Gastrointestinal Therapeutic System Research Articles

Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension?

The role of alpha-1 adrenoceptor antagonists (alpha-blockers) in the management of hypertension continues to evolve. Recent data support their use as add-on therapy in uncontrolled hypertension when used in combination with all other major classes of antihypertensive drug and there is increasing evidence suggesting that they have modest but significant beneficial effects on lipid and glucose metabolism. The availability of extended-release formulations has contributed to an excellent tolerability profile. New data from an observational analysis of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) suggest that doxazosin gastrointestinal therapeutic system (GITS) used as a third-line antihypertensive agent lowered blood pressure and caused modest reductions in plasma lipids. Furthermore, use of doxazosin in ASCOT was not associated with an increased risk of heart failure, in contrast to the earlier finding of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Overall, currently available data support the use of alpha-blockers as safe, well tolerated and effective add-on antihypertensive drugs, which have additional favourable metabolic effects.

Magnetic resonance imaging and relaxometry to study water transport mechanisms in a commercially available gastrointestinal therapeutic system (GITS) tablet

The hydration of 4 mg Cardura XL (Pfizer™), a commercially available gastrointestinal therapeutic system (GITS) tablet, was investigated using magnetic resonance imaging (MRI). A short echo time ( T e = 2.81 ms) technique for MRI of the hydration of a GITS tablet was implemented. From the MR images, signal intensity profiles were generated and interpreted in the context of diffusive and osmotic transport mechanisms. A distinct transition from diffusive to osmotic transport was measured at a timescale relevant to the measured drug release time. Diffusion and osmotic rate coefficients for water in the drug and polymer sweller layers of the tablet were quantified. Spin–lattice T 1 and spin–spin T 2 relaxation times of the water signal from within the tablet were measured as a function of hydration time in order to incorporate the effects of relaxation into interpretation of signal intensity and provide unique information on the distribution of water in different physical and chemical environments within the tablet.

Effects of α-blocker ‘add on’ treatment on blood pressure in symptomatic BPH with or without concomitant hypertension

We investigated the effects of ‘add on' treatment of α-blocker (AB) on blood pressure (BP) and the safety of ABs in men with symptomatic BPH with or without hypertension. We retrospectively reviewed 2,924 BPH outpatients who took ABs at our institution between 2005 and 2009. BPH symptom severity, prostate volume and BP were determined for 953 patients with their baseline data. BP level and International Prostate Symptom Score were measured within 2 months after AB treatment. Patients were assigned to four groups: group 1 had 272 normotensive patients on concomitant hypertensive medication; group 2 had 293 normotensive patients not on the medication; group 3 had 216 hypertensive patients on concomitant medication; and group 4 had 172 hypertensive patients not on the medication. The addition of AB lowered the mean systolic BP by 16.6 mm Hg for group 3 and by 8.6 mm Hg for group 4, and diastolic BP by 18.0 mm Hg for group 3 (P<0.05). However, normotensive groups on entry, irrespective of antihypertensive medication, showed no significant BP changes from baseline after AB medication. In the hypertensive groups on entry, the doxazosin gastrointestinal therapeutic system (GITS) resulted in significant reductions in systolic BP from 142.2 to 134.9 mm Hg and in diastolic BP from 97.6 to 84.6 mm Hg. When analyzed by AB regimen, the incidence of BP-related adverse events was comparable. AB therapy for BPH can have an appropriate and beneficial effect on BP, especially in baseline hypertensive patients. Doxazosin GITS treatment resulted in optimal management of BP within the normal range, especially in pharmacologically or physiologically hypertensive patients.

