The pharmacodynamic and pharmacokinetic profiles of controlled-release formulations of felodipine and metoprolol in free and fixed combinations in elderly hypertensive patients

AIMS: The aims of this study were to study the efficacy and tolerability of felodipine extended release (ER) 5 mg and metoprolol controlled release (CR/ZOC) 50 mg given as a fixed combination (Logimax) or as a free combination in elderly (age greater than 60 years) hypertensive patients, using ambulatory blood pressure (BP) monitoring. A secondary aim was to relate the efficacy of the free and fixed combinations with pharmacokinetic profiles. METHODS: This was a double-blind, placebo-controlled randomised three-way crossover multi-centre study. BP was measured for 26 h using ambulatory blood pressure monitoring (ABPM), which was performed on the last day of the three treatment phases. RESULTS: Mean sitting BPs, measured during the trough period with ABPM, were significantly lower with both the free and fixed combinations of metoprolol and felodipine than placebo (141/83 mmHg free, 140/83 mmHg fixed, 156/93 mmHg placebo). The mean BPs measured over 24 h using ABPM were 143/82 mmHg, 140/82 mmHg and 158/93 mmHg for the free, fixed and placebo treatment arms, respectively. The trough-to-peak ratios (T:P) were 75% and 79% for the systolic BP and 70% and 70% for the diastolic BP for the free and fixed combinations, respectively. Pharmacokinetic evaluation revealed identical plasma concentration-time curves for felodipine given as the free or fixed combination. Comparison of the plasma concentration-time curves for metoprolol revealed a delay in the release rate from the fixed combination formulation. No significant differences in BP control between the active treatments were noted during this period. Of 26 patients entered into the study, 3 withdrew during active phase for non-drug-related reasons. No patient withdrew from active treatment due to treatment-related adverse events. The frequency of adverse event reporting for the fixed combination of felodipine and metoprolol was similar to that for placebo (60% and 58%, respectively). CONCLUSION: The results suggest that once-daily dosing with either the free or fixed combination of felodipine 5 mg and metoprolol 50 mg produces a significant sustained reduction in systolic and diastolic BP with similar plasma concentration profiles over a 24-h period.     

Pharmacokinetic interactions between felodipine and metoprolol

Summary This double-blind, cross-over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. During three, five-day study periods, felodipine 10 mg b.d., metoprolol 100 mg b.d. and a combination of the two, were given in random order. There was at least a 7-day washout period between each pharmacokinetic study day. Plasma levels of unchanged felodipine and metoprolol were measured for 24 h after the last dose, on the 5th day of each treatment period.Eight subjects, aged 19–22 years, completed the study. Both felodipine and metoprolol, given alone and in combination, were well tolerated.None of the felodipine pharmacokinetic variables (t_max, C_max, C_min, AUC (0–12) and t_1/2) changed significantly when felodipine and metoprolol were given in combination. C_max and AUC (0–12) for metoprolol increased significantly when metoprolol and felodipine were combined, although t_max, C_min and t_1/2 for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.     

Steady-State Bioavailability and Day-to-Day Variability of a Multiple-Unit (CR/ZOK) and a Single-Unit (OROS) Delivery System of Metoprolol After Once-Daily Dosing

Steady-state bioavailability and day-to-day variability of plasma levels were evaluated in 18 healthy male subjects in a crossover study of multiple once-daily administration of two novel oral drug delivery systems of metoprolol and an immediate-release tablet (100 mg metoprolol tartrate). Data were collected over two consecutive 24-hr dosing intervals on treatment days 6 and 7. The two extended-release formulations investigated were metoprolol CR/ZOK (95 mg metoprolol succinate), a multiple-unit system consisting of several hundred membrane-coated delivery units, and metoprolol OROS (95 mg metoprolol fumarate), a single-unit osmotic delivery system. The extended drug release and absorption observed after administration of metoprolol CR/ZOK and metoprolol OROS resulted in similar steady-state plasma concentrations after once-daily dosing. Compared to the immediate-release tablet, they produced considerably lower plasma peaks, three- to fourfold higher trough concentrations, 8–9 hr longer mean residence times, and 20% lower relative bioavailability. Moreover, the two once-daily metoprolol products were found bioequivalent in C _max and AUC based on 90% confidence intervals for the mean ratio CR/OROS. Repeated plasma concentration measurements on two consecutive 24-hr periods suggested that all three metoprolol treatments produced reproducible and consistent plasma concentrations from day to day at steady state. Assessment of day-to-day variability, however, resulted in significantly lower variation in AUC for the multiple-unit CR/ZOK formulation compared to the single-unit OROS tablet. These results imply that there may be formulation-related differences in the in vivo behavior of the two products despite their being bioequivalent in extent and rate of absorption.     

