Slow-release Nifedipine Research Articles

Analysis of the efficiency and safety of using the slow-release calcium channel blocker nifedipine as a tocolytic drug in pregnant women with preterm labor

Analysis of the efficiency and safety of using the slow-release calcium channel blocker nifedipine as a tocolytic drug in pregnant women with preterm labor

Upward Shift and Steepening of the Blood Pressure Response to Exercise in Hypertensive Subjects at High Altitude.

BackgroundAcute exposure to high‐altitude hypobaric hypoxia induces a blood pressure rise in hypertensive humans, both at rest and during exercise. It is unclear whether this phenomenon reflects specific blood pressure hyperreactivity or rather an upward shift of blood pressure levels. We aimed at evaluating the extent and rate of blood pressure rise during exercise in hypertensive subjects acutely exposed to high altitude, and how these alterations can be counterbalanced by antihypertensive treatment.Methods and ResultsFifty‐five subjects with mild hypertension, double‐blindly randomized to placebo or to a fixed‐dose combination of an angiotensin‐receptor blocker (telmisartan 80 mg) and a calcium‐channel blocker (nifedipine slow release 30 mg), performed a cardiopulmonary exercise test at sea level and after the first night's stay at 3260 m altitude. High‐altitude exposure caused both an 8 mm Hg upward shift (P<0.01) and a 0.4 mm Hg/mL/kg per minute steepening (P<0.05) of the systolic blood pressure/oxygen consumption relationship during exercise, independent of treatment. Telmisartan/nifedipine did not modify blood pressure reactivity to exercise (blood pressure/oxygen consumption slope), but downward shifted (P<0.001) the relationship between systolic blood pressure and oxygen consumption by 26 mm Hg, both at sea level and at altitude. Muscle oxygen delivery was not influenced by altitude exposure but was higher on telmisartan/nifedipine than on placebo (P<0.01).ConclusionsIn hypertensive subjects exposed to high altitude, we observed a hypoxia‐driven upward shift and steepening of the blood pressure response to exercise. The effect of the combination of telmisartan/nifedipine slow release outweighed these changes and was associated with better muscle oxygen delivery.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830530.

UPWARD-SHIFT AND STEEPENING OF THE BLOOD PRESSURE RESPONSE TO EXERCISE IN HYPERTENSIVE SUBJECTS AT HIGH ALTITUDE

Objective: Acute exposure to high altitude hypobaric hypoxia induces a blood pressure rise in hypertensive humans, both at rest and during exercise. It is unclear whether this phenomenon reflects specific blood pressure hyperreactivity or rather an upward shift of blood pressure levels. We aimed at evaluating the extent and rate of blood pressure rise during exercise in hypertensive subjects acutely exposed to high altitude, and how these alterations can be counterbalanced by antihypertensive treatment. Design and method: Fifty-five mild hypertensive subjects, double-blindly randomized to placebo or to a fixed-dose combination of an angiotensin-receptor blocker (telmisartan 80 mg) and a calcium-channel blocker (nifedipine slow release 30 mg), performed a cardiopulmonary exercise test at sea level and after the first night of stay at 3260 m altitude. Results: High altitude exposure caused both a 8 mmHg upward-shift (p < 0.01) and a 0.4 mmHg/mL/Kg/min steepening (p < 0.05) of the systolic blood pressure/oxygen consumption relationship during exercise, independently of treatment (figure 1a). Telmisartan/nifedipine did not modify blood pressure reactivity to exercise, but downward shifted (p < 0.001) the relationship between systolic blood pressure and oxygen consumption by 26 mmHg, both at sea level and at altitude (figure 1a). Muscle oxygen delivery, as evaluated by means of the relationship between oxygen consumption and workload, was not influenced by altitude exposure, but was higher on telmisartan/nifedipine than on placebo (p < 0.01, figure 1b).Conclusions: In hypertensive subjects exposed to high altitude we observed a hypoxia-driven upward-shift and steepening of the blood pressure response to exercise. The effect of the combination of telmisartan/nifedipine slow-release outweighed these changes, and was associated with better muscle oxygen delivery.