Benefits of nifedipine GITS in stable coronary artery disease: Further analysis of the “ACTION” database

Retrospective analyses of specific subgroups of patients from the database of the ACTION study have evaluated the effectiveness of a nifedipine gastrointestinal therapeutic system (GITS) on clinical outcomes. These subgroups included those patients receiving: 1) full "optimal" therapy at baseline; 2) full "optimal" therapy at baseline but excluding renin angiotensin system (RAS)-blocking drugs; 3) treatment with nifedipine GITS who were not treated with RAS blockers versus those treated with RAS blockers but not nifedipine GITS. Analyses were performed on an intention-to-treat basis. Treatment groups were compared by log-rank test without adjustment for covariates. Hazard ratios with 95% confidence intervals were obtained using Cox proportional hazards models with treatment allocation as the only covariate. 2461 patients randomized in ACTION were receiving optimal therapy (beta blockers, nitrates, aspirin, statins) excluding RAS blockers at baseline. There were reductions associated with nifedipine GITS compared with placebo in all prespecified endpoints but statistical significance was only achieved for debilitating stroke (48%; P<0.02) and coronary angiography (14%; P<0.05). These benefits were paralleled by a -4.1 and -2.8 mmHg difference between the groups for systolic and diastolic blood pressure, respectively. Patients randomized to nifedipine GITS but no RAS blockers (n=2966) when compared to those receiving RAS blockers but no nifedipine GITS (n=880) had highly statistically significant reductions in cardiovascular events (22%), new-onset heart failure (53%), and debilitating stroke (45%). However, the groups differed in their baseline characteristics. Addition of nifedipine GITS to the treatment regimen of selected patient groups with symptomatic coronary artery disease results in a significant reduction of cardiovascular morbidity. While the interpretation of these subgroup analyses must obviously be cautious, there is a clear message relating to "best practice" treatment of angina, which suggests that "reliance" on RAS blockade may be misplaced and greater attention should be directed towards control of blood pressure.

Preferential benefits of nifedipine GITS in systolic hypertension and in combination with RAS blockade: further analysis of the ‘ACTION’ database in patients with angina

A retrospective analysis of the database from A Coronary Disease Trial Investigating Outcome with Nifedipine (ACTION) evaluated the effectiveness of nifedipine gastrointestinal therapeutic system (GITS) (i) in combination with renin angiotensin system (RAS) blockers and (ii) in patients with isolated systolic hypertension (ISH). Analysed on an intention-to-treat basis, treatment groups were compared by the log-rank test without adjustment for covariates and hazard ratios with 95% CIs were obtained using Cox proportional hazards models. Of 7665 randomized patients, 1732 patients were receiving RAS blockade at baseline, the addition of nifedipine GITS significantly reduced any cardiovascular (CV) event (−20% P<0.05), the composite of death, any CV event and revascularization (−16% P<0.05) and coronary angiography (−22% P<0.01). These benefits were achieved with relatively small differences in systolic (3.2 mm Hg) and diastolic blood pressure (BP) (2.3 mm Hg). In 2303 patients (30.0%) who had ISH at baseline (1145 nifedipine GITS and 1158 placebo), nifedipine significantly reduced the primary efficacy end point (−18% P<0.03), any CV event (−22% P<0.01) and new heart failure (−40% P<0.01). The benefits were associated with between-group differences in achieved BP of 4.7 and 3.3 mm Hg for systolic and diastolic BP, respectively. In summary, the lowest CV event rates were seen in those receiving (i) the combination of RAS blockade and nifedipine GITS and (ii) in those specifically treated for ISH.

Gender Differences in Cardiac Remodeling and Clinical Outcomes in Chronic Stable Angina Pectoris (from the ACTION Trial)