Haemodynamic and renal effects of felodipine in young and elderly subjects

Objective: To study the influence of age on renal and haemodynamic effects of the calcium antagonist felodipine. Methods: Eight young (mean age 27 years) and eight elderly (mean age 75 years) healthy normotensive subjects were given felodipine intravenously for 120 min aiming at close to therapeutic plasma level concentration. Renal blood flow (RBF) and renal vascular resistance (RVR) was estimated from para-aminohippuric acid (PAH) clearance ^51CrEDTA clearance was used to measure glomerular filtration rate (GFR) and used in the calculations of fractional excretion (FE) of electrolytes. Impedance cardiography was performed to assess stroke volume and for the calculation of cardiac output and ejection fraction. Results: At the end of felodipine infusion, the concentration of felodipine was on average 10.0 nmol · l⁻¹ in young and 12.0 nmol · l⁻¹ in elderly subjects (NS). During felodipine infusion blood pressure (BP) decreased from 138/76 to 120/68 in elderly subjects. The BP in young subjects was 126/74 at basal and 125/70 after infusion of felodipine. The systemic and renal vascular resistance decreased to a similar extent in young and elderly subjects after felodipine infusion. Felodipine caused a decrease in systemic vascular resistance from 25.6 to 23.3 in elderly and from 23.8 to 21.8 in the young subjects. Mean values for RVR at baseline and during infusion of felodipine were significantly higher in the elderly (10.1–15.1) than in the young subjects (5.4–6.7). Felodipine reduced RVR by 10% in the young and by 12% in the elderly at the end of infusion. The young subjects had 31% higher GFR than the elderly subjects at the start of infusion. Felodipine infusion did not affect GFR. There were no effects on stroke volume and ejection fraction. An initial natriuretic effect was found after infusion of felodipine in the young subjects. The fractional excretion of all electrolytes tended to increase after both felodipine and placebo, more in the elderly than in the young subjects. Conclusion: The effects of felodipine on central and renal haemodynamics previously observed in young and middle-aged subjects also seem to exist in the elderly. Volume expansion seems to increase the excretion of electrolytes more in elderly than in young people, and therefore the effect of felodipine on natriuresis is more evident in young subjects. Received: 25 October 1997 / Accepted: 7 April 1998     

Controlled release metoprolol formulations. A review of their pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and ischaemic heart disease.