Pre-Eclampsia and Eclampsia: An Update on the Pharmacological Treatment Applied in Portugal.

Pre-eclampsia and eclampsia are two hypertensive disorders of pregnancy, considered major causes of maternal and perinatal death worldwide. Pre-eclampsia is a multisystemic disease characterized by the development of hypertension after 20 weeks of gestation, with the presence of proteinuria or, in its absence, of signs or symptoms indicative of target organ injury. Eclampsia represents the consequence of brain injuries caused by pre-eclampsia. The correct diagnosis and classification of the disease are essential, since the therapies for the mild and severe forms of pre-eclampsia are different. Thus, this review aims to describe the most advisable antepartum pharmacotherapy for pre-eclampsia and eclampsia applied in Portugal and based on several national and international available guidelines. Slow-release nifedipine is the most recommended drug for mild pre-eclampsia, and labetalol is the drug of choice for the severe form of the disease. Magnesium sulfate is used to prevent seizures caused by eclampsia. Corticosteroids are used for fetal lung maturation. Overall, the pharmacological prevention of these diseases is limited to low-dose aspirin, so it is important to establish the safest and most effective available treatment.

Maintenance nifedipine therapy for preterm symptomatic placenta previa: A randomized, multicenter, double-blind, placebo-controlled trial.

ObjectiveTo assess the impact of maintenance nifedipine therapy on pregnancy duration in women with preterm placenta previa bleeding.MethodsPPADAL was a randomized, double-blind, placebo-controlled trial conducted between 05/2008 and 05/2012 in five French hospitals. The trial included 109 women, aged ≥ 18 years, with at least one episode of placenta previa bleeding, intact membranes and no other pregnancy complication, at gestational age 24 to 34 weeks and after 48 hours of complete acute tocolysis. Women were randomly allocated to receive either 20 mg of slow-release nifedipine three times daily (n = 54) or placebo (n = 55) until 36 + 6 weeks of gestation. The primary outcome for the trial was length of pregnancy measured in days after enrolment. Main secondary outcomes were rates of recurrent bleeding, cesarean delivery due to hemorrhage, blood transfusion, maternal side effects, gestational age at delivery and adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage > grade 2, perventricular leukomalacia > grade 1, or necrotizing enterocolitis). Analysis was by intention to treat.ResultsMean (SD) prolongation of pregnancy was not different between the nifedipine (n = 54) and the placebo (n = 55) group; 42.5 days ± 23.8 versus 44.2 days ± 24.5, p = 0.70. Cesarean due to hemorrhage performed before 37 weeks occurred more frequently in the nifedipine group in comparison with the placebo group (RR, 1.66; 95% confidence interval, 1.05–2.72). Adverse perinatal outcomes were comparable between groups; 3.8% for nifedipine versus 5.5% for placebo (relative risk, 0.52; 95% confidence interval 0.10–2.61). No maternal mortality or perinatal death occurred.ConclusionMaintenance oral nifedipine neither prolongs duration of pregnancy nor improves maternal or perinatal outcomes.Trial registrationClinicalTrials.gov NCT00620724

Effect of type 2 diabetes mellitus on the pharmacokinetics and transplacental transfer of nifedipine in hypertensive pregnant women.