Our objective was to determine the gender differences in the relation between the echocardiographic parameters of cardiac remodeling and clinical outcomes in patients with chronic stable angina. The baseline ejection fraction (EF), end-diastolic volume, and end-systolic volume were assessed in 7,016 patients in the study "A Coronary disease Trial Investigating Outcomes with Nifedipine gastrointestinal therapeutic system" (ACTION). All-cause and cardiac mortality and incident heart failure were determined after a median of 5.0 years. Cox proportional hazard models were fit to determine the effect of gender on the relation between the echocardiographic parameters and clinical outcomes (interaction p <0.10). The association between the EF and mortality differed significantly between men and women, with women demonstrating a marked increase in risk as the EF decreased, compared to men (interaction p = 0.03, adjusted p = 0.07). Also, a significant interaction by gender was seen for the association between the end-systolic volume and the risk of heart failure (interaction p = 0.01, adjusted p = 0.05). In conclusion, the relation between EF and mortality differed according to gender in patients with chronic coronary disease, with women having a greater risk of adverse outcomes as the EF decreased. Similar findings were observed with the end-systolic and end-diastolic volumes and the risk of heart failure. These findings may reflect inherent gender-based differences in ischemic heart disease and cardiac remodeling and might help to identify women at high risk.

Benefits of nifedipine GITS in stable coronary artery disease: further analysis of the “ACTION” database

Introduction Retrospective analyses of specific subgroups of patients from the database of the ACTION study have evaluated the effectiveness of a nifedipine gastrointestinal therapeutic system (GITS) on clinical outcomes. These subgroups included those patients receiving: 1) full “optimal” therapy at baseline; 2) full “optimal” therapy at baseline but excluding renin angiotensin system (RAS)-blocking drugs; 3) treatment with nifedipine GITS who were not treated with RAS blockers versus those treated with RAS blockers but not nifedipine GITS.

4225 Hematopoeitic stem cell donation: the sibling emotional experience

Background: The antihypertensive doxazosin works to decrease perivascular muscular tone, causing vasodilatation and hence a decrease in peripheral vascular resistance. To prevent the sharp decrease in blood pressure (BP), syncope, and other postural effects that may occur at the beginning of therapy with this drug, the dose must be adjusted. A new formulation, doxazosin gastrointestinal therapeutic system (GITS), allows slow release of the active agent so therapeutic serum levels are reached within 24 hours, rendering dose adjustment unnecessary and eliminating any first-dose effects.Objectives: The goals of this study were to evaluate the tolerability and effectiveness of (1) using doxazosin in the standard and new GITS formulations in adult patients with hypertension who either had uncontrolled or newly diagnosed disease, and (2) replacing standard-formulation doxazosin with doxazosin in the GITS formulation.Methods: This was a postmarketing, open-label, noncomparative, multicenter clinical study covering primary care patients diagnosed with essential uncontrolled arterial hypertension (AHT). Subjects could be patients who were undergoing drug therapy before enrollment or those diagnosed with AHT and/or treated for the disease for the first time on entering the study. The study covered a period of 6 to 9 months, divided into 2 phases. Phase 1 involved a minimum of 3 and maximum of 6 months of treatment with standard-formulation doxazosin. Phase 2 commenced with the changeover from standard-formulation doxazosin to the GITS formulation and lasted 12 weeks. The principal study variables included BP and the development of adverse events (AEs). At every visit, the patients were asked by an investigator whether they had suffered any AEs since the previous contact.Results: Of the total of 4512 patients initially enrolled, 3537 (78.4%) completed the study. A total of 285 patients were excluded for failing to comply with the inclusion criteria, leaving 4227 patients for analysis. In most instances, premature withdrawal from the study (16.3% [690/4227]) was due to loss to follow-up (37.2% [257/690]), followed by the development of AEs (27.8% [192/690]). Fifty-nine percent (2493/ 4226) of patients analyzed were men and 41.0% (1733/4226) were women (sex data not recorded for 1 patient), with a mean age of 62.4 years (SD, 10.6). Among the patients participating, 54.8% (2316/4227) presented with some type of associated disease. The percentage of patients undergoing monotherapy was 70.7% (2987/4227); the remainder (29.3% [1240/4227]) underwent a combined-therapy regimen using another antihypertensive drug in conjunction with doxazosin. The mean initial systolic and diastolic BPs were 160 ± 10.63 mm Hg and 95.26 ± 7.21 mm Hg, respectively. Reduction in systolic BP was 20.9 mm Hg in phase 1 and 3.8 mm Hg in phase 2. In the case of diastolic BP, the reduction was 13.3 mm Hg in phase 1 and 2.6 mm Hg in phase 2. The percentage of patients with controlled disease was 47.9% (1891/3949) by the end of phase 1 and 63.4% (2242/3537) by the end of phase 2. A total of 322 (7.6%) patients presented with 343 AEs, 37 (0.9%) of which were deemed severe (0.6% in phase 1 and 0.3% in phase 2). Limitations included the following: (1) the design of this study did not allow comparison of the 2 formulations regarding effectiveness or tolerability; (2) the patients who remained in the study after phase 1 were those less susceptible to toxicity from doxazosin; and (3) it is probable that the nonresponders were more likely to drop out of the study.Conclusions: Doxazosin in the standard formulation was effective and well tolerated for the purpose of lowering BP. Patients who tolerated the standard formulation also tolerated the switch to the GITS formulation. Finally, this substitution did not negatively impact the effectiveness of treatment of AHT.