Conventional formulations of metoprolol have become well established in cardiovascular medicine and are particularly useful in the management of hypertension and ischaemic heart disease. Recently developed controlled release metoprolol delivery systems (metoprolol CR/ZOK and metoprolol OROS) were designed to overcome the drug delivery problems of matrix-based sustained release forms by releasing the drug at a relatively constant rate over a 24-hour period, and thus producing sustained and consistent metoprolol plasma concentrations and beta 1-blockade while retaining the convenience of once daily administration. Clinically and statistically significant reductions in blood pressure have been observed with metoprolol CR/ZOK and metoprolol OROS 24 hours after administration in mildly or moderately hypertensive patients. Studies in patients with mild to moderate hypertension have demonstrated that a similar or higher percentage of patients achieved a goal response with metoprolol CR/ZOK compared with matrix-based sustained release formulations of metoprolol, or conventional atenolol or bisoprolol, while metoprolol OROS achieved an equal or greater response rate compared with conventional or matrix-based sustained release metoprolol preparations. In patients with stable effort angina pectoris, once daily administration of metoprolol CR/ZOK provided at least equal antianginal efficacy as conventional metoprolol in divided doses, while metoprolol OROS reduced the mean number of anginal attacks by the same margin as atenolol. Controlled release metoprolol formulations have been well tolerated in clinical trials. Metoprolol CR/ZOK was associated with a similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol. Metoprolol CR/ZOK also demonstrated less pronounced beta 2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects. Metoprolol OROS produced less pronounced bronchoconstrictor effects than atenolol, matrix-based sustained release metoprolol or long acting propranolol in patients with asthma or obstructive airways disease, and healthy volunteers. These results are presumably due to the beta 1-selectivity of metoprolol in addition to the relatively low plasma concentrations maintained by metoprolol CR/ZOK and metoprolol OROS, and the avoidance of high peak plasma concentrations with these agents. Despite the relative safety of the controlled release forms of metoprolol, the use of all beta-adrenoceptor antagonists should be avoided in patients with a history of bronchospasm. Thus, controlled release metoprolol formulations offer the potential to maximise the confirmed benefits of this agent in the management of hypertension and angina, by maintaining clinically effective plasma concentrations within a narrow therapeutic range over a 24-hour dose interval.     

Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine

Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements. Methods: Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake. Results: For cyclosporine, C_max was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and C_max (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and C_max were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg). Conclusion: A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and C_max of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine. Received: 28 August 1995/Accepted in revised form: 18 December 1995     

联合用药治疗高龄单纯收缩期高血压的疗效观察

目的探讨非洛地平缓释片联合小剂量美托洛尔加小剂量氢氯噻嗪治疗高龄（≥80岁）老年单纯收缩期高血压（ISH）的降压疗效和安全性。方法选择100例中、高危高龄（≥80岁）老年单纯收缩期高血压（ISH）患者,随机分为试验组和对照组,试验组：给予非洛地平缓释片（5mg,1次/d）;美托洛尔（12.5mg,2次/d）;氢氯噻嗪（12.5mg,2次/d）。对照组：给予硝苯地平缓释片（10mg,2次/d）;美托洛尔（12.5mg,2次/d）,氢氯噻嗪（12.5mg,2次/d）。比较两组治疗前后（2周末）的降压疗效及生化指标变化。结果试验组能显著降低收缩压与脉压,降压疗效试验组为94.0%、对照组为84.0%,两组比较差异有显著（P〈0.05）。两组心率及生化指标与基线值比较差异不显著（P〉0.05）。结论非洛地平缓释片联合小剂量美托洛尔加小剂量氢氯噻嗪能有效降低中、高危高龄（≥80岁）老年ISH患者的血压;以非洛地平缓释片为基础的降压治疗,在高龄（≥80岁）老年单纯收缩期高血压（ISH）的降压治疗中其疗效、安全性、依从性均较高。     

Conventional and controlled release diltiazem

Diltiazem CR tablets 120 mg b.i.d. for 1 week were compared with plain tablets 60 mg q.i.d. in 13 healthy male volunteers in a study of pharmcokinetic variables. Their antianginal efficacy was also compared in 23 patients with stable angina pectoris who were already on metoprolol. Both studies were of randomised, cross over design, and the clinical study was double blind.The pharmacokinetic variables of the two formulations were very similar except for the longer t_max of 4.4 h for diltiazem CR in comparison to 2.9 h for the plain tablets. The mean relative bioavailability of diltiazem CR in comparison with plain tablets was 1.14.The clinical study showed that after four weeks on diltiazem CR 120 mg b.i.d. or diltiazem plain tablets 60 mg q.i.d. in addition to metoprolol, there were significant decreases in weekly anginal attacks from 11 to 5 attacks/week, the number of nitroglycerin tablets consumed from 6 to 3 tablets/week, and an increase in the maximum workload from 116 to 126 and 123 W for diltiazem CR and plain diltiazem tablets, respectively, as compared to placebo. Five of the patients were angina free during diltiazem treatment. No difference in antianginal efficacy between the two preparations was seen. It was concluded that CR 120 mg b.i.d. appears bioequivalent to plain diltiazem tablets 60 mg q.i.d.     