Diabetes mellitus can inhibit cytochrome P450 3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women. The study was conducted in 12 hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20mg, 12/12h). On the 34th week of gestation, serial blood samples were collected (0-12h) after administration of the medication. At delivery, samples of maternal and fetal blood and amniotic fluid were collected for determination of nifedipine distribution in these compartments. The median pharmacokinetic parameters of CG were: peak plasma concentration (Cmax ) 26.41ngml-1 , time to reach Cmax (tmax ) 1.79h, area under the plasma concentration vs. time curve from 0-12h (AUC0-12 ) 235.99ng.hml-1 , half-life (t½) 4.34h, volume of distribution divided by bioavailability (Vd/F) 560.96l, and ClT /F 84.77lh-1 . The parameters for T2DM group were: Cmax 23.52ngml-1 , tmax 1.48h, AUC0-12 202.23ng.hml-1 , t½ 5.00h, Vd/F 609.40l, and apparent total clearance (ClT /F) 98.94lh-1 . The ratios of plasma concentrations of nifedipine in the umbilical vein, intervillous space and amniotic fluid to those in the maternal vein for CG and T2DM were 0.53 and 0.44, 0.78 and 0.87, respectively, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. The ratios of plasma concentrations in the umbilical artery to those in the umbilical vein were 0.82 for CG and 0.88 for T2DM. There was no influence of T2DM on the pharmacokinetics or placental transfer of nifedipine in hypertensive women with controlled diabetes.

74 Relationship between plasma concentration of nifedipine and pressure control in hypertensive pregnant women

Introduction Nifedipine is a calcium channel blocker used in treatment of hypertension in pregnant women. Objective The objective of the present study was to investigate the relation between the plasma concentration of nifedipine and pressure control in hypertensive pregnant women. Methods Twenty-two hypertensive pregnant women taking oral slow-release nifedipine 20 mg every 12 h were evaluated. Serial blood samples were collected at times 0–12 h after administration of the last nifedipine dose during the third trimester of pregnancy. The blood pressure of the patients was measured 4 in 4 hours from the time 0 to 12 h. Concentrations of nifedipine were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The plasma concentration and the mean arterial pressure were reported as mean and standard deviation. Results The maximum fall in the measurement of mean arterial pressure after 4 h (95.4 ± 10.2 mmHg) was observed right after the mean maximum plasma concentration (27.5 ± 10.6 ng/mL) at time of maximum concentration (1.5 ± 0.5 h). As well as the values of mean arterial pressure at time 12 h (102.0 ± 11.1 mmHg) was similar to the values from time zero (106.8 ± 11.5 mmHg). Conclusion The study demonstrate the action of the drug during the dose interval used, as well as its efficacy. Acknowledgement Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq).

Blood pressure response to six-minute walk test in hypertensive subjects exposed to high altitude: effects of antihypertensive combination treatment

ABSTRACT Background Limited evidence exists on blood pressure (BP) responses to exercise in hypertensive subjects exposed to high altitude, and on the effects of antihypertensive treatment in this setting. We aimed to asses BP response to submaximal exercise in hypertensive lowlanders acutely exposed to high altitude, and the effects of a calcium antagonist–angiotensin receptor blocker combination in this condition. Methods 89 mild-hypertensive participants in HIGHCARE-ANDES study performed a six-minute walk test in 3 conditions: at sea-level off-treatment; at sea-level after 6weeks of double-blind treatment with telmisartan 80mg+slow release nifedipine 30mg or with placebo; on the first full day of permanence at 3260m altitude under randomized treatment. Results The distance walked in 6min was reduced by about 10% at high altitude in both groups (p Conclusions In mild hypertensives, acute exposure to high altitude enhances the BP response to exercise. Such an enhanced response is effectively reduced by telmisartan/nifedipine combination therapy, without affecting exercise performance.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

