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Combination therapy with an Xa inhibitor and antihypertensive agent improved anticoagulant activity in patients with nonvalvular atrial fibrillation: the hypertension and atrial fibrillation treated by rivaroxaban for the morning and night with sYnergy with calcium antagonists (HARMONY) study.
Kabutoya, T, Ohmori, T, Fujiwara, T, Kario, K
Clinical and experimental hypertension (New York, N.Y. : 1993). 2020;(4):365-370
Abstract
Background: Anticoagulant activity and blood pressure increase in the morning. The aim of this study was to evaluate changes of anticoagulant activity, blood pressure and target organ damage in patients with nonvalvular atrial fibrillation (AF) given combination treatment with Xa inhibitor and antihypertensive agent.Methods: We enrolled 72 patients with nonvalvular AF. Rivaroxaban (10-15 mg) was continuously administered once daily over 8 weeks (study period I). For subjects (n = 50) who exhibited uncontrolled morning hypertension (home systolic blood pressure [SBP]≥125 mmHg) at the end of study period I (at 8 weeks), nifedipine CR (20-40 mg) was added at bedtime, and rivaroxaban administration was continued an additional 8 weeks. We assessed prothrombin fragment 1 + 2 (optimal range: 69-229 pmol/L) and D-dimer (negative D-dimer measurement: <1.0 μg/mL).Results: The percentage of patients with optimal-range prothrombin fragment 1 + 2 was significantly increased at 4 weeks compared to baseline (70.8% vs. 86.1%, p = .033). In period II, office and home morning SBP were reduced at 12 compared to 8 weeks (office SBP: 135.2 ± 15.7 vs. 125.6 ± 18.4mmHg, p < .001; home morning SBP: 133.5 ± 10.5 vs. 119.9 ± 12.1mmHg, p<.001).The percentage of patients with negative D-dimer was increased at 8 weeks compared to baseline (92% vs. 100%, p = .044), and remained at 100% at 16 weeks.Conclusions: Xa inhibitor therapy improved anticoagulant activity, and additional antihypertensive therapy maintained the anticoagulant activity in patients with nonvalvular AF.
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Effect of Calcium-Channel Blockade on the Cold-Induced Vasodilation Response.
Milliner, BHA, Brant-Zawadzki, G, McIntosh, SE
Wilderness & environmental medicine. 2020;(3):312-316
Abstract
INTRODUCTION Cold-induced vasodilation (CIVD) is seen in the extremities during exposure to cold. A strong vasodilation response has been associated with a decreased risk of cold injury. Increasing CIVD might further decrease this risk. The calcium-channel blocker nifedipine causes vasodilation and is used to treat Raynaud's syndrome and chilblains. Nifedipine is also used for high altitude pulmonary edema and could potentially serve a dual purpose in preventing frostbite. The effects of nifedipine on CIVD have not been studied. METHODS A double-blind crossover study comparing nifedipine (30 mg SR (sustained release) orally twice daily) to placebo was designed using 2 sessions of 4 finger immersion in 5°C water, with 24 h of medication pretreatment before each session. Finger temperatures were measured via nailbed thermocouples. The primary outcome was mean finger temperature; secondary outcomes were mean apex and nadir temperatures, first apex and nadir temperatures, subjective pain ranking, and time of vasodilation onset (all presented as mean±SD). RESULTS Twelve volunteers (age 29±3 [24-34] y) completed the study. No significant difference in finger temperature (9.2±1.1°C nifedipine vs 9.0±0.7°C placebo, P=0.38) or any secondary outcome was found. Pain levels were similar (2.8±1.6 nifedipine vs 3.0±1.5 placebo, P=0.32). The most common adverse event was headache (32% of nifedipine trials vs 8% placebo). CONCLUSIONS Pretreatment with 30 mg of oral nifedipine twice daily does not affect the CIVD response in healthy individuals under cold stress.
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A randomized controlled trial on the blood pressure-lowering effect of amlodipine and nifedipine-GITS in sustained hypertension.