The interaction effect of grapefruit juice is maximal after the first glass

Objective: To compare the acute effect of grapefruit juice intake on the pharmacokinetics and haemodynamic effects of felodipine ER tablets with the interaction after 14 days′ intake of drug with juice. Methods: Twelve healthy male volunteers were included in this cross-over trial and randomly allocated to a daily intake of a 10-mg felodipine extended release tablet with water or grapefruit juice for 14 days. The two study periods were separated by at least 14 days. The pharmacokinetics of felodipine and dehydrofelodipine, as well as the haemodynamic effects of the drug, were studied during day 1 and 14 in each period. Results: Similarly to previous single-dose studies, the treatment during the first day with grapefruit juice increased the AUC (+73%) and C_max (+138%) of felodipine when compared with the control treatment. On day 14 a similar effect of grapefruit juice was observed, with an increased AUC₂₄ (+57%) and C_max (+114%) of felodipine compared with the control experiment. A significant accumulation of felodipine occurred during both the control (+37%) and grapefruit juice (+25%) period. The extent of accumulation was not significantly different in the two treatment periods. The pharmacokinetics of the metabolite dehydrofelodipine were affected to a similar extent by the juice on day 1 and day␣14. The first dose of felodipine together with grapefruit juice was associated with a significant additional increase in heart rate when compared with the control therapy, whereas there was no additional effect on blood pressure when therapy included grapefruit juice. On day 14 the intake of drug with juice resulted in an additional increase in heart rate and reduction in diastolic blood pressure in comparison with the control experiment. Furthermore, the vascularly related adverse events were more frequent in the period including grapefruit juice. Conclusion: The interaction between grapefruit juice and felodipine appears to be already fully developed after the first glass of grapefruit juice, as the change in pharmacokinetics in comparison with the control experiment is similar on day 1 and on day 14. Concomitant intake of 10 mg felodipine ER and the juice is associated with increased haemodynamic effects in healthy subjects both after a single dose and following 14 days of concomitant intake. Received: 6 June 1997 / Accepted in revised form: 12 November 1997     

Pharmacokinetics and tolerability of a new manidipine and delapril fixed oral combination in young and elderly subjects

OBJECTIVES: The aim of the present study was to compare the pharmacokinetic and pharmacodynamic properties of a fixed combination tablet containing 10 mg of manidipine dihydrochloride (CAS 89226-75-5), a calcium channel antagonist, and 30 mg of delapril hydrochloride (CAS 83435-67-0), an angiotensin converting enzyme (ACE) inhibitor, during once daily repeated dosing in young and elderly subjects and to assess the bioequivalence of the fixed combination tablet and the single ingredient tablets taken simultaneously in young healthy subjects after a single dose administration. METHODS: Eighteen young healthy male volunteers received a single oral dose of 10 mg manidipine and 30 mg delapril as two separate tablets or a fixed combination tablet, followed by a week of once daily dosing with the fixed combination. Eight male and eight female elderly volunteers also received a week of once daily dosing with the fixed combination. Blood samples were collected during 24 h on the first and last treatment day for plasma determination of manidipine, delapril and their main metabolites, using specific LC-MS/MS methods. Blood pressure and heart rate were also recorded during 24 h. RESULTS: Bioequivalence was strictly demonstrated between the extemporaneous and the fixed combination tablet after single dose administration. At steady-state in young subjects, manidipine AUC and Cmax were lower (-8 and -12%) and t1/2 was longer (+45%), while delapril and metabolites were little affected as compared to single dose. In elderly subjects, manidipine Cmax was 4% lower than after single dose, AUC was 13% higher, and t1/2 was increased 2.4-fold. For delapril and active metabolites, Cmax and AUC increased modestly. Blood pressure and heart rate versus time profiles after single dose and at steady-state were almost superimposable. In elderly compared to young subjects at steady-state, peak concentrations of manidipine and delapril changed by +35% and -15% while AUCs increased by +70% and +9.7%. CONCLUSION: The fixed combination tablet of 10 mg manidipine and 30 mg delapril is bioequivalent to mono-ingredient tablets. At steady-state, the pharmacokinetic and pharmacodynamic profiles in young and elderly subjects undergo minor changes and indicate negligible accumulation. Drug exposure is higher in elderly subjects.     