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Objectives Nifedipine is a dihydropyridine calcium channel blocker used in treatment of hypertension in pregnant women. The objective of the present study was to investigate the influence of T2DM on the pharmacokinetics and the placental transfer of nifedipine in hypertensive pregnant women. Methods Twelve hypertensive pregnant women (HP) and ten hypertensive pregnant women with T2DM (HDP) taking oral slow-release nifedipine 20 mg every 12 h were evaluated. Serial blood samples were collected at times 0–12 h after administration of the last nifedipine dose during the third trimester of pregnancy. Umbilical venous (UV) and arterial (UA) blood, placental intervillous space (PIS) and amniotic fluid (AF) and maternal blood (MB) were obtained at delivery. Concentrations of nifedipine were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The pharmacokinetics and placental transfer results of the two groups, reported as median and 25th and 75th percentile, were compared statistically using the Mann–Whitney test, with the level of significance set at p Results The pharmacokinetic parameters and the rates of nifedipine’s placental transfer detected for HP and HDP patients, reported as median respectively were: elimination half-life 4.33 and 5.00 h; time to maximum concentration 1.79 and 1.47 h; maximum concentration 26.41 and 23.52 ng/mL; area under the plasma concentration-time curve from time zero to 12 h 235.99 and 202.23 ng · h/mL; apparent total oral clearance 84.77 and 98.94 L/h; apparent volume of distribution after oral administration 560.96 and 609.40 L; UA/UV 0.82 and 0.88; MB/PIS 0.99 and 0.87; MB/AF 0.05 in both groups; placental transfer of nifedipine 55% versus 44%. No significant differences were observed between the groups. Conclusions T2DM in the presence of insulin use does not influence the pharmacokinetics and placental transfer of nifedipine slow-release in hypertensive pregnant patients, demonstrating the absence of a need to increase the dose. Disclosures R.C. Cavalli: None. G.G. Filgueira: None. V.L. Lanchote: None. O.O. Filgueira: None. D.M. Carvalho: None. E.C. Moises: None. G. Duarte: None.

Pathophysiological functions of adrenomedullin and natriuretic peptides in patients with primary aldosteronism.

To measure the plasma concentrations of adrenomedullin (ADM),atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP), and investigate their pathophysiological functions in patients with primary aldosteronism (PA). Between June 2006 and December 2012, we recruited 25 patients with untreated PA, 30 patients with untreated low-renin essential hypertension (EH), and 35 healthy control subjects. The plasma concentrations of ADM, ANP, and BNP were measured in all the subjects. After 4 weeks of effective antihypertensive therapy with slow-release nifedipine, the three peptides were measured again in the PA and low-renin EH subjects. Unilateral laparoscopic adrenalectomy was performed in all the PA patients; 2 weeks after surgery, the three peptides were measured again. The PA patients had significantly higher plasma concentrations of ADM, ANP, and BNP than the low-renin EH and control subjects. The low-renin EH and control subjects significantly differed in the concentrations of the three peptides between low-renin EH and control subjects. ADM was the most important peptide associated with aldosterone or blood pressure in the PA patients. Plasma ADM concentration was not only correlated with plasma aldosterone concentrations, but also with systolic and diastolic blood pressures, and plasma ANP and BNP concentrations in the PA patients. By contrast, ADM concentration was not related to blood urea nitrogen levels, serum creatinine levels, and glomerular filtration rates. After antihypertensive treatment, the concentrations of the three peptides significantly decreased in the low-renin EH patients, but remained unchanged in the PA subjects. However, these concentrations significantly decreased 2 weeks after laparoscopic adrenalectomy in the PA subjects. ADM, ANP, and BNP possibly participate in the mechanisms counteracting further elevation of blood pressure or plasma volume expansion resulting from aldosterone hypersecretion in PA patients. An ADM/aldosterone local regulatory mechanism may be involved in regulating adrenal adenoma functions.

Two strategies for arterial hypertension treatment in patients with secondary chronic pyelonephritis

