hypertension has been extensively reported to cause endothelial dysfunction. The aim of this study was to evaluate the effects of barnidipine or lercanidipine, in addition to losartan, on some parameters indicative of endothelial damage and oxidative stress in hypertensive, type 2 diabetic patients. Methods One hundred and fifty one patients were randomised to barnidipine, 20 mg/day, or lercanidipine, 20 mg/day, both in addition to losartan, 100 mg/day, for 6 months. We assessed BP every month, in addition, patients underwent ambulatory blood pressure monitoring (ABPM). We also assessed: fasting plasma glucose (FPG), glycated hemoglobin (HbA 1c ), some markers such as high-sensitivity C-reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α), metalloproteinase-2 (MMP-2) and -9 (MMP-9), soluble vascular adhesion protein-1 (sVCAM-1), soluble intercellular adhesion protein-1 (sICAM-1), isoprostanes and paraoxonase-1 (PON-1). Results Both barnidipine and lercanidipine resulted in a significant reduction in blood pressure, even if the reduction obtained with barnidipine + losartan was greater than that obtained with lercanidipine + losartan. Data recorded with ABPM also showed a similar trend. Barnidipine + losartan reduced the levels of Hs-CRP, TNF-α, sVCAM-1, sICAM-1, and isoprostanes both compared to baseline and to lercanidipine + losartan. Conclusions Barnidipine + losartan gave an improvement of some parameters indicative of endothelial damage and oxidative stress in diabetic and hypertensive patients. Trial registration NCT02064218 , ClinicalTrials.gov

The objective of this study was to evaluate the efficacy and safety of the lercanidipine/valsartan combination compared with lercanidipine monotherapy in patients with hypertension. Part 1 of this study was the randomized, multicenter, double-blind, parallel group, Phase III, 8-week clinical trial to compare superiority of lercanidipine 10 mg/valsartan 80 mg (L10/V80) and lercanidipine 10 mg/valsartan 160 mg (L10/V160) combinations with lercanidipine 10 mg (L10) monotherapy. At screening, hypertensive patients, whose diastolic blood pressure (DBP) was >90 mm Hg after 4 weeks with L10, were randomized to 3 groups of L10, L10/V80, and L10/V160. The primary end point was the change in the mean sitting DBP from baseline (week 0) after 8 weeks of therapy. Patients who were randomly assigned to L10/V160 and whose mean DBP was still ≥ 90 mm Hg in part 1 were enrolled to the up-titration extension study with lercanidipine 20 mg/valsartan 160 mg (L20/V160) (part 2). Of 772 patients screened, 497 were randomized to 3 groups (166 in the L10 group, 168 in the L10/V80 group, and 163 in the L10/V160 group). Mean (SD) age was 55 (9.9) years, and male patients comprised 69%. The mean (SD) baseline systolic blood pressure (SBP)/DBP were 148.4 (15.1)/94.3 (9.5) mm Hg. No significant differences were found between groups in baseline characteristics except the percentages of previous history of antihypertensive medication. The primary end points, the changes of mean (SD) DBP at week 8 from the baseline were −2.0 (8.8) mm Hg in the L10 group, −6.7 (8.5) mm Hg in L10/V80 group, and −8.1 (8.4) mm Hg in L10/V160 group. The adjusted mean difference between the combination groups and the L10 monotherapy group was −4.6 mm Hg (95% CI, −6.5 to −2.6; P < 0.001) in the L10/V80 group and −5.9 mm Hg (95% CI, −7.9 to −4.0, P < 0.001) in the L10/V160 group, which had significantly greater efficacy in BP lowering. A total of 74 patients were enrolled in the part 2 extension study. Changes of mean (SD) DBP and SBP from week 8 to week 12 and week 16 were −5.6 (7.9)/−8.0 (12.0) mm Hg and −5.5 (7.0)/−8.5 (11.3) mm Hg, respectively. For evaluation of the safety profile, the frequencies of adverse events between groups were also not significantly different. The most frequently reported adverse events were headache (6 cases, 20.7%) in the L10 group, dizziness (8 cases, 16.3%) in L10/V80 group, and nasopharyngitis (3 cases, 9.4%) in L10/V160 group, and the incidences of adverse events were not different between groups. Treatment of L10/V80 or L10/V160 combination therapy resulted in significantly greater BP lowering compared with L10 monotherapy. Moreover, the L20/V160 high dose combination had additional BP lowering effect compared with nonresponders with the L10/V160 combination. ClinicalTrials.gov: NCT01928628.

Purpose Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion. Method Doses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination. Results Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline. Conclusion This study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.