Felodipine/metoprolol: a review of the fixed dose controlled release formulation in the management of essential hypertension

The main objective of fixed dose combination therapy for hypertension is to improve blood pressure (BP) control with lower, better tolerated dosages of 2 antihypertensives rather than higher dosages of a single agent. Felodipine and metoprolol lower BP via different, but complementary, mechanisms and controlled release formulations of these 2 drugs are available as a fixed dose combination, felodipine/metoprolol. In clinical trials in patients with hypertension, felodipine/metoprolol was significantly more effective than placebo and the respective monotherapies administered at the same dosages. Mean BP was reduced to < 155/90 mm Hg in patients treated with combination therapy and controlled in approximately 70% of patients. In one study that titrated dosages to effect, fewer felodipine/metoprolol than felodipine or metoprolol monotherapy recipients required dosage increases to achieve BP control (45 vs 60 and 67%, respectively). Data from double blind comparative studies show that the antihypertensive efficacy of felodipine/metoprolol 5 to 10/50 to 100 mg/day is significantly greater than that of enalapril monotherapy or captopril plus hydrochlorothiazide and equivalent to nifedipine/atenolol and amlodipine. In comparisons with enalapril, fewer felodipine/metoprolol than enalapril recipients required dosage titration to achieve BP control. Compared with amlodipine, felodipine/metoprolol significantly reduced mean 24-hour average BP (8.9/5.5 vs 14.4/9.5 mm Hg after 6 weeks; p < 0.001). Both treatments preserved diurnal rhythm. Long term follow-up studies show that the antihypertensive effect of felodipine/metoprolol occurs mostly during the first month of treatment with small additional decreases in BP being observed in the second and third months, and a relatively constant effect thereafter. According to a validated questionnaire, quality of life was relatively similar during 12 weeks treatment with felodipine/metoprolol, enalapril or placebo. In a retrospective pharmacoeconomic analysis conducted in Sweden, felodipine/metoprolol was more cost effective than enalapril as initial treatment for hypertension. Peripheral oedema, headache and flushing were the most commonly reported adverse events with felodipine/metoprolol and felodipine monotherapy, whereas dizziness, fatigue, headache and respiratory infection were more frequent with metoprolol monotherapy. Dose-dependent adverse events such as oedema may occur less often in patients taking lower dosages in combination than in those taking higher dosages of felodipine monotherapy. Thus, patients with hypertension treated with felodipine/metoprolol experience greater control of BP, with less need for dosage titration, than those treated with felodipine, metoprolol or enalapril monotherapy. Importantly this greater efficacy does not appear to be associated with a higher incidence of adverse events relative to monotherapy. Additionally, in short term studies felodipine/metoprolol had a similar (minimal) effect on QOL to enalapril monotherapy but was more cost effective.     

Effect of menthol on the pharmacokinetics and pharmacodynamics of felodipine in healthy subjects

Objectives The present study was undertaken to determine whether menthol affects the metabolism of and pharmacological responses to the calcium channel antagonist felodipine in people.Methods Eleven healthy subjects (ten female, one male) participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of felodipine ER tablet (Plendil, 10 mg) with menthol (test) or placebo (reference) capsules. Ten subjects completed the study. At the beginning of the study, a 10-mg felodipine ER tablet and a 100-mg menthol or placebo capsule were given. During the 2^nd, 5^th and 7^th hours of the study, 50, 25 and 25 mg menthol or placebo capsules were given, respectively. Blood samples and cardiovascular measurements were obtained at frequent intervals. Serum felodipine and dehydrofelodipine concentrations were determined by means of gas chromatography/mass spectrometry.Results Pharmacokinetic parameters of felodipine and dehydrofelodipine (AUC_0–24, C _max, t _max, dehydrofelodipine/felodipine AUC_0–24 ratio) were not markedly changed with menthol coadministration. Only eight female subjects cardiovascular data were included in the analysis because of technical problems during the measurements. There were no statistically significant differences in blood pressures and heart rates between the two treatments.Conclusions We conclude that the pharmacokinetics and pharmacodynamics of felodipine were essentially unaltered by menthol.     

