Efficacy and safety of the single pill combination of amlodipine 10 mg plus valsartan 160 mg in hypertensive patients not controlled by amlodipine 10 mg plus olmesartan 20 mg in free combination

ABSTRACT

Background and objective: For patients with moderate hypertension (grade 2, defined as systolic blood pressure [SBP] 160–179?mmHg and/or diastolic blood pressure [DBP] 100–109?mmHg), current guidelines recommend initial combination therapy and rapid dose-adjustment to achieve blood pressure goal. In this study we investigated the efficacy and tolerability of the single pill combination of amlodipine 10?mg plus valsartan 160?mg (A?10?+?Val 160) in patients not controlled by the free combination of amlodipine 10?mg plus olmesartan 20?mg (A?10?+?O 20).

Methods: In this prospective, open-label, non-randomized trial, 257 patients with mean sitting DBP of 100–109?mmHg at trough entered a 4 week treatment phase with A?10?+?O 20 in free combination once daily. Patients in whom DBP remained uncontrolled were switched in a second 4 week treatment phase to A?10?+?Val 160. The primary efficacy variable was the reduction in DBP at week 8 compared to week 4 in the intent-to-treat population.

Results: In the total cohort, baseline SBP/DBP of 164.2?±?9.8/103.6?±?2.1?mmHg decreased by 19.2?±?12.4/14.1?±?7.4?mmHg at week 4. In patients who did not achieve BP control (n?=?175), subsequent treatment with A?10?+?Val 160 for 4 weeks reduced SBP from 149.6?±?11.1 at week 4 by 7.9?mmHg at week 8 (95% CI: 6.1–9.6, p?<?0.0001) and DBP from 93.4?±?3.9?mmHg by 9.1?mmHg (95% confidence interval: 8.1–10.2, p?<?0.0001). The combination of A?10?+?Val 160 was well tolerated, and the observed adverse events (15.3% of patients in phase 2) were consistent with the known drug profiles.

Conclusions: In a study designed to reflect typical clinical practice, in patients not controlled by the free combination of A?10?+?O 20, the single pill combination of A?10?+?Val 160 produced a statistically and clinically significant additional BP reduction and was well tolerated. Potential limitations of the design (open-label, non-controlled design, short term treatment) have to be taken into account.     

Efficacy and tolerability of the single-pill combination of aliskiren 300 mg/amlodipine 10 mg in hypertensive patients not controlled by olmesartan 40 mg/amlodipine 10 mg

Abstract

Objective:

We aimed to investigate whether the single pill combination (SPC) of aliskiren 300?mg and amlodipine 10?mg (ALIS 300/AMLO 10) improves blood pressure (BP) reduction in hypertensive patients not adequately controlled by the SPC olmesartan 40?mg and amlodipine 10?mg (OLM 40/AMLO 10).     

Rofecoxib 12.5 mg,rofecoxib 25 mg,and celecoxib 200 mg in the treatment of symptomatic osteoarthritis: results of two similarly designed studies

ABSTRACT

Objective: To compare the efficacy of rofecoxib and celecoxib for the treatment of knee or hip OA over 6 weeks.

Methods: Two similarly designed, multicenter, randomized, double-blind, placebo-controlled studies. Patients were randomly assigned 3:3:3:1 in Study 1 to once daily (QD) rofecoxib 12.5?mg (N = 456), rofecoxib 25?mg (N = 459), celecoxib 200?mg (N = 456), or placebo (N = 150) and 3:3:1 in Study 2 to QD rofecoxib 25?mg (N = 471), celecoxib 200?mg (N = 460), or placebo (N = 151). There was no rofecoxib 12.5?mg arm in Study 2. The primary outcome measure of both studies was pain at night over 6 weeks for rofecoxib 25?mg vs. celecoxib 200?mg. Efficacy comparisons with rofecoxib 12.5?mg in Study 1 were included as pre-specified study objectives but not as pre-specified study hypotheses. Secondary endpoints included Patient Global Assessment of Response to Therapy (PGART) over 6 weeks and over 1 week. Safety was evaluated through the assessment of spontaneously reported adverse experiences (AEs), evaluation of vital signs, and laboratory data reported by investigators and patients.

Results: For the primary endpoint, reduction in pain at night over 6 weeks in Study 1 was not significantly different between active treatments; in Study 2 rofecoxib 25?mg significantly (?p = 0.023) reduced pain at night compared with celecoxib 200?mg over 6 weeks. For the secondary endpoints, in both studies, significantly (?p < 0.05) more patients treated with rofecoxib 25?mg than celecoxib 200?mg had a good or excellent PGART over 6 weeks, and over the first week (?p < 0.01). In both studies, there were no significant differences between active medications in the incidence of reported overall, serious, or drug-related AEs. The reported AE rates with the active treatments were generally similar to those with placebo in the two studies.