Huang, QF, Sheng, CS, Li, Y, Dou, Y, Zheng, MS, Zhu, ZM, Wang, JG, ,
Journal of clinical hypertension (Greenwich, Conn.). 2019;(5):648-657
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Abstract
In a multicenter, randomized trial, we investigated whether the long half-time dihydropyridine calcium channel blocker amlodipine was more efficacious than the gastrointestinal therapeutic system (GITS) formulation of nifedipine in lowering ambulatory blood pressure (BP) in sustained hypertension (clinic systolic/diastolic BP 140-179/90-109 mm Hg and 24-hour systolic/diastolic BP ≥ 130/80 mm Hg). Eligible patients were randomly assigned to amlodipine 5-10 mg/day or nifedipine-GITS 30-60 mg/day. Ambulatory BP monitoring was performed for 24 hours at baseline and 4-week treatment and for 48 hours at 8-week treatment with a dose of medication missed on the second day. After 8-week treatment, BP was similarly reduced in the amlodipine (n = 257) and nifedipine-GITS groups (n = 248) for both clinic and ambulatory (24-hour systolic/diastolic BP 10.3/6.5 vs 10.9/6.3 mm Hg, P ≥ 0.24) measurements. However, after missing a dose of medication, ambulatory BP reductions were greater in the amlodipine than nifedipine-GITS group, with a significant (P ≤ 0.04) between-group difference in 24-hour (-1.2 mm Hg) and daytime diastolic BP (-1.5 mm Hg). In conclusion, amlodipine and nifedipine-GITS were efficacious in reducing 24-hour BP. When a dose of medication was missed, amlodipine became more efficacious than nifedipine-GITS.
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Proposed Dynamics of CDB3 Activation in Human Erythrocytes by Nifedipine Studied with Scanning Flow Cytometry.
Yastrebova, ES, Konokhova, AI, Strokotov, DI, Karpenko, AA, Maltsev, VP, Chernyshev, AV
Cytometry. Part A : the journal of the International Society for Analytical Cytology. 2019;(12):1275-1284
Abstract
Nifedipine is calcium channels and pumps blocker widely used in medicine. However, mechanisms of nifedipine action in blood are not clear. In particular, the influence of nifedipine on erythrocytes is far from completely understood. In this work, applying scanning flow cytometry, we observed experimentally for the first time the dynamics behind a significant increase of HCO3- /Cl- transmembrane exchange rate of CDB3 (main anion exchanger, AE1, Band 3, SLC4A1) of human erythrocytes in the presence of nifedipine in blood. It was found that the rate of CDB3 activation is not limited by the rate of nifedipine binding and/or Ca2+ transport. In order to explain the experimental data, we suggested a kinetic model assuming that the rate of CDB3 activation is limited by the dynamics of the balance between two intracellular processes (1) the activation of CDB3 limited by its interaction with intracellular Ca2+ , and (2) the spontaneous deactivation of CDB3. Thus the use of scanning flow cytometry allowed to clarify quantitatively the molecular kinetic mechanism of nifedipine action on human erythrocytes. In particular, the efficiency (~30) and rates of activation (~0.3 min-1 ) and deactivation (~10-3 min-1 ) of CDB3 in human erythrocytes was evaluated for two donors. © 2019 International Society for Advancement of Cytometry.
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Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease.
Farrah, TE, Anand, A, Gallacher, PJ, Kimmitt, R, Carter, E, Dear, JW, Mills, NL, Webb, DJ, Dhaun, N
Hypertension (Dallas, Tex. : 1979). 2019;(2):323-330
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Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.
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Blood pressure-lowering effects of nifedipine/candesartan combinations in high-risk individuals: subgroup analysis of the DISTINCT randomised trial.