In?Silico Comparison Between Metoprolol Succinate and Bisoprolol on 24-Hour Systolic Blood Pressures

Objective

To compare the effects of bisoprolol and metoprolol CR/ZOK (metoprolol succinate controlled release) on systolic blood pressure (bp_sys) over a 24-h period in an in silico model.

Methods

On the basis of the observed data from ambulatory blood pressure measurements (ABPM), a model with an appropriate distribution and correlation structure was derived for simulation of 24-h bp_sys patterns during treatment with commonly studied doses, assumed to be equipotent, of bisoprolol and metoprolol CR/ZOK. Input into the simulations was aligned with the available data on the diurnal efficacy and pharmacology profiles of these substances. The validity of the model was tested in a bootstrap model.

Results

The simulation model reproduced the observed data with high congruence (p = 1.0). The mean 24-h bp_sys values did not significantly differ between the two simulated groups (estimated overall change in bp_sys [∆bp_sys] for metoprolol versus bisoprolol = 2.7 mmHg [95 % confidence interval −0.3 to 5.7 mmHg]; p = 0.08). There were clear diurnal differences, with bisoprolol being more effective earlier and metoprolol CR/ZOK being more effective later in the 24-h day. A validity test with 100 repeated samples gave an overall mean group difference of 1.4 ± 3.59 mmHg (p = 0.63 relative to simulation).

Conclusion

In a robust model for the simulation of 24-h ABPM, comparisons between bisoprolol and metoprolol CR/ZOK indicate a comparable overall blood pressure-lowering effect but different diurnal patterns, consistent with the pharmacokinetics of the two drugs. This difference may be of clinical relevance, given the recognized diurnal pattern of cardiovascular events.     

Subjective symptoms and pharmacokinetics/dynamics of metoprolol CR in elderly subjects — a comparison with atenolol

Summary In a double-blind, randomised, cross-over study, the pharmacokinetic/dynamic effects and subjective symptoms of a new controlled-release (CR) formulation of metoprolol (50 and 100 mg) have been compared with atenolol (50 mg) and placebo in 20 elderly healthy subjects.The metoprolol CR formulation displayed an even plasma concentration-time profile over the dosage interval while atenolol produced a peak at 2–4 h. All three active treatments produced significant ₁-blockade at 24 h compared to placebo. Four hours after dose intake, the degree of ₁-blockade was significantly greater with conventional atenolol 50 mg than with either dose of metoprolol CR. Subjective well-being was examined with a self-administered questionnaire (MSE-profile), including three dimensions: Contentment, Vitality and Sleep. No significant differences were detected between placebo and either dose of metoprolol CR. At 2 h, following atenolol, a deterioration in Vitality was observed compared to placebo and metoprolol CR 100 mg. At the end of the dosage interval there was no longer any significant difference between the treatments. Perceived leg fatigue during exercise, evaluated 4 h after dosing, was more pronounced during treatment with atenolol than metoprolol CR 50 mg.The results suggest that the metoprolol CR formulation was not associated with significant effects on subjective well-being, whereas atenolol caused a deterioration at the time of the peak plasma concentration of the drug.     