Aim. To compare the antihypertensive effectiveness, cardio- and nephroprotection, and metabolic effects of the combinations “enalapril + indapamide” vs. “enalapril + nifedipine slow release (SR)” in patients with arterial hypertension (AH) and secondary chronic pyelonephritis (CPN). Material and methods. In total, 60 patients with AH and secondary CPN, aged 45-65 years, were divided into two groups: Group I (n=30) receiving combined therapy with enalapril (mean dose 15,9±2,3 mg/d) and indapamide (2,5 mg/d); and Group II (n=30) receiving the combination of enalapril (16,1±2,4 mg/d) and nifedipine SR (40 mg/d). The complex examination included 24-hour blood pressure monitoring (BPM), echocardiography, measurement of morning urine specific gravity, microalbuminuria (MAU), urine levels of ß2-microglobulines, blood creatinine and glomerular filtration rate (GFR) calculation by MDRD formula, fasting glucose, potassium, uric acid, total cholesterol, and triglycerides. The follow-up time was 12 weeks. Results. The combinations “enalapril + indapamide” and “enalapril + nifedipine SR” had similar effects in terms of BP lowering, MAU reduction, and improvement of proximal renal tubular function. In both groups, there was a decrease in the number of patients with circadian BP rhythm disturbances, adverse left ventricular remodelling types, or diastolic dysfunction. The combination of enalapril and indapamide was significantly more effective in terms of restoring renal concentrating function, compared to the combination “enalapril + nifedipine SR”. Both antihypertensive therapies were metabolically neutral, not affecting carbohydrate, purine, lipid, or electrolyte metabolism parameters.Conclusion. The combinations “enalapril + indapamide” and “enalapril + nifedipine SR” demonstrated high antihypertensive effectiveness, cardio- and nephroprotection, and metabolic neutrality.

Evaluation of the clinical efficacy of antihypertensive drugs in elderly patients with isolated systolic hypertension

Objective. To evaluate the antihypertensive and organoprotective effects of the calcium antagonist - slow release Nifedipine (Cordaflex RD) and diuretic Indapamid MR in patients with isolated systolic hypertension (ISH). Design and methods. 46 patients with ISH (66,2 ± 4,8 years) were included. Patients were divided into 2 clinical groups: 1st group (n = 26) took cordaflex RD, and 2nd group (n = 20) was given the Indapamide MR. The cardio- and angioprotective effects of the medications was evaluated. Results and conclusions. Cordaflex leads to the decrease of both systolic and diastolic blood pressure (SBP and DBP), whereas Indapamide influences SBP more, than DBP. Based on echocardiography results, both medications decreased the heart wall thickness, improved systolic and diastolic left ventricular function. Cordaflex RD significantly improved the diastolic left ventricular function. Both Cordaflex RD and Indapamide favorably influenced peripheral arteries endothelial function in elderly subjects with ISH. Both medications effectively reduced the index of the true stiffness CAVI.

Plasma Renin Activity and Aldosterone Concentration are not Altered by the Novel Calcium Channel Antagonist, Azelnidipine, in Hypertensive Patients

In hypertensive patients, primary aldosteronism (PA) is the most prevalent type of secondary hypertension, and screening for PA has become very important. Calcium channel blockers (CCB) are widely used to treat hypertension, but most CCBs stimulate plasma renin activity (PRA) and increase plasma aldosterone concentration (PAC), both of which are used in the screening for PA. The aim of this study was to determine whether the newly introduced CCB, azelnidipine, affects PRA and PAC. 40 hypertensive patients were treated with 16 mg of azelnidipine for 4 weeks. Azelnidipine treatment in drug-naïve (DN) cases significantly decreased systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). PRA and PAC in the DN group on azelnidipine treatment were indistinguishable from those in the DN group before treatment. Compared with other CCB treatments such as amlodipine, manidipine and slow-release nifedipine, azelnidipine showed comparable or significant reductions in SBP, DBP and HR. In patients who were switched from other CCBs to azelnidipine, PRA and PAC were decreased, except for PAC on amlodipine treatment. Since the PRA reduction rate exceeded that of PAC, the aldosterone/renin ratio (ARR) was significantly increased in those on azelnidipine treatment who had been switched from manidipine or nifedipine treatment, suggesting the restoration of possibly underestimated ARR values. These data indicate that azelnidipine does not affect PRA or PAC, suggesting that azelnidipine could be a useful antihypertensive CCB while undergoing PA screening.

