The antihypertensive efficacy and tolerability of a low dose combination of ramipril and felodipine ER in mild to moderate essential hypertension

1. The antihypertensive efficacy and tolerability of a low dose combination of the angiotensin converting enzyme inhibitor ramipril (2.5 mg) and the extended release formulation of the dihydropyridine calcium channel antagonist felodipine (5 mg) were assessed in a double-blind, double dummy placebo controlled, randomised, crossover study in 20 patients (mean age 55.4 years; range 46-69) with uncomplicated mild to moderate hypertension (supine diastolic > 90 mmHg < 115 mmHg after 4 weeks of single-blind wash-out on placebo). The four randomised, double-blind, crossover study phases evaluated the response to 4 weeks of once daily treatment with placebo, monotherapy with each drug and the combination. Noninvasive ambulatory blood pressure monitoring (Spacelabs 90207) was performed for 24 h at the end of each phase. 2. The mean 24 h ambulatory blood pressure (mmHg) was 147.9/92.0 following placebo, 141.3/87.8 following monotherapy with ramipril 2.5 mg, 136.8/85.8 following monotherapy with felodipine ER 5 mg and 131.1/82.6 following the combination of ramipril 2.5 mg and felodipine ER 5 mg. All active treatment phases significantly reduced mean 24 h ambulatory diastolic pressure by comparison with placebo. The antihypertensive efficacy of the combination was additive. 3. The coadministration of ramipril did not attenuate the incidence of headache attributable to felodipine ER.     

Felodipine extended release in mild to moderate hypertension

A multi-centre study was carried out to examine the antihypertensive effect and adverse event profile of felodipine in an extended-release (ER) formulation given once daily as monotherapy. Doses of 5 mg, 10 mg or 20 mg felodipine ER were compared with placebo in 183 patients with mild or moderate hypertension. All antihypertensive medication was discontinued on entering a 4-week placebo run-in period. If, at the end of the run-in period, supine diastolic blood pressure was in the range greater than 95 less than 120 mmHg, patients were randomly allocated to double-blind treatment with felodipine, 5 mg, 10 mg or 20 mg, or placebo, to be taken once daily for 4 weeks. Supine and standing blood pressure, heart rate and body weight were measured every 2 weeks during the trial. Assessments were made 24 hours after intake of the study drug. Adverse events were recorded at each review. Over the 4-week treatment period, a dose-related decrease in supine diastolic blood pressure was observed, this reduction occurring already during the first 2 weeks of active treatment. In the placebo group and the felodipine 5 mg, 10 mg and 20 mg groups, supine blood pressure (systolic/diastolic) decreased by 7/6 mmHg, 9/8 mmHg, 12/10 mmHg and 14/11 mmHg, respectively. Supine diastolic blood pressure reduction in the felodipine 10 mg group and both systolic and diastolic blood pressure reductions in the 20 mg group were significantly greater than with placebo. Standing diastolic blood pressure reduction was significantly greater in all three dose groups on felodipine compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

A double-blind randomized cross-over study of the efficacy and tolerability of nifedipine and nitrendipine in the treatment of mild to moderate hypertension.

1. In order to examine whether nitrendipine was superior to slow release nifedipine as monotherapy in the treatment of mild to moderate essential hypertension, the two agents were administered to 22 patients in a double-blind randomized cross-over study, incorporating low and titrated dose regimes. 2. Six patients failed to complete the study because of vasodilator side-effects such as headache, flushing and ankle swelling. Three were taking nitrendipine and three took nifedipine and all withdrawals occurred at the introduction of the drug. 3. Both agents reduced blood pressure in the 16 patients who completed the study, and neither agent was superior to the other; mean blood pressure after the placebo phase was 177 +/- 5.5/100 +/- 2.6 mm Hg supine and 175 +/- 5.3/113 +/- 2.4 mm Hg standing. At the end of therapy with nifedipine pressures were 160 +/- 4.0/91 +/- 3.0 mm Hg supine and 158 +/- 4.6/103 +/- 2.7 mm Hg standing. After 8 weeks treatment with nitrendipine blood pressures were 162 +/- 4.4/90 +/- 2.9 mm Hg supine and 161 +/- 6.2/104 +/- 2.7 mm Hg standing. Comparisons of these attained blood pressures on both agents showed no statistically significant differences. 4. Nitrendipine did not appear to be effective on a once daily basis.     

