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Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension: A First-in-human, Concept-proven, Prospective, Dose-escalation, Multicenter Study.

ABSTRACT: The combination of low rather than high dose of dextromethorphan (DXM) with amlodipine (AM) could improve blood pressure (BP) reduction in hypertensive animals. The study aimed to evaluate the feasibility of different doses of DXM combined with standard AM treatment in clinical hypertension.This was a prospective, 14-week, dose-escalation, multicenter study. After 2-week run-in period with AM 5?mg/day, hypertensive patients who got the BP goal of 140/90?mmHg kept receiving AM monotherapy for another 12 weeks. The nonresponders, while kept on AM 5?mg/day, received additional DXM treatment for 3 sequential dose-titrated periods with initially 2.5?mg/day, followed by 7.5?mg/day, and finally 30?mg/day. Each period was for 4 weeks. The patients at BP goal after each treatment period were defined as the responders and kept on the same combination till the end of the study. The responder rate of each treatment period was recorded. The changes of BP and serum antioxidant/endothelial markers between week 14 and week 2 were evaluated.Of the 103 patients initially enrolled, 89 entered the treatment period. In the 78 patients completing the study, 31 (40%) at BP goal after 2-week AM run-in kept on AM monotherapy (DXM0). The addition of 2.5 (DXM2.5) and 7.5?mg/day (DXM7.5) of DXM enabled BP goal achievement in 22 (47%) nonresponders to AM monotherapy including 16 (29%) with DXM2.5 and 6 (18%) with DXM7.5. Only 4 patients (16%) reached BP goal with the combination of DXM 30?mg/day (DXM30). Overall, 73% of the 78 patients reached BP goal at the end of the 14-week study. Mean systolic BP was reduced by 7.9%?±?7.0% with DXM2.5 (P?

SUBMITTER: Yin WH

PROVIDER: S-EPMC4998419 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension: A First-in-human, Concept-proven, Prospective, Dose-escalation, Multicenter Study.

Yin Wei-Hsian WH Chen Pei P Yeh Hung-I HI Wang Kuo-Yang KY Hung Yi-Jen YJ Tseng Wei-Kung WK Wen Ming-Shien MS Wu Tao-Cheng TC Wu Chau-Chung CC Cheng Shu-Meng SM Chen Jaw-Wen JW

Medicine 20160301 12

The combination of low rather than high dose of dextromethorphan (DXM) with amlodipine (AM) could improve blood pressure (BP) reduction in hypertensive animals. The study aimed to evaluate the feasibility of different doses of DXM combined with standard AM treatment in clinical hypertension.This was a prospective, 14-week, dose-escalation, multicenter study. After 2-week run-in period with AM 5 mg/day, hypertensive patients who got the BP goal of 140/90 mmHg kept receiving AM monotherapy for ano ...[more]

PMID: 27015224

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Project description:To evaluate the blood pressure (BP) lowering efficacy and safety of CKD-828, a fixed-dose combination of S-amlodipine (the more active isomer of amlodipine besylate, which is calcium channel blocker) and telmisartan (long acting angiotensin receptor blocker), in patients with hypertension inadequately controlled with S-amlodipine monotherapy.Eligible patients (N=187) who failed to respond after 4-week S-amlodipine 2.5 mg monotherapy (sitting diastolic blood pressure [sitDBP] ?90 mmHg) to receive CKD-828 2.5/40 mg (n=63), CKD-828 2.5/80 mg (n=63), or S-amlodipine 2.5 mg (n=61) for 8 weeks. The primary efficacy endpoint, mean sitDBP change from baseline to Week 8, was compared between the combination (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) and S-amlodipine monotherapy groups. The safety was assessed based on adverse events, vital signs, and physical examination findings.After the 8-week treatment, changes in sitDBP/systolic BP (SBP) were -9.67±6.50/-12.89±11.78, -10.72±6.19/-13.79±9.41, and -4.93±7.26/-4.55±11.27 mmHg in the CKD-828 2.5/40 mg (P<0.0001/P<0.0001), CKD-828 2.5/80 mg (P<0.0001/P<0.0001), and S-amlodipine 2.5 mg (P<0.0001/P=0.0027) groups, respectively, which were all significant BP reductions. At Week 8, the CKD-828 2.5/40 mg (sitDBP/SBP: P=0.0002/P<0.0001) and CKD-828 2.5/80 mg (sitDBP/SBP: P=0.0001/P<0.0001) showed superior BP-lowering effects to S-amlodipine 2.5 mg (P<0.001). At Week 4, all groups showed significant antihypertensive effects but both CKD-828 combinations (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) exhibited superior BP-lowering effects to that of S-amlodipine 2.5 mg (sitDBP/SBP: P=0.0028/P=0.0001 and P<0.0001/P=0.0012, respectively). The adverse event incidence was significantly lower in the CKD-828 2.5/40 mg (9.52%, P=0.0086) than in the S-amlodipine 2.5 mg group (27.87%) and increasing the telmisartan dose induced no unexpected adverse events, suggesting the safety of CKD-828.CKD-828 is an effective and safe option for patients with inadequate responses to S-amlodipine monotherapy.

Project description:IntroductionCentral blood pressure (BP), an important measure of cardiovascular risk, has been shown to be effectively reduced by calcium channel blockade with amlodipine (AML) plus renin-angiotensin system blockade by the angiotensin-converting enzyme inhibitor, perindopril (PER). The aim of the SEVITENSION study was to compare the central effects of PER/AML against renin-angiotensin system blockade with the angiotensin II receptor blocker olmesartan (OLM) plus AML.MethodsIn this multicenter, parallel group, non-inferiority study, patients received AML 10 mg during a 2- to 4-week run-in before randomization to 24 weeks of double-blind treatment with the fixed-dose combination of OLM/AML 40/10 mg or PER/AML 8/10 mg. Hydrochlorothiazide was added at Weeks 4, 8, or 12 in patients with inadequate BP control. The primary efficacy variable was the absolute change in central systolic BP (CSBP) from baseline to the final examination, measured by radial artery applanation tonometry and analyzed by parametric analysis of covariance. Secondary variables included 24-h ambulatory and seated BP measurements as well as BP normalization.ResultsOf 600 patients enrolled, 486 were randomized (244 to OLM/AML 40/10 mg, 242 to PER/AML 8/10 mg). The reduction in CSBP was larger with OLM/AML (14.5 ± 0.83 mmHg) than with PER/AML (10.4 ± 0.84 mmHg). The between-group difference was -4.2 ± 1.18 mmHg with 95% confidence intervals (-6.48 to -1.83 mmHg) within the predefined non-inferiority margin (2 mmHg). An integrated superiority test confirmed that OLM/AML was superior to PER/AML (p < 0.0001) in reducing CSBP. The superiority of OLM/AML over PER/AML was also established for the majority of secondary efficacy variables; at the final examination, 75.6% of OLM/AML recipients achieved BP normalization (mean seated systolic BP/diastolic BP <140/90 mmHg) compared with 57.5% of PER/AML recipients (p < 0.0001).ConclusionThe combination of OLM/AML was superior to PER/AML in reducing CSBP and other efficacy measures, including a significantly higher rate of BP normalization.

Dataset Information

Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension: A First-in-human, Concept-proven, Prospective, Dose-escalation, Multicenter Study.

Publications

Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension: A First-in-human, Concept-proven, Prospective, Dose-escalation, Multicenter Study.

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