Pharmacokinetics of felodipine extended-release tablets in healthy Taiwanese subjects: a retrospective review

The objective of this study was to investigate the pharmacokinetics of felodipine (CAS 72509-76-3) in healthy male Taiwanese subjects. This is a retrospective review of five felodipine pharmacokinetic studies completed in Taiwan. A total of 100 evaluable healthy Taiwanese males were enrolled in these studies. The subjects received 5 mg (n = 80) or 10 mg (n = 20) of Plendil (felodipine extended-release tablets; felodipine ER) once daily for 6 days. The mean +/- SD t(max,ss,) CG(max,ss) and AUG(tau) of dose normalized to 10 mg felodipine was 3.32 +/- 1.33 h, 13.12 +/- 5.34 nmol/L and 136.33 +/- 63.18 nmol x h/L, respectively. By using Kolmogorov-Smirnov's test and probit plots, the results indicated that the frequency distribution of AUC/dose, C(min)/dose and CL/F was bimodal. Compared to data from the literature, the mean C(max,ss) and AUG(tau) of 5 mg felodipine in healthy young Taiwanese subjects were similar to or slightly lower than data from Swedish, Danish, Turkish and Canadian studies in healthy young subjects who received 10 mg felodipine. Comparable C(max) values and approximately 30% lower AUC values were observed when comparing the 5 mg Taiwanese data to data in healthy elderly German subjects who also received 5 mg felodipine. Taiwanese subjects might have lower CYP3A4 activity to metabolize felodipine, which is similar to the phenomenon observed with nifedipine.     

Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets

The pharmacokinetic and pharmacodynamic properties of a new multiple-unit, controlled-release (CR) formulation of metoprolol¹ (metoprolol succinate, 95 mg once daily), which has almost constant (zero-order) release properties over most of a 24-h dose interval, have been compared with those of conventional metoprolol tablets (metoprolol tartrate, 100 mg once daily and 50 mg twice daily), in 12 healthy male volunteers.The steady-state plasma concentrations of metoprolol after five days of treatment varied less throughout the day with the CR than with the conventional formulation. This was associated with a considerably lower peak plasma concentration and the achievement of a significantly higher plasma concentration at the end of the dose interval.     

消炎汤调节肠道微生态改善大鼠慢性盆腔炎的研究

目的探讨消炎汤通过调节肠道微生态的变化对慢性盆腔炎大鼠的治疗作用。方法采用子宫内注射苯酚胶浆建立大鼠慢性盆腔炎模型,造模2周后ig消炎汤5、10、20 g/kg,连续14 d,观察大鼠子宫内膜形态,qPCR检测子宫组织中细胞间黏附分子(ICAM-1mRNA)表达情况,并采用16SrRNA高通道测序观察慢性盆腔炎大鼠肠道菌群的构成和比例。结果各给药组中充血水肿现象少见,且炎症浸润程度好于妇科千金片组。与模型组相比,消炎汤各剂量组子宫组织中ICAM-1mRNA的表达均有下调,尤以消炎汤20 g/kg组为甚(P0.01)。与模型组相比,消炎汤20 g/kg组Simpson指数显著上升(P0.05)。给予消炎汤治疗后肠道菌群多样性、丰度均得到一定程度改善,但未见统计学差异。与模型组相比,消炎汤10、20g/kg组乳杆菌、梭状芽孢杆菌OUT比例有不同程度升高。治疗后,消炎汤20、10g/kg组OUT比例较模型组明显下降。结论消炎汤能够明显改善慢性盆腔炎大鼠子宫的炎症程度,有效减少黏连的发生,作用机制与其调节肠道微生态影响雌激素代谢有关。     

非洛地平-美托洛尔透皮贴剂与缓释片在兔体内药动学及生物利用度比较

目的：研究非洛地平-美托洛尔复方透皮贴剂与两药市售缓释片在兔体内药动学和生物利用度差异。方法：采用三周期随机交叉试验法，6只健康白兔随机分为3组，分别给予复方非洛地平-美托洛尔静脉注射液、透皮贴剂及两药市售缓释片各l片，以气相色谱-电子捕获法分别测定非洛地平和美托洛尔血药浓度，用DAS软件计算药动学参数和生物利用度，通过统计学检验评价不同剂型间差异。结果：透皮贴剂较口服缓释片药物吸收时间显著延长（P〈0.05），达峰时间显著推后（P〈0．05），血药浓度平稳，波动性小，体内作用时间长达2d-3d。贴剂中非洛地平和美托洛尔的生物利用度分别是其口服缓释片的114．30％和192．92％。结论：该贴荆缓释特征明显，达到了预期提高生物利用度、延长药物体内驻留时间、维持平稳血药浓度和方便用药的新剂型设计目的。     

Antihypertensive efficacy and tolerability of a fixed combination of metoprolol and felodipine in comparison with the individual substances in monotherapy. The Swedish/United Kingdom Study Group.