Irrespective of their clinical relevance, side effects cannot be considered a negligible problem in antihypertensive therapy. The aim of this trial was to evaluate the tolerability profile of lercanidipine with that of two other calcium antagonists (amlodipine and lacidipine) in elderly hypertensives. In a multicenter, double-blind, parallel study 828 elderly (aged ≥60 years) hypertensives were randomized to lercanidipine 10 mg/day ( n = 420), amlodipine 5 mg/day ( n = 200), or lacidipine 2 mg/day ( n = 208) (ratio 2:1:1). If blood pressure (BP) control was unsatisfactory (systolic BP/diastolic BP ≥140/90 mm Hg), the dose of the double-blind medication was doubled and, as a further step, enalapril or atenolol (plus diuretic, if needed) was added. Patients were treated for an average of 12 months. Amlodipine patients had significantly ( P < .001) higher rates of edema (19%) and of early study discontinuations due to edema (8.5%) compared with lercanidipine (9% and 2.1%) and lacidipine patients (4% and 1.4%). Similarly, edema-related symptoms (lower limb swelling and heaviness) occurred significantly ( P < .01) more often with amlodipine (50% and 45%, respectively) than with lercanidipine (35% and 33%) and lacidipine (34% and 31%). Most edema cases occurred in the first 6 months, a between-treatment difference being evident since beginning of treatment. Other drug-related adverse events did not differ between treatments. Blood pressure was equally and effectively reduced in the three groups. The two lipophilic dihydropyridine calcium antagonists, lercanidipine and lacidipine, have an antihypertensive effect comparable to that of amlodipine, but a better tolerability profile.

A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was −23.6/−14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and −20.3/−13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (−15.7/−9.9 mm Hg in OLM (20); −15.0/−9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (−22.1/−13.5 and −18.2/−10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (−12.1/−6.9 and −12.0/−6.9 mm Hg). The proportion of patients achieving the SeBP goal (<130/85 mm Hg for normal BP or <140/90 mm Hg for high-normal BP) was significantly higher in the O/A (20/16) combination group than in the monotherapy groups. The incidence of adverse events was similar in the O/A combination groups and the monotherapy groups. These results showed that combination therapy with O/A was well tolerated and exerted a stronger antihypertensive effect compared with monotherapy with OLM or AZL in patients with essential hypertension.

Background and Objective : Metabolic syndrome is common in patients with hypertension and increases the risk of developing diabetes mellitus. The objective of this study (the MARCADOR study) was to compare the effects of manidipine 20 mg with the extemporary combination of manidipine 10mg/lisinopril 10 mg, amlodipine 10 mg and telmisartan 80 mg on insulin sensitivity, as well as metabolic, inflammatory and prothrombotic markers, in hypertensive non-diabetic patients with metabolic syndrome. Methods : This study had a prospective, randomized, open-label, blinded endpoint (PROBE) design. A total of 120 patients aged 35–75 years with stage I—II essential hypertension (systolic blood pressure [BP] 140–179 mmHg, diastolic BP 90–109 mmHg) and metabolic syndrome were recruited from general practitioner clinics in Northern Gran Canaria Island, Spain and randomized to receive amlodipine 10 mg (n = 30), telmisartan 80 mg (n = 30), manidipine 20 mg (n = 30) or (low-dose) manidipine 10 mg/lisinopril 10 mg (n=30), all administered once daily. At baseline and after 14 weeks of treatment, BP, insulin sensitivity, lipid profile, and albumin and metanephrin excretion as well as several other metabolic, inflammatory, prothrombotic and growth/adhesion markers were measured. The primary endpoint was the change in insulin sensitivity. Results : A total of 115 patients completed the study. All treatments significantly lowered BP from baseline. Compared with amlodipine, manidipine had significantly superior effects (p<0.05) on insulin resistance (−26.5% vs −3.0%), albumin/creatinine ratio (−28.2% vs −3.6%), low-density lipoprotein (LDL) cholesterol (−6.8% vs +1.7%), and several other metabolic, inflammatory and prothrombotic markers. Manidipine was associated with a slightly greater increase in insulin sensitivity than manidipine/lisinopril, but manidipine/lisinopril was significantly more effective than manidipine and telmisartan for improving a number of metabolic, inflammatory, prothrombotic and growth/adhesion markers. Amlodipine was associated with a significantly greater incidence of adverse effects compared with telmisartan, manidipine and manidipine/lisinopril (26.7% vs 3.3%, 3.3% and 13.3%, respectively). Conclusion : In patients with hypertension and metabolic syndrome, manidipine, both alone and in combination with the ACE inhibitor lisinopril, is significantly superior to amlodipine for improving insulin sensitivity as well as several metabolic, inflammatory and prothrombotic markers. Furthermore, the combination of manidipine and lisinopril appears to have greater efficacy than manidipine alone and telmisartan with respect to the improvement of metabolic, inflammatory and prothrombotic markers.