Evaluation of the therapeutic efficacy and tolerability of levocarnitine propionyl in the treatment of chronic obstructive arteriopathies of the lower extremities: a multicentre controlled study vs. placebo.

The treatment of symptomatic chronic obstructive peripheral arteriopathies is a difficult task since it requires the prolonged administration of drugs which are often unable to correct the various pathogenetic factors reponsible for the disability. The authors, on the basis of recent studies demonstrating the rheological and vasoactive as well as metabolic activities of levocarnitine propionyl, have decided to use this substance in the treatment of arteriopathics affected by intermittent claudication. Levocarnitine propionyl administered orally to 142 arteriopathics affected by intermittent claudication was responsible for a marked increase in initial as well as absolute walking distances. It is particularly important to note that these clinical results were obtained primarily due to the metabolic activities of levocarnitine propionyl.     

非洛地平缓释片与尼群地平片治疗高血压病的疗效比较

目的：比较非洛地平缓释片与尼群地平片治疗高血压病的疗效。方法：轻、中度高血压病病人１６２例,其中９８例（男性６７例,女性３１例,年龄５１ａ±ｓ６ａ）用非洛地平缓释片５～１０ｍｇ,ｐｏ,ｑｄ×４ｗｋ治疗。另６４例（男性４７例,女性１７例,年龄５０ａ±８ａ）用尼群地平片１０ｍｇ,ｐｏ,ｂｉｄ或ｔｉｄ×４ｗｋ治疗。结果：非洛地平缓释片组总有效率９５％,与尼群地平片组（８１％）相比,差别有非常显著意义（Ｐ＜０．０１）。不良反应发生率非洛地平缓释片组１５％,与尼群地平片组（２０％）比较,差别有显著意义（Ｐ＜０．０５）。结论：非洛地平缓释片对高血压病的疗效显著而又安全,优于尼群地平片。     

Comparison of the efficacy and tolerability of telmisartan and enalapril in patients of mild to moderate essential hypertension

Background:

Theoretically, angiotensin II receptor blockers (ARBs) have certain advantages over angiotensin-converting enzyme inhibitors, but the contribution of these advantages to the clinical effect of ARBs is not known.

Objective:

To compare the efficacy and tolerability of telmisartan with enalapril in patients of essential hypertension.

Materials and Methods:

Patients of mild to moderate hypertension were randomized to receive either 40 mg of telmisartan or enalapril 10 mg once a day orally for 12 weeks. At each visit, the systolic blood pressure (BP), diastolic BP and heart rate of each patient were recorded. Investigations such as hemogram hemoglobin, total leucocytes count (Hb, TLC), serum creatinine, serum glutamic oxaloacetic transaminase, serum glutamic pyruric transaminase (SGOT, SGPT) random blood sugar and urine examination were performed at baseline and after 12 weeks of the treatment period.

Results:

The mean reduction in systolic BP in the telmisartan/enalapril group was 26.38 ± 10.98/26.74 ± 8.24 mmHg while the mean reduction in diastolic BP in the telmisartan/enalapril group was 14 ± 2.98/9.71 ± 4.23 mmHg, respectively, at 12 weeks. When the reduction in systolic BP in the two groups was compared, there was no significant difference between the groups (P > 0.05). However, the mean reduction in diastolic BP achieved with telmisartan at 12 weeks was significantly higher (P < 0.001) than that achieved with enalapril after the corresponding period. The overall frequency of adverse-effects was similar. However, in the enalapril group, the incidence of dry cough was higher as compared to that in the telmisartan group (11.43% vs. 0%, respectively; P < 0.05).

Conclusion:

Telmisartan produces a greater reduction in diastolic BP than enalapril and is free from the adverse-effect of dry cough that is commonly encountered with enalapril.     