Arg347Cys polymorphism of α1A-adrenoceptor gene is associated with blood pressure response to nifedipine GITS in Chinese hypertensive patients

Our objectives were to evaluate whether polymorphisms in the alpha1A- and beta2-adrenoceptor genes influence blood pressure response to nifedipine gastrointestinal therapeutic system (GITS). Hypertensive patients received daily treatment with an oral dosage of 30 mg nifedipine GITS for 16 days. Genotypes of the Arg347Cys polymorphism in the alpha1A-adrenoceptor gene and the Arg16Gly and Gln27Glu polymorphisms in the beta2-adrenoceptor gene were determined by TaqMan single-nucleotide polymorphism genotyping assay. The sixteenth-day steady-state plasma concentration of nifedipine was measured using HPLC with UV detection. Multivariate linear regression was performed in a total of 447 patients to evaluate the effects of these polymorphisms on blood pressure response to nifedipine GITS. Patients carrying the Cys347 allele of the alpha1A-adrenoceptor gene had a greater systolic blood pressure reduction than did those carrying two Arg347 alleles of the alpha1A-adrenoceptor gene (32.5+/-14.0 versus 27.3+/-15.5 mm Hg, respectively, P=0.006). However, diastolic blood pressure reduction was not associated with the Arg347Cys polymorphism in the alpha1A-adrenoceptor gene. In addition, no significant associations were observed between blood pressure reduction and two polymorphisms in the beta2-adrenoceptor gene. Our data suggest that the Arg347Cys polymorphism in the alpha1A-adrenoceptor gene may be used to predict blood pressure response to nifedipine GITS in Chinese hypertensive patients.

Nifedipine Concentration in Maternal and Umbilical Cord Blood After Nifedipine Gastrointestinal Therapeutic System for Tocolysis

Objective To determine nifedipine concentrations in maternal plasma at steady state, and maternal and umbilical cord plasma at delivery, after tocolysis with nifedipine gastrointestinal therapeutic system (GITS) tablets. Design Prospective clinical pharmacokinetic study. Setting Department of Obstetrics at the Zurich University Hospital. Population Pregnant women treated for threatened preterm labour. Methods GITS dosage titrated to clinical response (30–150 mg/day). Nifedipine concentrations by high-performance liquid chromatography and turbo ion spray tandem mass spectrometry. Main outcome measures Steady-state nifedipine concentrations in maternal blood and nifedipine concentrations in maternal and corresponding umbilical cord blood at delivery. Results Steady-state nifedipine concentrations (micrograms/l, mean ± SE) were 54 ± 6 (all doses, n = 31), 38 ± 8 (60 mg/day, n = 13), and 92 ± 12 (150 mg/day, n = 7) (P < 0.002). Umbilical cord and maternal concentrations both declined in a ln-linear regression with elimination half-lives of 20.4 and 17.4 hours. Linear regression showed a correlation between umbilical and maternal concentrations of 0.77 ± 0.1 (n = 21, mean ± SE). Conclusions Steady-state plasma nifedipine concentrations after repeated dosing with nifedipine GITS 30–150 mg/day in pregnant women with preterm labour do not exceed 100 micrograms/l; fetal levels are 77% of maternal levels.