Use of the combination of an angiotensinconverting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) is considered a rational approach in patients whose hypertension is not controlled by monotherapy, providing better blood pressure (BP) control than the individual components with a lower incidence of adverse effects. In particular, such combinations have been found to reduce the incidence of ankle edema, the most common adverse effect of dihydropyridine annhypertensives. The present study was undertaken to evaluate the effect on the development of ankle edema of adding the ACEI delapril to the CCB manidipine in patients with mild to moderate essential hypertension. Patients between the ages of 30 and 70 years who had mild to moderate hypertension (diastolic BP [DBP] >90 and <110 mm Hg) were included in the study. After a 4-week placebo run-in period, eligible patients were randomized to receive 6 weeks each of manidipine 10 mg/d, delapril 30 mg/d, and both in a crossover fashion. There was a 2-week washout period between treatments. Ankle edema was assessed based on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). Sitting BP, AFV, and PSTP were measured at the end of the placebo run-in period and the end of each active-treatment period. The study enrolled 40 patients with previously untreated hypertension (21 women, 19 men). Both manidipine and delapril monotherapy were associated with significant reductions from baseline in systolic BP (SBP) (mean [SD], -17.3 [4] and -14.8 [4] mm Hg, respectively; both, P < 0.01) and DBP (-14.6 [3] and -12.9 [3] mm Hg; both, P < 0.01). Compared with monotherapy, the combination of manidipine and delapril was associated with greater reductions from baseline in SBP (-21.8 [5] mm Hg; P < 0.001) and DBP (-18.6 [4] mm Hg; P < 0.001). Manidipme monotherapy was associated with significant increases from baseline in both AFV (7.9%; P < 0.001) and PSTP (36.6%; P < 0.01). Compared with manidipine alone, the combination of manidipine and delapril was associated with less pronounced increases in AFV (3.3%; P < 0.05) and PSTP (10.4%; P < 0.05). Ankle edema was clinically evident in 3 patients after receipt of manidipine monotherapy and in 1 patient after receipt of combination treatment. In these patients with mild to moderate essential hypertension, the addition of delapril to manidipine partially counteracted the manidipine-induced microcirculatory changes responsible for ankle edema.

Objective: The aim of this study was to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and its active M-1 metabolite in healthy Chinese men. Methods: This Phase I, randomized, open-label, single- and multiple-dose study included healthy, nons-moking male volunteers aged 18 to 45 years. In the single-dose study, subjects were randomly assigned to receive oral sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. In the multiple-dose study, volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study received this dose for 7 days. In the single-dose study, blood samples for the PK analyses were obtained immediately before dosing and at regular intervals up to 36 hours after dosing. In the multiple-dose study, predose blood samples were collected on days 4 through 7; on the last day of treatment, blood samples were drawn at the same times as in the single-dose study. Plasma concentrations of aranidipine and M-1 were determined using a high-performance liquid chromatography method with tandem mass-spectrometric detection. For the PD analyses, blood pressure (BP) and heart rate were measured before dosing, at regular intervals up to 24 hours after dosing, and after the final dose during repeated administration. Tolerability was assessed throughout the study, based on adverse events, physical examinations, electrocardiography, vital signs, and laboratory tests. Results: The study enrolled 30 healthy Chinese men (mean [SD] age, 23 [2] years; mean body weight, 66 [7] kg; mean height, 174 [6] cm). In the single-dose study, the mean t 1/2 for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; mean T max was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; mean C max was 1.1 (0.6), 2.4 (0.8), and 4.0 (2.0) μg/L; and mean AUC last was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) μg · h/L. There were no significant differences in any PK parameter between dose groups. For M-1, the corresponding values were 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours for t 1/2; 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours for T max; 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) μg/L for C max; and 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) μg · h/L for AUC last. Only dose-normalized Cmax and AUC last differed significantly between dose groups ( P < 0.001 and P = 0.018, respectively). After multiple doses, the mean values for t 1/2, T max, C max, and AUC 0-∞ for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) μg/L, and 13.8 (3.6) μg · h/L, respectively. Repeated oral administration of aranidipine 10 mg was associated with a significant increase in AUC last ( P = 0.027). The corresponding values for M-1 were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) μg/L, and 381.8 (161.2) μg · h/L. There were no significant differences between dose groups in any PK parameter for M-1 after single or multiple doses. In the PD analyses, the mean change from baseline in diastolic BP was statistically significant in all groups ( P < 0.01) except the aranidipine 10-mg group in the single-dose study. Three volunteers (10%) reported adverse events after administration of a single dose: headache (10-mg group), palpitations (20-mg group), and dizziness (20-mg group). The headache and palpitations were considered possibly related to study drug. Conclusions: The results of this small study in healthy Chinese men suggest that the PK properties of aranidipine were linear with respect to dose, whereas the PK properties of the active M-1 metabolite were not fully linear. There was no apparent accumulation of aranidipine or M-1 with administration of single and multiple doses. Aranidipine was generally well tolerated.