In this double-blind, randomized, parallel-group study, the aim was to compare the efficacy and tolerability of a new fixed combination of felodipine and metoprolol with the individual components in monotherapy. After a placebo period of 4 weeks, 159 patients with mild to moderate essential hypertension were randomized to extended-release formulations of either felodipine plus metoprolol 10 + 100 mg (FM), felodipine 10 mg (F), or metoprolol 100 mg (M) once daily if supine diastolic blood pressure greater than 95 mm Hg. After 12 weeks of active treatment, the reductions in supine blood pressure (24 h after dosing) were 20/14, 13/10, and 11/8 mm Hg for FM, F, and M, respectively. The difference in change was 7/4 mm Hg (p = 0.004/p = 0.006) and 8/5 mm Hg (p = 0.0002/p less than 0.0001) for the fixed combination and F or M, respectively. Blood pressure control (diastolic blood pressure less than 90 mm Hg after 12 weeks) was significantly better for the combination than for F and M, i.e., 71%, 49% (p = 0.008), and 34% (p = 0.004), respectively. Adverse experiences were those to be expected from previous studies with felodipine and metoprolol and did not differ in frequency between groups. It can be concluded that a fixed combination of metoprolol and felodipine has a clinically relevant and significantly better blood pressure reduction 24 h postdose than the individual substances in monotherapy, without decreased tolerability.     

Mesalazine granules are superior to Eudragit-L-coated mesalazine tablets for induction of remission in distal ulcerative colitis - a pooled analysis

Aliment Pharmacol Ther 2011; 34: 1115–1122

Summary

Background Different oral formulations of ‘mesalazine (mesalamine)’ may have different efficacy in distal ulcerative colitis. Aim  To evaluate the efficacy of mesalazine granules (Salofalk granules) vs. mesalazine tablets (Salofalk tablets) as induction therapy in patients with distinct extensions of ulcerative colitis. Methods A pooled analysis of 705 patients from four prospective, randomised, double‐blind phase III trials was performed. The efficacy of 8 weeks’ induction with 3 g/day mesalazine granules [3 g once daily (o.d.) or 1 g three times daily (t.d.s)] vs. 3 g/day mesalazine tablets (1 g t.d.s.) was compared in terms of clinical remission (CR: CAI ≤ 4) and endoscopic remission (ER: EI ≤ 3) (both according to Rachmilewitz) in subgroups with pancolitis, left‐sided colitis, or proctosigmoiditis. Results Mesalazine granules were equipotent to mesalazine tablets in pancolitis regarding CR (72% vs. 71%, P = 0.909) and ER (58% vs. 49%, P = 0.338). In left‐sided colitis, both mesalazine formulations were equipotent regarding CR (66% vs. 67%; P = 0.843) but mesalazine granules were superior regarding ER (56% vs. 37%; P = 0.025). In proctosigmoiditis, mesalazine granules were significantly more effective than mesalazine tablets regarding CR (78% vs. 55%P < 0.001) and ER (67% vs. 43%P < 0.001). Furthermore, o.d. application of mesalazine granules was more effective than t.d.s. dosing in left‐sided colitis (CR 73% vs. 62%, P = 0.181; ER 71% vs. 48%P = 0.005) and proctosigmoiditis (CR 86% vs. 73%, P = 0.020; ER 75% vs. 61%, P = 0.021), but not in pancolitis. Conclusion This pooled analysis supports the hypothesis that mesalazine granules are superior to mesalazine tablets in induction of remission in distal colitis and should be taken once daily.