Conclusions: Rofecoxib 25?mg was significantly better than celecoxib 200?mg in relieving night pain at 6 weeks in one study; this was not confirmed in the accompanying study.     

A placebo-controlled study of three agomelatine dose regimens (10 mg, 25 mg, 25–50 mg) in patients with major depressive disorder

A randomised placebo-controlled “dose relation study” was conducted in 549 patients who met the criteria for major depressive disorder, to evaluate the efficacy and safety of three doses regimens of agomelatine during 6 weeks: low fixed dosage (10 mg/day, n=133), fixed dosage (25 mg/day, n=138) and a flexible dosage with up-titration in case of insufficient improvement at week 2 (25–50 mg/day, n=137). At last post-baseline assessment, there were significant and incremental placebo-agomelatine differences on mean HAM-D₁₇ total scores in favour of each agomelatine dose regimen (2.46±0.76 points, p=0.001 at 10 mg; 4.71+0.75 points, p<0.0001 at 25 mg and 4.92±0.76 points, p<0.0001 at 25–50 mg) with statistically significant differences between 25 mg and 25–50 mg dose regimens compared to the 10 mg dose. The response rate according to HAM-D₁₇ was significantly higher in patients taking agomelatine than those taking placebo (difference of 16.1% at 10 mg p=0.005; 25.9% and 27.4% respectively at 25 mg and 25–50 mg, p<0.0001). The benefit of agomelatine was demonstrated in the subgroup of severely depressed patients in the 25 mg and 25–50 mg/day regimens. Consistent clinical response according to CGI variables and better social functioning were found in patients receiving agomelatine. All dose regimens of agomelatine were well tolerated and no unexpected adverse event was reported. This study provides evidence of a dose effect for agomelatine between 10 mg and the therapeutic dose regimen of agomelatine 25–50 mg: the efficacy of the higher dose regimens being more efficacious than the lowest (10 mg) daily dose. The data support a definitive statement regarding the utility of 25 mg as the threshold dose for initiating agomelatine in depressed patients.     

25 mg米非司酮用于紧急避孕的临床观察

用于临床的紧急避孕方法有很多,小剂量米非司酮用于紧急避孕已有多年,目前用于72小时内紧急避孕,已取得较好的避孕效果。为探讨25mg米非司酮用于无保护性性交后72～120小时内紧急避孕的效果,本文对146例无保护性性交后72～120小时内紧急避孕的健康妇女,一次性服用25mg米     

Relative bioavailability of a 5 mg mosapride/10 mg rabeprazole fixed dose combination tablet versus separate single tablets in healthy volunteers: a single-dose randomized open-label crossover study

Abstract

Objective:

To evaluate the relative bioavailability of a new formulation containing 5?mg mosapride and 10?mg rabeprazole (T) and compare it with the branded formulations of both drugs co-administered in separate tablets (R) to meet the regulatory requirements of bioequivalence in Argentina.     

Steady state bioequivalence study of dipyridamole ER and acetyl salicylic acid 200 mg + 25 mg capsules in adult healthy male and female volunteers under fasting condition

Abstract

The aim of the study was to evaluate the steady state pharmacokinetics and establish bioequivalence between the test (dipyridamole ER and acetyl salicylic acid 200?mg?+?25?mg capsules of Dr. Reddy’s Laboratories Limited, India) against equal doses of reference (AGGRENOX® retard capsule of Boehringer Ingelheim Pharma GmbH & Co., KG 55216 Ingelheim am Rhein, Germany) formulations in 72 healthy adult male and female volunteers under fasting conditions. This was an open-label, block randomized, multiple dose, two-period, two-sequence, cross-over study separated by a washout period of 8 days. On day 5 of each period, post-dose blood samples were collected up to 12?h and analyzed for dipyridamole, salicylic acid and acetyl salicylic acid using a validated LC-MS/MS method. The 90% CI for dipyridamole (AUC_(0–τ).ss, C_max.ss and C_min.ss) and for salicylic acid (AUC_(0–τ).ss, C_max.ss and %ptf) lie within the accepted bioequivalence range of 80.00–125.00%, thus permitting one to conclude for bioequivalence. In conclusion, both the formulations were well tolerated and the test product was bioequivalent to the reference product in terms of the rate and extent of absorption at steady state.     