Re-evaluation of the efficacy and tolerability of venlafaxine vs SSRI: meta-analysis

Rationale A number of reviews have claimed that the selective serotonin and noradrenalin re-uptake inhibitor venlafaxine is more effective than selective serotonin re-uptake inhibitors (SSRIs) in achieving remission and symptom reduction in major depression. Objectives The aim of this study was to systematically review studies on the efficacy of venlafaxine vs SSRI and to evaluate the influence of methodological issues on the effect sizes. Materials and methods Following a systematic literature search, we pooled data on depression scores, response, remission and dropout rates. We also performed sub-group analyses. Results Seventeen studies were included. We found no significant superiority in remission rates (risk ratio [RR] = 1.07, 95% confidence intervals [95%CI] = 0.99 to 1.15, numbers needed to treat [NNT] = 34) and a small superiority in response rates (RR = 1.06, 95%CI = 1.01 to 1.12, NNT = 27) over SSRIs. There was a small advantage to venlafaxine in change scores (effect size = −0.09, 95%CI = −0.16 to −0.02, p = 0.013), which did not reach significance when post-treatment scores were used (effect size = −0.06, 95%CI = −0.13 to 0.00). Discontinuation rates due to adverse events were 45% higher in the venlafaxine group. The main reasons for the differences between this analysis and previous reviews were the exclusion of studies with methodological limitations, avoiding to pool selectively reported study results and exclusion of studies available as abstracts only. Conclusions Our analysis does not support a clinically significant superiority of venlafaxine over SSRIs. Differences between our study and previous reviews were not accounted for by technical aspects of data synthesis, but rather by study selection and choice of outcome parameters. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Meta-analysis: Alvimopan vs. placebo in the treatment of post-operative ileus

BACKGROUND: Alvimopan is a selective, competitive mu-opioid receptor antagonist with limited oral bioavailability which may be used to reduce length of post-operative ileus. AIM: The study compared alvimopan with placebo following bowel resection or total abdominal hysterectomy. METHODS: A meta-analysis of randomized-controlled trials published between 2001 and 2006 of alvimopan vs. placebo was performed. The primary efficacy end-points were composite measures of passage of flatus, stool, and tolerance of solid food (GI-3) and passage of stool and tolerance of solid food (GI-2). The incidence of treatment emergent adverse events was assessed. RESULTS: Five trials matched the selection criteria, reporting on 2195 patients. A total of 1521 (69.3%) had alvimopan and 674 (30.7%) placebo. GI-3 significantly improved (hazard ratio 1.30; 95% confidence intervals 1.16, 1.45, P < 0.001), as did GI-2 (hazard ratio 1.61; 95% confidence intervals 1.26, 2.05, P < 0.001) on alvimopan 12 mg. Time to discharge (hazard ratio 1.26; 95% confidence intervals 1.13, 1.40, P < 0.001), time to bowel motion (hazard ratio 1.74; 95% confidence intervals 1.29, 2.35, P < 0.001), and time to solid food (hazard ratio 1.14; 95% confidence intervals 1.01, 1.30, P < 0.04) also improved significantly. No difference was noted in the incidence of treatment emergent adverse events. CONCLUSIONS: Alvimopan showed significant advantages over placebo in restoring gastro-intestinal function, and reduced time to discharge following major abdominal surgery, with acceptable side effects.     

Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability.

1. In a double-blind, randomised, three-way-crossover study, 25 patients with sitting diastolic blood pressure between 95 and 120 mm Hg (Phase V) after 4 weeks' run-in on atenolol 50 mg twice daily, received atenolol 50 mg twice daily alone, atenolol 50 mg plus nifedipine 20 mg each twice daily and atenolol 50 mg plus nifedipine 40 mg each twice daily in three treatment periods each lasting 4 weeks. 'Washout' periods were not included. 2. The two combination treatment regimes lowered the 12 h post-dose blood pressure more effectively than did atenolol alone, but the high dose nifedipine combination was no more effective than the low dose nifedipine combination. Sitting systolic BP (+/- s.e. mean) at the end of each period was 174 +/- 5 mm Hg after the atenolol run-in, 170 +/- 5 mm Hg with atenolol alone, 156 +/- 5 mm Hg with the low dose combination and 158 +/- 4 mm Hg with the high dose combination. Corresponding diastolic BP readings were 106 +/- 2 mm Hg, 106 +/- 2 mm Hg, 97 +/- 2 mm Hg and 99 +/- 2 mm Hg respectively. 3. Side-effects tended to occur less commonly with the low dose of the fixed combination than with atenolol alone. An increased number of side-effects occurred with the 40 mg twice daily doses of nifedipine, particularly flushing/erythema, oedema of the ankles/feet, and a hot feeling in the legs. These differences did not reach significance. 4. Overall compliance was good (98 +/- 0.7 s.e. mean %) and was similar within the different treatment regimes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder

Patients (n = 150) were randomized to a 6-week, double-blind study to evaluate the relative efficacy and safety of mirtazapine, amitriptyline, and placebo in the treatment of major depressive disorder symptoms. Average daily modal doses were mirtazapine, 18 mg; amitriptyline, 111 mg; and placebo, 4.6 capsules. Mirtazapine- and amitriptyline-treated patients had statistically significantly greater mean Hamilton Rating Scale for Depression (HAM-D) score reductions (weekly visits 1, 2, 4, and endpoint) compared to placebo. These findings were supported by the Montgomery-Asberg Depression Rating Scale (MADRS); the Zung Self-rating Depression Scale (SDS); and the Clinical Global Impressions (CGI) scales. Somnolence and weight gain were the only adverse clinical experiences (ACEs) reported substantially more often by mirtazapine-treated patients than by those in the placebo group. However, more amitriptyline-treated patients reported decreased visual accommodation, dry mouth, dyspepsia, constipation, tachycardia, hypertension, hypotension, discoordination, dizziness, and tremor than mirtazapine- or placebo-treated patients. Results of this study indicate that mirtazapine is more effective than placebo in the treatment of these patients, and superior to amitriptyline in respect to anticholinergic and cardiovascular effects.     

Optimizing antidepressant treatment: efficacy and tolerability

It has been suggested that dual-action antidepressants acting on both serotonin and noradrenaline pathways in the brain may offer superior therapeutic benefit over classical antidepressants, particularly in severe depression. Directly acting dual-action antidepressant drugs include venlafaxine and milnacipran. In addition, mirtazapine and nefazodone, may indirectly potentiate serotonergic and noradrenergic transmission, although evidence that they do indeed do so in vivo is limited. Meta-analysis of clinical trials suggests that venlafaxine has a more rapid onset of action than selective serotonin reuptake inhibitors (SSRIs), and the same may also be true for milnacipran and mirtazapine. Efficacy, both in terms of extent of antidepressant effect and in the proportion of patients responding, is probably superior to that of SSRIs, at least for venlafaxine and milnacipran. In terms of tolerability, all dual-action drugs clearly appear to be better tolerated than tricyclic antidepressants. Mirtazapine and nefazodone have specific side-effect profiles as a result of their antagonist action at biogenic amine and other receptors. Milnacipran, and to a lesser extent venlafaxine, are slightly better tolerated than SSRIs.     

Felodipine vs hydralazine: a controlled trial as third line therapy in hypertension. Cooperative Study Group.

In a placebo-controlled, double-blind, randomized, parallel group study one hundred and one patients with supine diastolic blood pressure greater than or equal to 100 mm Hg phase V, despite treatment with atenolol 100 mg plus chlorthalidone 25 mg once daily also received either felodipine 5-20 mg twice daily or hydralazine 25-100 mg twice daily for 6 weeks. Felodipine achieved a lower supine blood pressure (mean +/- s.d. 177/108 +/- 29/8-138/82 +/- 19/8 mm Hg) than hydralazine (174/109 +/- 25/8-149/92 +/- 26/11 mm Hg), (P less than 0.05/P less than 0.001). Felodipine also lowered supine diastolic blood pressure to less than 90 mm Hg more often than hydralazine (42 vs 22 patients, P less than 0.001). The incidence of unwanted effects was similar in both groups. The felodipine treated patients experienced more ankle swelling and flushing than those in the hydralazine group who experienced more headache and minor gastro-intestinal upset.     

Low molecular weight heparin (tinzaparin) vs. placebo in the treatment of mild to moderately active ulcerative colitis