Mancia, G, Cha, G, Gil-Extremera, B, Harvey, P, Lewin, AJ, Villa, G, Kjeldsen, SE
Journal of human hypertension. 2017;(3):178-188
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The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS-Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate<90 ml min-1, n=422), type 2 diabetes mellitus (n=202), hypercholesterolaemia (n=206) and cardiovascular (CV) risk factors (n=971), as well as the impact of gender, age and body mass index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a dose-response effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C combinations in each high-risk subgroup. The benefits of combination therapy vs monotherapy were additionally observed in patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy.
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White coat effect in hypertensive patients: the role of hospital environment or physician presence.
Wang, XX, Shuai, W, Peng, Q, Li, JX, Li, P, Cheng, XS, Su, H
Journal of the American Society of Hypertension : JASH. 2017;(8):498-502
Abstract
This study was to evaluate the role of hospital environment or physician presence for white coat effect (WCE) in hypertensive patients. At first, 54 hypertensive outpatients diagnosed on office blood pressure (OBP) were included for 2-week placebo run in. During the second week of the run in period, home BP was measured using electronic BP monitors for 5-7 days. Finally, 26 sustained hypertensive patients with home systolic BP/diastolic BP over 135/85 (but <180/110) mm Hg were enrolled for 8-week treatment of nifedipine controlled-release tablet. In the visit day, BP was measured by patient-self (OBP-p) or by doctor (OBP-d) according to order determined with randomization method. The self-BP measurement was performed in a reception room of hospital. The differences between home BP and OBP-d or OBP-p were calculated as WCE calculated on doctor-measurement (WCE-d) or WCE calculated on patient-measurement (WCE-p), respectively. The home and OBP were measured with the same BP device for each patient during the study period. In the total 54 outpatients received placebo, the WCE-d was similar to the WCE-p (for systolic BP 6.6 ± 14.4 vs. 6.8 ± 15.8 mm Hg, NS; for diastolic BP 3.3 ± 8.8 vs. 2.9 ± 9.2 mm Hg, NS). Meanwhile, the 26 sustained hypertensive patients had similar systolic WCE-d and WCE-p (4.8 ± 10.3 vs. 5.0 ± 12.2 mm Hg, NS) at placebo stage. Similarly, these values were comparable (3.0 ± 14.0 vs. 2.2 ± 14.4 mm Hg, NS) in treatment stage. Hospital environment plays a main role for the WCE in hypertensive patients.
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[Management of ureteric colic with ketorolac and nifedipin vs. ketorolac and tamsulosin in the emergency room].
Montiel-Jarquín, ÁJ, Rocha-Rocha, VM, Solís-Mendoza, HA, Romero-Figueroa, MS, Etchegaray-Morales, I, Alvarado-Ortega, I
Revista medica del Instituto Mexicano del Seguro Social. 2017;:S20-S25
Abstract
BACKGROUND Ureteric colic is the most common symptom of lithiasis. It is caused by the presence of stones accumulated in the renal papillae. These stones often migrate down the ureter, causing a ureteric colic, characterized by a severe pain in the lumbar region. The aim of this study was to compare the use of ketorolac and nifedipine vs. ketorolac and tamsulosin for the medical treatment of pain caused by stones in the lower ureter. METHODS Longitudinal study of 150 patients of 21-years or older with stones in the lower third of the ureter. 50% received ketorolac and nifedipine and the other 50%, ketorolac and tamsulosin. The Numeric Pain Rating Scale (NPRS) was used for the assessment of pain at admission and 4 and 12 hours after the treatment was administered. We used descriptive and inferential statistics (Mann-Whitney-Wilcoxon, chi-squared and Poisson regression). RESULTS Mean age was 38.17 years; 54.7% were male and 45.3% female. NPRS mean was 9.69 (initially), 7.42 (at 4 hours) and 2.05 (at 12 hours). There were no significant differences in the initial measurement of pain between groups (p < 0.005); four and 12 hours later the pain decreased more in patients managed with ketorolac and nifedipine, p = 0.0041. There were no complications nor side effects in both treatments. CONCLUSION The use of ketorolac and nifedipine is more effective than the use of ketorolac and tamsulosin for the management of pain caused by lower ureteral colic during the first 12 hours of treatment.