α-Monofluoromethyldopa (MFMD) in combination withl-DOPA

Summary We have investigated the interaction of -monofluoromethyldopa (MFMD) with the effects of i.p. injectedl-DOPA (200 mg·kg^–1) on blood pressure and tissue catecholamines in normal and spontaneously hypertensive rats (SHR). MFMD 10 mg·kg^–1 (i.p.) effectively antagonizes thel-DOPA induced increase in heart dopamine (DA). This action is also seen after 15 or 50 mg·kg^–1. The accumulation of DA in the brain is very much reduced by MFMD 50 mg ·kg^–1 while after 15 or, especially, 10 mg·kg^–1 more DA is formed in the rrain than afterl-DOPA alone, probably due to the peripheral decarboxylase inhibition which presents morel-DOPA to the brain. We conclude that MFMD 10 mg ·kg^–1 gives a relatively selective peripheral inhibition of the decarboxylation ofl-DOPA and this dose combination was accordingly found to result in a reduction of blood pressure in conscious animals. This hypotensive response tol-DOPA was attenuated after MFMD 15 mg·kg^–1 and was absent after MFMD 50 mg·kg^–1. Interestingly, the hypotensive effect ofl-DOPA after MFMD 10 or 15 mg·kg^–1 was more pronounced in SHR.     

Effect of food on the pharmacokinetics of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet in healthy volunteers

ABSTRACT

Objective: Vildagliptin is an orally active, potent and selective DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha- and beta-cell responsiveness to glucose.

Research design and methods: This open-label, single-center, randomized, two-period crossover study in healthy subjects (n = 23) ages 18–45 years investigated the effect of food on the pharmacokinetics of vildagliptin and metformin following administration of a vildagliptin/metformin (50/1000?mg) fixed-dose combination tablet.

Results: Administration of the fixed-dose combination tablet following a high-fat meal had no effect on vildagliptin AUC_0–∞ (ratio of geometric mean for fed:fasted state, 1.10 [90?%?CI 1.03, 1.18]), C_max (ratio of means 0.98 [90?%?CI 0.85, 1.13]) or median t_max (2.5?h in fed and fasted states). The rate of absorption of metformin was decreased when given with food, as reflected by the prolonged t_max (2–4?h) and reduction in C_max (by 26?%?), but the extent of absorption was not changed. The food effect on the metformin component of the fixed-dose combination tablets was consistent with, but of a lesser magnitude compared with data stated.

Conclusions: The vildagliptin/metformin (50/1000?mg) fixed-dose combination tablet can be administered in the same manner as metformin, and can be recommended to be taken with meals to reduce the gastrointestinal symptoms associated with metformin.     

Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg,omeprazole 20 mg,pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms

Objective To compare the effect of esomeprazole 40 mg with lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg on intragastric pH during single and repeated dosing in four separate studies in patients with symptoms of gastro-oesophageal reflux disorder (GERD).Methods In four randomised crossover studies, patients with symptoms of GERD received once-daily treatment with esomeprazole 40 mg or lansoprazole 30 mg (study A), omeprazole 20 mg (study B), pantoprazole 40 mg (study C) and rabeprazole 20 mg (study D) for 5 days. Continuous 24-h intragastric pH recording was performed on days 1 (except study B) and 5. Percentage of time over 24 h with intragastric pH greater than 4, 24-h median pH and the proportion of patients with pH greater than 4 for greater than or equal to 12 h and 16 h during the 24-h recording periods were investigated.Results In all four studies, esomeprazole 40 mg OD maintained intragastric pH greater than 4 for a significantly higher mean percentage of the 24-h period compared with all other proton pump inhibitors (PPIs) on days 1 (esomeprazole 40.6% versus lansoprazole 33.4%, P=0.0182; esomeprazole 50.3% versus pantoprazole 29.1%, P<0.001; esomeprazole 41.0% versus rabeprazole 29.4%, P=0.002) and 5 (esomeprazole 57.7% versus lansoprazole 44.5%, P<0.0001; esomeprazole 69.8% versus omeprazole 43.7%, P<0.0001; esomeprazole 67.0% versus pantoprazole 44.8%, P<0.001; esomeprazole 59.4% versus rabeprazole 44.5%, P<0.0001). Higher 24-h median pH and a higher proportion of patients with intragastric pH greater than 4 for greater than or equal to 12 h and 16 h were reported with esomeprazole 40 mg OD than with all the other PPIs in each study.Conclusion Esomeprazole 40 mg provides greater acid control in more patients and maintains intragastric pH greater than 4 for a longer period than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with symptoms of GERD.The experiments within this paper comply with the current laws of the countries in which they were conducted.     