The ACTION study: nifedipine in patients with symptomatic stable angina and hypertension

Coronary heart disease and cerebrovascular disease continue to be the leading causes of illness and death in adults from developed countries. High blood pressure is the most prevalent cardiovascular risk factor and, in clinical practice, coronary disease and hypertension often occur concurrently. Calcium antagonists are used in the treatment of hypertension and angina. In the mid-1990s there was considerable debate concerning the safety of calcium antagonists in the treatment of cardiovascular disease. A Coronary Disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system (ACTION) study was designed as a consequence of this discussion on calcium antagonists to investigate the effects of the long-acting calcium antagonist nifedipine gastrointestinal therapeutic system on clinical outcomes in patients with stable, symptomatic coronary disease (52% of whom were hypertensive). The aim of this review is to provide an update on the status of the reported ACTION study results from different studies and subgroups.

Effect of Vardenafil on Blood Pressure Profile of Patients With Erectile Dysfunction Concomitantly Treated With Doxazosin Gastrointestinal Therapeutic System for Benign Prostatic Hyperplasia

We investigated the effect of the combination of the doxazosin gastrointestinal therapeutic system and 10 mg vardenafil on the hemodynamic status of patients with benign prostatic hyperplasia and erectile dysfunction. This was a double-blinded, randomized, placebo controlled crossover trial. Patients with benign prostatic hyperplasia and erectile dysfunction treated with the doxazosin gastrointestinal therapeutic system on a regular basis, with no other antihypertensive events, were recruited. Subjects took 10 mg vardenafil or placebo in a randomized crossover fashion with a washout period of at least 7 days between each treatment. The supine and standing blood pressure of the subjects was recorded from 1 hour before to 6 hours after the administration of vardenafil or placebo. The primary outcome of the study was the maximal change in standing systolic blood pressure of the subjects from 1 half hour before to 6 hours after the administration of drugs. A total of 37 patients, 25 (67.6%) and 12 (32.4%) on the doxazosin gastrointestinal therapeutic system at 4 mg and 8 mg, respectively, completed the trial. The combination drug therapy resulted in a maximal decrease in standing systolic blood pressure of 6.18 mm Hg (95% CI -12.02, -0.33; p = 0.039). Only 1 patient had an asymptomatic standing systolic blood pressure of less than 85 mm Hg. Otherwise no symptomatic hypotension or clinically significant adverse cardiovascular event was observed during the study. In patients on the doxazosin gastrointestinal therapeutic system for benign prostatic hyperplasia a single 10 mg dose of vardenafil had no symptomatic hemodynamic effects.

Chronotherapy With Nifedipine GITS in Hypertensive Patients: Improved Efficacy and Safety With Bedtime Dosing

Previous studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium-channel blockers (CCBs), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the administration-time dependent antihypertensive efficacy of the slow-release, once-a-day nifedipine gastrointestinal-therapeutic-system (GITS) formulation. We studied 180 untreated hypertensives (86 men and 94 women), 52.5 +/- 10.7 years of age, randomly assigned to receive nifedipine (30 mg/day) as a monotherapy either upon awakening or at bedtime. BP was measured for 48 h before and after 8 weeks of treatment. The BP reduction after treatment was significantly larger with bedtime dosing mainly during night time sleep (P < 0.012). The number of patients with controlled ambulatory BP after treatment was greater with bedtime than morning treatment (P = 0.016). The baseline prevalence of nondipping was unaltered after ingestion of nifedipine on awakening, but reduced from 51 to 35% after bedtime dosing (P = 0.025). The morning surge of BP, a risk factor for stroke, was significantly reduced (P < 0.001) only after bedtime administration of nifedipine. Bedtime in comparison to awakening-time ingestion of nifedipine was also associated with a reduction in the incidence of edema from 13 to 1% (P < 0.001). The increased efficacy on ambulatory BP as well as the significantly reduced prevalence of edema after bedtime as compared to morning ingestion of nifedipine should be taken into account when prescribing this medication to patients with essential hypertension.