Influence of the angiotensin II receptor antagonist losartan on diuretic-induced metabolic effects in elderly hypertensive patients: comparison with a calcium channel blocker

Diuretic therapy frequently induces undesirable biochemical changes and side effects. We compared metabolic effects of a low-dose diuretic (D) given in combination with an angiotensin II receptor antagonist, losartan (L), with those resulting from a diuretic given in combination with a calcium channel blocker, slow-release nifedipine (N). Thirty-seven elderly patients with mild to moderate hypertension (mean age: 71 +/- 3 years) were treated with either L+D (n = 18) or N+D (n = 19) for 1 year. Diuretic therapy included low-dose trichlormethiazide or low-dose furosemide in numbers of patients that were similar between L+D and N+D groups. Blood pressure, serum electrolytes, uric acid, blood glucose, renal function and lipid parameters were measured at baseline, 6 months and 1 year. Effective blood pressure control was observed in both groups at 6 months, and with further improvement at 1 year. Serum potassium was significantly decreased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but not in the L+D group. Serum uric acid was significantly increased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but had minimally decreased at 1 year in the L+D group (p < 0.1). Blood glucose, renal function and lipid parameters did not change in either group. The combination of losartan and low-dose diuretics effectively treated hypertension in elderly patients while minimizing the metabolic consequences of diuretic therapy. Larger trials will be necessary to confirm this finding.

Two Dose Regimens of Nifedipine for Management of Preterm Labor: A Randomized Controlled Trial

We compared two dose regimens of tocolytic oral nifedipine. Women with singleton pregnancies admitted in preterm labor (24 to 34 weeks) were randomized to high-dose (HD) nifedipine ( N = 49; 20 mg loading dose, repeated in 30 minutes, daily 120 to 160 mg slow-release nifedipine for 48 hours followed by 80 to 120 mg daily until 36 weeks) or low-dose (LD) nifedipine ( N = 53; 10 mg, up to four doses every 15 minutes, daily 60 to 80 mg slow-release nifedipine for 48 hours followed by 60 mg daily until 36 weeks). Uterine quiescence at 48 hours (primary outcome); delivery at 48 hours, 34 and 37 weeks; and recurrent preterm labor were similar. Gestational age at delivery was higher in HD (36.0 +/- 2.8 versus 34.7 +/- 3.7 weeks, P = 0.049). Rescue treatment was needed more in LD (24.5 versus 50.9%, odds ratio = 0.3; 95% confidence interval 0.1 to 0.7). Maternal adverse effects, birth weight, intensive care nursery admission, and composite neonatal morbidity were similar. However, neonatal mechanical ventilation was needed less and nursery stay was shorter in HD. HD nifedipine does not seem to have an advantage over LD in achieving uterine quiescence at 48 hours. Further studies should address the optimal dose and formulation of tocolytic nifedipine.

The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) Study: Rationale and Study Design

Previous studies have shown that transient treatment of animal models of hypertension with an angiotensin receptor blocker (ARB) causes a sustained decrease in blood pressure values that persists even after the drug treatment is discontinued (J Am Soc Nephrol 12: 659-666, 2001; Nephron 91: 710-718, 2002; Hypertens Res 30: 63-75, 2007). These results have been shown to be clinically relevant by the recent TROPHY study (N Engl J Med 354: 1685-1697, 2006). We have recently found that transient treatment with an ARB may also cause regression of established hypertension in hypertensive rats (J Am Soc Nephrol 18: 157A, 2007). The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) study is a prospective, randomized, open, blinded end-point study in patients aged 30-59 with a positive family history of hypertension that will be conducted in several centers in Japan. The aim of the study is to evaluate the antihypertensive drug withdrawal success rate, the median duration of drug withdrawal, and the changes in home and office blood pressure values in patients with mild hypertension after tapering and withdrawal of antihypertensive treatment following treatment for 1 year with the ARB candesartan or the calcium channel blocker (CCB) nifedipine slow-release. A unique feature of this study is the use of a home blood pressure monitoring telemedicine system (i-TECHO) to allow frequent evaluation of the changes in blood pressure in the trial patients. This study will be the first clinical study to examine if regression from stage 1 (mild) hypertension to prehypertension (high-normal blood pressure) is possible using an ARB or CCB.