全剂量ARB／HCTZ正式在全国上市

本刊讯 （《中国当代医药》记者凌寒）“我国是一个高血压大国,流行病学调查提示,目前我国高血压防控现状呈现“三高三低”,即患病率高、死亡率高、致残率高和知晓率低、治疗率低、控制率低。因此,加强我国高血压临床诊疗规范性,普及患者教育,提高其对治疗的依从性是高血压防控工作中的重要内容,而优化的高血压治疗方案可增加疗效,从而改善患者依从性。血管紧张素Ⅱ受体拮抗剂（ARB）与利尿剂是两种不同降压机制药物,其联合治疗是国内外指南推荐的优选组合之一。”这是中国老年学学会心脑血管病专业委员会主任委员胡大一教授对我国高血压现状所做的介绍。     

Clinical effectiveness of low-dose chlorthalidone (6.25 mg) + atenolol combination in stage I hypertensive patients: a multicenter,randomized, controlled study

ABSTRACT

Objective: To compare the efficacy and safety of low-dose chlorthalidone + atenolol combination with atenolol and atenolol + amlodipine combination in stage I hypertensive patients uncontrolled on active run-in monotherapy.

Methods: Newly diagnosed stage I hypertensive patients were randomized to active run-in monotherapy either with atenolol 25?mg (98/300) or chlorthalidone 6.25?mg (100/300) or amlodipine 2.5?mg (102/300). A total of 282/300 patients (atenolol 92, chlorthalidone 91, amlodipine 99) completed the active run-in phase successfully. Patients uncontrolled on active run-in monotherapy (atenolol 33, chlorthalidone 45, amlodipine 47) received the study treatment, namely atenolol 50?mg alone, chlorthalidone 6.25?mg + atenolol 25?mg and atenolol 25?mg + amlodipine 2.5?mg, respectively. Efficacy of the therapy was evaluated by BP measurement at weeks 12 and 20 post-therapy.

Results: Post-active run-in monotherapies, the study treatment groups showed a significant fall in mean SBP and DBP from baseline (p?<?0.05). The mean fall in SBP and DBP was comparable for study treatments (atenolol 50?mg, atenolol 25?mg + chlorthalidone 6.25?mg and atenolol 25?mg + amlodipine 2.5?mg) (p = 0.337 for SBP and p = 0.054 for DBP) at week 12 and (p = 0.744 for SBP and p = 0.855 for DBP) at week 20; also, the percentage of responders was comparable for the three study treatment groups (p = 0.799) indicating that the low-dose chlorthalidone + atenolol combination is non-inferior to the high-dose atenolol alone and atenolol + amlodipine combination. No serious laboratory/clinical adverse events were reported in this study.

Conclusion: Chlorthalidone 6.25?mg in combination with atenolol 25?mg is effective and safe in stage I (JNC 7) essential hypertensive patients. This low dose of chlorthalidone could reduce dose-related concerns over metabolic adverse effects and may lead to wider usage of this proven antihypertensive agent in combination therapy.     

A comparative double-blind study of loprazolam, 1 mg and 2 mg,versus placebo in anxiety-induced insomnia

Summary

A double-blind trial was carried out in 40 anxious in-patients with insomnia to compare the hypnotic effectiveness and tolerance of loprazolam, 1?mg and 2?mg, versus placebo. Groups of 10 patients received one or other dose of loprazolam or placebo for 7 nights and then placebo for the following 3 nights. Sleep quality and morning residual efiects were assessed each morning during the 10-day trial period by means of a sleep questionnaire. The results showed that I?mg loprazolam was superior to placebo but less effective than 2?mg loprazolam. No side-effects were reported at either dose level.     

Pharmacokinetic Dose Proportionality Between Two Strengths (12.5?mg and 25?mg) of Doxylamine Hydrogen Succinate Film-Coated Tablets in Fasting State: A Single-Dose,Randomized, Two-Period Crossover Study in Healthy Volunteers

Background

Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years.

Objective

The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects.

Study Design

This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study.

Setting

The study was conducted in a phase I clinical unit.

Subjects and Methods

A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration–time curve (AUC_{t normalized}). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG).

Results

In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (C_max) and area under the concentration–time curve from time zero to time t (AUC_t) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean C_max 61.94 ng/mL, coefficient of variation (CV) 23.2 %; mean AUC_t 817.33 ng·h/mL, CV 27.4 %; and 25 mg: mean C_max 124.91 ng/mL, CV 18.7 %; mean AUC_t 1630.85 ng·h/mL, CV 22.8 %]. Mean AUC_{t normalized} was 815.43 ng·h/mL, CV 22.8 % for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUC_t was 98.92 (90 % CI: 92.46, 105.83). The most common adverse event was somnolence.

Conclusions

Exposure to doxylamine was proportional over the therapeutic dose range of 12.5–25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.