Effect of Doxazosin Gastrointestinal Therapeutic System as Third-Line Antihypertensive Therapy on Blood Pressure and Lipids in the Anglo-Scandinavian Cardiac Outcomes Trial

The role of doxazosin in treatment of hypertension remains controversial. We evaluated the effects on blood pressure (BP) and biochemical parameters of doxazosin GITS (gastrointestinal therapeutic system) as a third-line antihypertensive agent among 10,069 participants in the Anglo-Scandinavian Cardiac Outcomes Trial--Blood Pressure Lowering Arm (ASCOT-BPLA) whose BP remained above 140/90 mm Hg (130/80 mm Hg in those with diabetes mellitus). Among those who received doxazosin, mean age was 63 years (SD 9 years), 79% were male, and 32% had diabetes. Doxazosin was initiated a median of 8 months (interquartile range 3 to 24 months) after randomization and was added to a mean of 2.0 (SD 0.3) other antihypertensive drugs; the mean starting and final doses were 4.1 (SD 0.6) and 7.0 (SD 3.1) mg, respectively. During a median of 12 months (interquartile range 4 to 31 months) of uninterrupted doxazosin treatment, during which other antihypertensive treatments remained unchanged, mean BP fell 11.7/6.9 mm Hg (SD 18.8/9.6 mm Hg, P<0.0001) from 158.7/89.2 mm Hg (SD 18.3/10.6 mm Hg). After the addition of doxazosin, 29.7% of participants achieved target BP. There was no apparent excess of heart failure among doxazosin users. There were associated modest favorable effects on plasma lipid profiles, but a small rise in fasting plasma glucose was observed. Doxazosin was generally well tolerated, with 7.5% of participants discontinuing the drug because of adverse events, most frequently dizziness, fatigue, headache, and edema. alpha-Blockers are no longer recommended as add-on therapy in some hypertension guidelines. However, although they are nonrandomized and were not placebo-controlled, the present findings suggest that doxazosin is a safe and effective third-line antihypertensive agent.

Nifedipine gastrointestinal therapeutic system (GITS): a guide to its use in hypertension and angina pectoris

Nifedipine gastrointestinal therapeutic system (GITS): a guide to its use in hypertension and angina pectoris

Nifedipine gastrointestinal therapeutic system (GITS) as an alternative to slow-release for tocolysis—Tolerance and pharmacokinetic profile

Objective To determine nifedipine plasma concentrations after a loading dose of nifedipine 10 mg capsules, 40 mg over 1 h followed by slow-release tablets (60 mg/d) versus gastrointestinal therapeutic system (GITS) tablets (90 mg/d) for tocolysis. Study design Prospective study in 14 pregnant women treated for threatened preterm labor. Results Following capsule administration there was a rapid rise in plasma concentration of drug achieving a peak of 97.5 μg/l (median) at 1 h, then declined to 59.5 μg/l (median) at 5 h. The concentration measured at 7200 min (120 h) was non-significantly higher in the slow-release group (median 25.5, range 6.9–67.2 μg/l) than in the GITS group (median 14.6, range 6.0–20.0 μg/l). Area under the curve (AUC) increased with the applied dose in both groups in a linear regression. Headache was more frequent in the slow-release group than in the GITS group ( P = 0.001). Conclusions GITS tablets 90 mg/d are an alternative dosage regimen to previous used slow-release tablets 60 mg/d for tocolysis with similar pharmacokinetic profile and a good tolerance. However, tocolysis with GITS tablets is simpler than that with slow-release tablets and may be associated with a higher compliance. GITS tablets are therefore also qualified for home monitoring.

