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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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Abstract
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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Control of edema in hypertensive subjects treated with calcium antagonist (nifedipine) or angiotensin-converting enzyme inhibitors with Pycnogenol.
Belcaro, G, Cesarone, MR, Ricci, A, Cornelli, U, Rodhewald, P, Ledda, A, Di Renzo, A, Stuard, S, Cacchio, M, Vinciguerra, G, et al
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2006;(4):440-4
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The presence of edema in different phases and stages of essential hypertension may be due to antihypertensive treatment. Some drugs may cause edema by inducing vasodilatation, increasing the capillary exchange surface and capillary filtration. Pycnogenol has an important anti-edema effect in diabetic microangiopathy and chronic venous insufficiency. This 8-week study evaluated capillary filtration in 2 comparable treatment groups with hypertension treated with a calcium antagonist (nifedipine) or angiotensin-converting enzyme inhibitor to define its efficacy in preventing edema caused by antihypertensives. A significant decrease in filtration was observed in the Pycnogenol groups. Pycnogenol controls this type of edema, it helps to prevent and limit long-term damage in the microcirculation in hypertensive patients, and allows the dose of anti-hypertensive drugs to be reduced in most patients.
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Single- or double-blind treatment With Balsamodendron mukul and nifedipine in hypertensive patients.
Panneerselvam, J, Sambandam, G, Nalini, N
Journal of clinical hypertension (Greenwich, Conn.). 2005;(6):340-5
Abstract
This study assessed and compared the effects of Balsamodendron mukul (an extract of the gum of a small tree) and nifedipine (a calcium-channel-blocking reference drug) on blood pressure, lipids, lipoproteins, and phospholipids in randomly selected patients with essential hypertension. Fifty-seven newly diagnosed hypertensive patients were randomly divided into three groups. They received either single-blind B. mukul (1.5 g/d) or single-blind nifedipine (10 mg/d) double-blind therapy with nifedipine (10 mg/d) and B. mukul (1.5 g/d) for 6 weeks. These groups were compared with control subjects. On treatment with B. mukul, levels of systolic blood pressure, diastolic blood pressure, plasma total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, triglycerides, free fatty acids, and phospholipid levels were significantly reduced, and high-density lipoprotein cholesterol levels were significantly elevated, as compared with untreated hypertensive patients. Combined therapy with B. mukul and nifedipine was more beneficial than the treatment with B. mukul alone. Our study suggests that B. mukul may be an effective antihypertensive and hypolipidemic agent.
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Comparison of once-daily nifedipine controlled-release with twice-daily nifedipine retard in the treatment of essential hypertension.
Minami, J, Numabe, A, Andoh, N, Kobayashi, N, Horinaka, S, Ishimitsu, T, Matsuoka, H
British journal of clinical pharmacology. 2004;(5):632-9
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AIMS: Nifedipine is a short-acting calcium antagonist formulated into several different oral preparations, each of which may have different effects on haemodynamics and autonomic nervous function. We compared the effects of nifedipine controlled-release (CR) and nifedipine retard on 24-h blood pressure, heart rate, rate-pressure product, and power spectral measures of heart rate variability in patients with essential hypertension. METHODS After 4 weeks of a drug-free period, 25 patients were randomized to receive either once-daily treatment with nifedipine CR (20-40 mg daily; 12 patients) or twice-daily treatment with nifedipine retard (20-40 mg daily; 13 patients) for 12 weeks. The ambulatory blood pressure, heart rate, and ECG R-R intervals were measured during a 24-h period using a portable recorder (TM-2425) at the end of the drug-free and the treatment periods. A power-spectral analysis of R-R intervals was performed to obtain the low-frequency (LF) and high-frequency (HF) components. RESULTS Nifedipine CR and nifedipine retard reduced 24-h blood pressure significantly by 15.9 +/- 3.2 (SE)/8.7 +/- 1.4 mmHg and by 10.9 +/- 2.8/9.4 +/- 1.7 mmHg, respectively, after the 12-week treatment. Nifedipine CR did not change the 24-h heart rate significantly, while nifedipine retard increased it significantly by 3.9 +/- 2.1 beats min(-1). Nifedipine CR produced a significant reduction in rate-pressure product throughout a 24-h period, while nifedipine retard did not change the rate-pressure product significantly. In addition, nifedipine retard significantly decreased the 24-h and daytime average values of the LF and HF components, while nifedipine CR affected the nighttime LF component alone and did not change the HF component throughout a 24-h period. CONCLUSIONS These results demonstrate that both nifedipine CR and nifedipine retard are effective as antihypertensive agents, but nifedipine CR has less influence on the autonomic nervous system and heart rate than nifedipine retard.