Nifedipine Improves Endothelial Function

Nifedipine has been shown to improve endothelial function. Recent studies have indicated that endothelial function is correlated with the number of circulating endothelial progenitor cells (EPCs), but it is unclear whether nifedipine affects the number and function of EPCs. The aims of this study were to determine the effects of nifedipine on the number and function of EPCs and to investigate the relationship between improvement of endothelial function and EPC numbers in patients with hypertension. Stage 1 hypertensive men (n=37) were randomly divided into the nifedipine group and the control untreated group. The nifedipine group was administered slow-release nifedipine (20 mg) once daily. At baseline and after 4 weeks, flow-mediated dilation, blood pressure, biochemical data, and number of circulating CD34+CD133+ progenitor cells and EPCs were measured. The direct effects of nifedipine on EPC number and function were assessed in vitro. In the nifedipine group, flow-mediated dilation and the numbers of circulating CD34+CD133+ progenitor cells and EPCs were increased, along with a decrease of serum malondialdehyde low-density lipoprotein. The improvement of flow-mediated dilation by nifedipine was correlated with the increase of circulating CD34+CD133+ progenitor cells. Nifedipine also improved angiogenesis-related functions of EPCs (differentiation, migration, and resistance to oxidative stress) in vitro. Thus, nifedipine improved endothelial function and EPC function in stage 1 hypertensive subjects. The latter action may be mediated by reduction of oxidative stress and suppression of EPC apoptosis. These results demonstrate that nifedipine preserves endothelial integrity in patients with hypertension, at least partly, by enhancing EPC numbers and activity.

Abaisser la pression artérielle: urgent ou pas urgent?

Severe hypertension represents a frequent problem for the general practitioner. One has to decide if the blood pressure needs to be decreased immediately (hypertensive emergency), or if the blood pressure maybe progressively decreased in a few hours and normalized in a few days (hypertensive crisis). Thus it is crucial to identify on the basis of the clinical history and a careful physical examination, the patients for whom the arterial blood pressure elevation represents an acute danger for organ damage or a vital threat in the absence of immediate blood pressure control. In the case of hypertensive crisis, oral medication is usually sufficient (slow release or GITS nifedipine, nitroglycerin, labetalol, captopril). The hypertensive emergency sometimes requires an oral medication before the admission to the emergency room, then followed by intravenous drug administration (sodium nitroprussiate, nitroglycerin, labetalol).

Nifedipine Pharmacokinetics and Plasma Levels in the Management of Preterm Labor

The aim of this study was to determine if the dose regimen of nifedipine used for tocolysis was effective to achieve uterine quietness, and at which plasma concentration levels this tocolysis was achieved to optimize our dose regimen of nifedipine. In women with preterm labor, nifedipine was administered orally to achieve uterine quietness to prevent preterm birth. Patients (n = 5) were administered 10 mg nifedipine capsules (Adalat capsules, Bayer AG) orally every 15 minutes up to 40 mg in the first hour, and were subsequently given 1 tablet of 20 mg nifedipine slow release (Adalat retard, Bayer AG) t = 90 min. Plasma levels of nifedipine were measured at regular intervals during the first 4 hours after starting tocolysis. In all 5 patients tocolysis was achieved with nifedipine. Peak plasma concentration of nifedipine was 127.2 +/- 44 ng/mL at 1.2 +/- 0.1 hours. Mean plasma concentrations of nifedipine was 67.4 +/- 28.4 ng/mL. In all patients, tocolysis was achieved during the 4 hours of blood sampling. There were no adverse hemodynamic side effects seen before and after starting tocolysis with nifedipine. Initial dose regimen of 4 times 10 mg nifedipine capsule orally in the first hour, followed by 20 mg slow release nifedipine at t = 90 min is effective in achieving tocolysis in women with preterm labor. In steady state, the mean nifedipine plasma concentration to achieve tocolysis is about the half of that measured after initial tocolysis. Use of nifedipine for preterm labor was not associated with any adverse hemodynamic side effects.