BACKGROUND: Heparin has anti-inflammatory and immunomodulatory activity which may be of therapeutic benefit in the treatment of ulcerative colitis. AIM: To test whether low molecular weight heparin, given subcutaneously, would provide a significant therapeutic response compared with placebo in the treatment of mild to moderate ulcerative colitis. STUDY DESIGN: A prospective, double-blind, randomized, placebo-controlled, multi-centre trial comparing tinzaparin 175 anti-Xa IU/kg/day (innohep, LEO Pharma) subcutaneously for 14 days followed by tinzaparin 4500 anti-Xa IU/day subcutaneously for 28 days with placebo, administered subcutaneously once daily for up to 42 days. The primary outcome measure was the mean change in colitis activity from baseline to the end of study treatment assessed by the sum of scores of stool frequency, rectal bleeding, sigmoidoscopic appearance and histology. Secondary outcome measures included changes in individual activity indices and laboratory parameters. Patients were assessed at weekly intervals for 6 weeks and within 1 week of completing treatment. RESULTS: One hundred patients with active ulcerative colitis (up to six bloody stools per day, no fever, no tachycardia or systemic disturbances) were randomized. Forty-eight received tinzaparin and 52 received placebo. The difference in the mean percentage change in colitis activity from baseline to end of treatment (tinzaparin-placebo) was not statistically significant (P = 0.84). There was no difference between tinzaparin and placebo in any secondary outcome measure. One major bleed (rectal), occurred in a patient receiving placebo. CONCLUSION: This is the largest trial to date of heparin in ulcerative colitis. The results show no benefit of low molecular weight heparin over placebo in mild to moderately active ulcerative colitis.     

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.     

多中心平行对照比较布洛芬与安乃近的疗效和安全性

目的：比较布洛芬与安乃近的疗效和安全性。方法：本试验为双盲双模拟，单剂量，多中心，随机，平行对照试验设计，210例6月到12周岁发热儿童被随机分入布洛芬治疗组和安乃近治疗组，观察其退热镇痛疗效和不良反应。结果：与安乃近组相比，布洛芬组的总体疗效好(99．3％)，退热起效时间早，退热持续时间长，P值均小于0．05。试验过程中没有发现不良反应。结论：布洛芬混悬剂用于儿童发热安全高效，应为儿科急诊临床应用的较好选择。     

Gastroduodenal tolerability of lumiracoxib vs placebo and naproxen: a pilot endoscopic study in healthy male subjects

BACKGROUND: Lumiracoxib (Prexige) is a cyclooxygenase-2 (COX-2) selective inhibitor. AIM: To compare the gastroduodenal tolerability of lumiracoxib with placebo and naproxen in a randomized, parallel-group, double-blind study. METHODS: : Sixty-five healthy male subjects were randomized to receive 8 days' dosing with lumiracoxib 200 mg twice daily (b.d.) (n = 21), placebo (n = 22) or naproxen 500 mg b.d. (n = 22). Endoscopic evaluations of gastric and duodenal mucosae were conducted at baseline and after 8 days' dosing. Serum was assayed for ex-vivo concentrations of thromboxane B2 (TxB2) to determine cyclooxygenase-1 (COX-1) inhibitory activity. RESULTS: Sixty subjects (20 per group) completed the study. No gastroduodenal erosions were observed in subjects receiving lumiracoxib. Thirteen subjects receiving naproxen developed duodenal erosions. At the gastric site, one subject in each of the naproxen and placebo groups had erosions; one subject receiving naproxen also developed a small asymptomatic gastric ulcer. Gastrointestinal adverse events accounted for 42.3% of all adverse events, occurring in 3/21, 4/22 and 6/22 of the lumiracoxib, placebo and naproxen groups, respectively. TxB2 levels were similar for patients receiving placebo or lumiracoxib, but were reduced by > 95% in patients receiving naproxen, compared with placebo. CONCLUSIONS: Multiple doses of lumiracoxib resulted in gastroduodenal tolerability similar to placebo and superior to naproxen.     

缬沙坦和氯沙坦在轻中度原发性高血压患者中的疗效比较

目的：比较具有不同药理学特性的血管紧张素Ⅱ受体拮抗剂缬沙坦和氯沙坦，在轻中度原发性高血压中的抗高血压疗效。方法：40例患者随机接受缬沙坦80mg,qd或氯沙坦50mg,qd，持续治疗4wk,然后缬沙坦组和氯沙坦组互换药物接受4wk的治疗。治疗期间每隔2wk对患者进行24h动态血压监测，并测量患者的偶测血压和心率。结果：氯沙坦和缬沙坦都具有明确的抗高血压疗效。和氯沙坦相比，缬沙坦显示出更良好的抗高血压效果。结论：在抗高血压效果方面不同的血管紧张素Ⅱ受体拮抗剂的药代学和药动学差异具有潜在重要性。