High doses of lercanidipine are better tolerated than other dihydropyridines in hypertensive patients with metabolic syndrome: results from the TOLERANCE study

Aims/IntroductionThe TOlerabilidad de LERcanidipino 20 mg frente a Amlodipino y Nifedipino en CondicionEs normales de uso study was aimed to compare the tolerability of high doses of lercanidipine with amlodipine and nifedipine gastro-intestinal therapeutic system (GITS) in the treatment of hypertension in daily clinical practice.Patients/methodsEssential hypertensives ≥ 18 years, treated during at least 1 month with lercanidipine 20 mg, amlodipine 10 mg or nifedipine GITS 60 mg, after a previous treatment course of at least 1 month with half the dose of the corresponding drugs were included. We present the data of the subgroup of patients with metabolic syndrome (MetS).ResultsThree hundred and thirty-seven of the 650 study population fulfilled criteria of MetS, 233 (69.1%) on lercanidipine and 104 (30.9%) on amlodipine/nifedipine GITS. Overall, a significantly lower proportion of lercanidipine-treated patients showed adverse reactions (ARs) when compared with patients receiving other-dihydropyridines (DHPs) (60.1% vs. 73.1%, p = 0.003). Similarly, the most common vasodilation-related ARs (oedema, swelling, flushing and headache) were significantly less frequent in lercanidipine group (all p < 0.01).ConclusionIn conclusion, lercanidipine appears to exhibit a better tolerability profile and less vasodilation-related ARs compared with other DHPs in hypertensive patients with MetS.

Nifedipine concentration in maternal and umbilical cord blood after nifedipine gastrointestinal therapeutic system for tocolysis

To determine nifedipine concentrations in maternal plasma at steady state, and maternal and umbilical cord plasma at delivery, after tocolysis with nifedipine gastrointestinal therapeutic system (GITS) tablets. Prospective clinical pharmacokinetic study. Department of Obstetrics at the Zurich University Hospital. Pregnant women treated for threatened preterm labour. GITS dosage titrated to clinical response (30-150 mg/day). Nifedipine concentrations by high-performance liquid chromatography and turbo ion spray tandem mass spectrometry. Steady-state nifedipine concentrations in maternal blood and nifedipine concentrations in maternal and corresponding umbilical cord blood at delivery. Steady-state nifedipine concentrations (micrograms/l, mean +/- SE) were 54 +/- 6 (all doses, n = 31), 38 +/- 8 (60 mg/day, n = 13), and 92 +/- 12 (150 mg/day, n = 7) (P < 0.002). Umbilical cord and maternal concentrations both declined in a ln-linear regression with elimination half-lives of 20.4 and 17.4 hours. Linear regression showed a correlation between umbilical and maternal concentrations of 0.77 +/- 0.1 (n = 21, mean +/- SE). Steady-state plasma nifedipine concentrations after repeated dosing with nifedipine GITS 30-150 mg/day in pregnant women with preterm labour do not exceed 100 micrograms/l; fetal levels are 77% of maternal levels.

Add-On Therapy with a Nighttime Dose of Doxazosin in Patients with Uncontrolled Hypertension: Effects on Autonomic Modulation of the Cardiovascular System