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Acute efficacy of a sublingual dose of nifedipine on uterine arterial blood flow: preliminary data in prematurely menopausal women.
Huissoud, C, Hadj, S, Bied-Damon, V, Benchaïb, M, Salle, B
Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2004;(7):781-6
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OBJECTIVES To determine whether the calcium blocker nifedipine alters Doppler velocimetry and impedance parameters in the uterine artery in prematurely menopausal women. METHODS Uterine artery Doppler examinations were performed transvaginally in seventeen prematurely menopausal women without the use of calcium blocker (T0). Following a 10-mg sublingual dose of nifedipine patients were subsequently rescanned at successive time intervals (T25 = 25, T40 = 40, T60 = 60 min). PI (normalized (NPI) for heart rate) and maximum, minimum and average velocities of the uterine artery were recorded and waveforms were qualitatively assessed using Goswamy and Steptoe's waveform classification. RESULTS Quantitative analysis showed a significant decrease in NPI at T(25) in the right and left uterine arteries (T0: PI = 2.95 and 3.01; T25: PI = 1.52 and 1.52, respectively; P < 0.001) and until the end of the experiment. Minimum and average blood flow velocities increased strongly (P < 0.001) whereas the maximum velocities did not change significantly (P = 0.12). Qualitative analysis revealed more conspicuous results: eight subjects presented 'abnormal' spectra: one was type A (absence of protodiastole), three were type B (absence of telediastole) and four were type O (no diastolic blood flow); all of them recovered type C waveforms (normal spectrum) during the hour following nifedipine administration. CONCLUSIONS Nifedipine induces a reversible decrease in NPI and an increase in blood flow velocities in the uterine artery in prematurely menopausal women. These results suggest that nifedipine is a potent uterine arterial vasodilator.
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Effects of protocol-driven care versus usual outpatient clinic care on survival rates in patients with type 2 diabetes.
So, WY, Tong, PC, Ko, GT, Leung, WY, Chow, CC, Yeung, VT, Chan, WB, Critchley, JA, Cockram, CS, Chan, JC
The American journal of managed care. 2003;(9):606-15
Abstract
OBJECTIVE To determine whether clinical outcomes in patients with type 2 diabetes were improved by protocol-driven care in a Diabetes Centre compared with usual outpatient care. STUDY DESIGN Descriptive analysis of a prospective cohort. PATIENTS AND METHODS During a median 7-year observational period, 91 patients with type 2 diabetes and no cardiovascular or renal complications were monitored by a nurse and a diabetologist in a clinical trial setting according to a structured protocol. Another 81 patients with comparable clinical characteristics were monitored by generalists at the medical clinic in the same hospital. Clinical end points, defined as death and cardiovascular and renal events, were evaluated in 1997 by review of case records. RESULTS Patients receiving structured care had lower mortality (relative risk [RR] = 0.21; 95% confidence interval [CI] = 0.07, 0.65; P = .006) than the usual-care group, as well as a lower incidence of combined clinical end points (RR = 0.43; 95% CI = 0.22, 0.84; P = .01). In the usual-care group, patients who had no monitoring of glycosylated hemoglobin or plasma lipid levels during the entire observational period (8.6%) had a 14.6-fold (P < .01) and 15.7-fold (P < .01) increased risk of death and combined clinical end points, respectively, compared with those who had at least one measurement (60.5%). CONCLUSION Management by protocol-driven care model improved survival and clinical outcomes in patients with type 2 diabetes. Definitive studies are required to confirm these findings and compare the cost effectiveness of these care models.
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A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia.