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Nifedipine GITS/Candesartan Combination Therapy Lowers Blood Pressure Across Different Baseline Systolic and Diastolic Blood Pressure Categories: DISTINCT Study Subanalyses.
Kjeldsen, SE, Cha, G, Villa, G, Mancia, G, ,
Journal of clinical pharmacology. 2016;(9):1120-9
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DISTINCT was an 8-week, double-blind, randomized study to investigate the antihypertensive efficacy and safety of various nifedipine gastrointestinal treatment system (GITS)/candesartan cilexetil (N/C) dose combinations, vs respective monotherapies or placebo, in patients with diastolic blood pressure (DBP) ≥95 to <110 mm Hg. The current prespecified analysis compared BP reduction in participants with mild vs moderate baseline hypertension (ie, systolic [S]BP <160 mm Hg vs ≥160 mm Hg and DBP <100 mm Hg vs ≥100 mm Hg). A total of 1362 patients were analyzed by descriptive statistics. In all patient subgroups investigated, the NC combinations (ie, N: 20, 30, or 60 mg; C: 4, 8, 16, or 32 mg daily) provided greater SBP and DBP lowering and higher rates of BP control (defined as BP <140/90 mm Hg) than respective monotherapies or placebo, with greatest absolute BP reductions observed in the moderately elevated SBP or DBP subgroups. A trend to dose-response relationship was observed in each subgroup. In each SBP and DBP subgroup, treatment-related vasodilatory events (flushing, headache, or edema) were less frequent for patients receiving NC combination therapy than N monotherapy. These analyses support the use of calcium antagonist and angiotensin receptor blocker combination therapy in patients with both mild and moderate hypertension, for whom effective BP normalization and good drug tolerance would greatly reduce the risk of cardiovascular events.
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Nifedipine Treatment for Hypertension is Associated with Enhanced Lipolytic Activity and Accelerated Clearance of Postprandial Lipemia.
Grosskopf, I, Shaish, A, Charach, G, Harats, D, Kamari, Y
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2016;(4):257-62
Abstract
Hypertension, advanced age, postprandial hyperlipidemia, and insulin resistance are major risk factors for atherosclerosis. The calcium channel blocker nifedipine is reported to ameliorate insulin resistance possibly by activating PPARγ. This is expected to become accentuated in elderly individuals due to age-related insulin resistance. Insulin resistance modulates lipoprotein metabolism. Therefore, we reasoned that nifedipne offers the potential for improving postprandial lipemia in association with increasing age. We studied the effect of nifedipine on fasting lipids, postprandial lipemia, insulin sensitivity, and plasma lipolytic activity in 24 and 15 hypertensive subjects aged 70-75 years and 40-45 years, respectively. As expected, nifedipine significantly lowered systolic and diastolic blood pressure. Nifedipine decreased fasting triglyceride level (23%) and increased HDL-C (15%) in the elderly group. At baseline, postprandial triglyceride levels were remarkably elevated in elderly compared to younger patients (1 288±798 vs. 501±260 mg·dl(-1)·h, p<0.05), as was retinyl palmitate (surrogate marker for intestinally-derived cholesterol) in the chylomicrons (45.0±26.5 vs. 23.4±10.6 mg·l(-1)·h, p<0.05) and chylomicron remnant (15.2±5.4 vs. 11.7±4.7 mg·l(-1)·h, p<0.05) fractions. Importantly, while the level of chylomicron remnants in the group of younger subjects remained unchanged after treatment, nifedipine was associated with a significantly decreased chylomicron remnants retinyl palmitate in the elderly group, which dropped to levels, observed in younger subjects. This was accompanied by enhanced insulin sensitivity and augmented plasma lipolytic activity. The present work suggests that nifedipine has favorable metabolic effects that are beyond the known enhancement of insulin sensitivity. The improvement in postprandial lipidemia by nifedipine may add to its anti-atherogenic effects in hypertensive patients.