This study was designed to determine whether or not the addition of a single nighttime dose of doxazosin in extended-release form (GITS; gastrointestinal therapeutic system) would affect the autonomic modulation of the cardiovascular system in patients with uncontrolled hypertension treated with a multi-drug regimen. Resting 5-min noninvasive finger blood pressure and ECG signals, as well as 24-h Holter ECGs, were recorded in 30 patients with uncontrolled hypertension on multi-drug treatment before and after 16-week add-on therapy with doxazosin GITS. Cardiovascular autonomic modulation was evaluated by spectral analysis of heart rate variability (HRV) and a cross-correlation method for spontaneous baroreflex sensitivity (BRS) in 5-min resting recordings, and by the analysis of Poincaré plots and phase-rectified signal averaging of the duration of cardiac cycles in 24-h ECG recordings. This combined therapy significantly reduced systolic pressure (19.4+/-3.5 mmHg; p<0.0001), diastolic blood pressure (9.4+/-2.0 mmHg; p=0.0003), and pulse pressure (10.0+/-2.8 mmHg; p=0.0021). Concomitantly, there was a significant increase in resting spontaneous BRS (p=0.0191) and increases in 24-h short-term (p=0.0129) and total (p=0.0153) HRV, but with no significant change in heart rate or other measures of HRV. The improvements in HRV and BRS were observed mainly in patients already treated with thiazide diuretics. There was a significant association (r=0.49; p=0.0065) between the degree of change in diastolic blood pressure and short-term HRV caused by the combined treatment. The addition of 4 mg doxazosin GITS to multi-drug antihypertensive therapy is associated with an improvement in cardiovascular autonomic control.

Comparison of the effects of doxazosin and atenolol on target organ damage in adults with type 2 diabetes mellitus and hypertension in the CARDHIAC study: A 9-month, prospective, randomized, open-label, blinded-evaluation trial

Objective: The CARDHIAC® (CARduran en pacientes Diabéticos con HIpertensi'on Arterial no Controlada) trial examined the effects of doxazosin gastrointestinal therapeutic system (GITS) and atenolol on 3 separate measures of target-organ damage-left ventricular mass index (LVMI), carotid intima media thickness (IMT), and urinary albumin excretion (UAE) in patients with type 2 diabetes mellitus and hypertension. Method: This trial had a prospextive, open-label, blinded-evaluation design and a duration of 9 months. Patients whose blood pressure (BP) was uncontrolled (systolic BP≥130 mm Hg and/or diastolic BP≥80 mm Hg) despite at least 1 month of treatment with a reninangiotensin blocker and diuretic were randomly allocated to receive doxazosin GITS 4 mg or atenolol 50 mg once daily in addition to their existing treatment. Seated BP was measured at study visits at 1, 3, 6 and 9 months; if the BP goal was not achieved at any visit, the dose of doxazosin or atenolol was titrated upward to 8 or 100 mg, respectively. Treatment complaince (pill count) and adverse reactions were monitored at each visit. Each patient underwent echocardiography and Doppler ultrasonography at baseline and at the end of the study for evaluation of the change in LVMI. The change in carotid IMT was evaluated by carotid ultrasound examination at the same time points. UAE also was measured at baseline and the end of the study. Results: Sixty patients (100% white; 51% female; mean [SD] age, 63.4 [7.5] years; body mass index, 28.2 [3.4] kg/m 2) were randomized to receive doxazosin GITS (n=32) or atenolol (n=28) .At baseline, mean BP was 150.2 (10.6)/90.1 (7.3) mm Hg in the doxazasin group and 153.1 (13.8)/92.3 (6.1) mm Hg in the atenolol group ( P=NS). At the end of the study, BP had decreased by 10.1 (3.2)/5.2 (1.3) mm Hg in the doxazosin group and 12.2 (4.2)/6.3 (2.1) mm Hg in the atenolol group (both, P<0.001 vs baseline; P=NS between groups). Heart rate at the end of the study was 78(6) beats/min in the doxazosin group ( P=NS vs baseline) and 66(7) beats/min in the atenolol group ( P < 0.01 vs baseline and between groups). LVMI decreased by 10.8 in the doxazosin group ( P=0.001 vs baseline) and 4.2% in the atenolol group ( P=NS vs baseline; P=0.03 between groups). The changes in carotid IMT and UAE were not statistically significant between groups. Conclusions: In this study in hypertensive patients with type 2 diabetes, LVMI was significantly decreasded in doxazosin-treated patients relative to baseline and compared with atenolol-treated patients. The differences in carotid IMT and UAE were not statistically significant between groups.