Belfort, MA, Anthony, J, Saade, GR, Allen, JC, ,
The New England journal of medicine. 2003;(4):304-11
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OBJECTIVE Magnesium sulfate may prevent eclampsia by reducing cerebral vasoconstriction and ischemia. Nimodipine is a calcium-channel blocker with specific cerebral vasodilator activity. Our objective was to determine whether nimodipine is more effective than magnesium sulfate for seizure prophylaxis in women with severe preeclampsia. METHODS We conducted an unblinded, multicenter trial in which 1650 women with severe preeclampsia were randomly assigned to receive either nimodipine (60 mg orally every 4 hours) or intravenous magnesium sulfate (given according to the institutional protocol) from enrollment until 24 hours post partum. High blood pressure was controlled with intravenous hydralazine as needed. The primary outcome measure was the development of eclampsia, as defined by a witnessed tonic-clonic seizure. RESULTS Demographic and clinical characteristics were similar in the two groups. The women who received nimodipine were more likely to have a seizure than those who received magnesium sulfate (21 of 819 [2.6 percent] vs. 7 of 831 [0.8 percent], P=0.01). The adjusted risk ratio for eclampsia associated with nimodipine, as compared with magnesium sulfate, was 3.2 (95 percent confidence interval, 1.1 to 9.1). The antepartum seizure rates did not differ significantly between groups, but the nimodipine group had a higher rate of postpartum seizures (9 of 819 [1.1 percent] vs. 0 of 831, P=0.01). There were no significant differences in neonatal outcome between the two groups. More women in the magnesium sulfate group than in the nimodipine group needed hydralazine to control blood pressure (54.3 percent vs. 45.7 percent, P<0.001). CONCLUSIONS Magnesium sulfate is more effective than nimodipine for prophylaxis against seizures in women with severe preeclampsia.
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Efficacy of calcium channel blockers as maintenance therapy for asthma.
Ann Twiss, M, Harman, E, Chesrown, S, Hendeles, L
British journal of clinical pharmacology. 2002;(3):243-9
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AIMS: Previous bronchoprovocation studies indicate that nifedipine attenuates airway responsiveness to several stimuli whereas diltiazem has no effect. The aim of this study was to determine whether such studies predict the efficacy of calcium channel blockers as maintenance therapy for persistent asthma. METHODS Twenty-one otherwise healthy adults with persistent asthma, mean age 25 years, completed treatment with maximum tolerated doses of placebo (P), nifedipine (N), and diltiazem (D) in a double-blind, randomized, three-treatment, three-period, crossover manner, each for 4 weeks. Frequency and severity of asthmatic symptoms were recorded twice daily, as well as peak expiratory flow and frequency of 'prn' use of inhaled terbutaline. Blood pressure, heart rate, P-R interval of the ECG and spirometry were measured biweekly. At the end of each treatment, airway responsiveness to exercise was measured. RESULTS The mean (s.e. mean)% of days with wheeze was 69plus minus7% during P, 75plus minus6% during N and 72plus minus6% during D (P=0.7). FEV1 was 79plus minus2% of predicted during P, 81plus minus2% during N and 79plus minus2% during D (P=0.6). The decrease in FEV1 after exercise was 32plus minus4% during P, 32plus minus5% during N and 27plus minus4% during D (P=0.5). Heart rate was elevated during N (P=0.0002) whereas P-R interval was prolonged during D (P=0.0001). CONCLUSIONS Maintenance therapy with calcium channel blockers, at doses that produce cardiovascular effects, do not suppress the signs and symptoms of persistent asthma. Previous bronchoprovocation studies did not predict these results.
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Renoprotective role of nifedipine during gentamicin therapy: randomized controlled trial.
Vlasic-Matas, J, Rumboldt, Z, Karelovic, D
Croatian medical journal. 2000;(4):417-22
Abstract
AIM: To investigate the protective effect of nifedipine, a dihydropyridine calcium-channel blocker, on renal function (glomerular and tubular) in patients treated with gentamicin, an aminoglycoside antibiotic. METHODS Thirty-two patients with gentamicin sensitive upper urinary tract infection have been screened and randomized to two groups. The placebo group was given gentamicin and placebo, and the intervention group gentamicin and nifedipine. Gentamicin was given in slow intravenous injection every 12 hours for 10 days, and nifedipine 10 mg orally, 3 times a day. RESULTS Nifedipine administration during gentamicin therapy promoted primarily the glomerular filtration. In 62% of the patients treated with nifedipine creatinine clearance increased significantly by the end of the study. In the placebo group, 69% of the patients had a creatinine clearance significantly below the baseline at the end of the study. The decrease in creatinine clearance by more than 50% from the initial values was found in 2 patients (1 in each group). There was a significant increase in gammaGT/creatinine clearance ratio in both groups at the end of therapy, indicating that nifedipine did not prevent the brush-border membranous enzyme release caused by gentamicin. CONCLUSION Nifedipine has positive effects on renal hemodynamics in patients treated with gentamicin. Most likely, the mechanism of action is an increase in glomerular filtration caused by preglomerular vasodilatation.
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Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.
Chan, JC, Ko, GT, Leung, DH, Cheung, RC, Cheung, MY, So, WY, Swaminathan, R, Nicholls, MG, Critchley, JA, Cockram, CS
Kidney international. 2000;(2):590-600
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UNLABELLED Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. BACKGROUND In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. METHODS After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). RESULTS In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006). CONCLUSION In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.