Placebo Washout Research Articles

Effect of amlodipine–atorvastatin combination on fibrinolysis in hypertensive hypercholesterolemic patients with insulin resistance

The aim of this study was to evaluate the effect of the amlodipine-atorvastatin combination on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) activity in hypercholesterolemic, hypertensive patients with insulin resistance. The study population included 45 patients, aged 41 to 70 years, with mild to moderate essential hypertension (diastolic blood pressure [BP] > or = 95 and < or = 105 mm Hg), hypercholesterolemia (total cholesterol > 200 and < 350 mg/dL), and insulin resistance (HOMA index > 2.5) After a 4-week wash-out period, they were randomized to amlodipine (5 mg) or atorvastatin (20 mg) or their combination at the same oral dosage for 12 weeks in three cross-over periods each separated by a 4-week placebo period (3 by 3 latin square design). At the end of the placebo wash-out and of each treatment period, office BP, total cholesterol, PAI-1, and t-PA activity were evaluated. The amlodipine-atorvastatin combination, in addition to the expected hypocholesterolemic effect, produced: 1) a greater decrease in PAI-1 activity (-10.2 U/mL, P <.01 v placebo) and an even greater increase in t-PA activity (+0.26 U/mL, P <.01 v placebo) than amlodipine (-0.5 U/mL for PAI-1, P = not significant; +0.17 U/mL for t-PA, P <.01 v placebo) and atorvastatin alone (respectively, -9.9 U/mL, P <.01 v placebo and +0.08 U/mL, P <.05 v placebo); and 2) a greater systolic BP/diastolic BP mean reduction (-22/17 mm Hg, P <.005 v placebo) than amlodipine (-18/14 mm Hg, P <.01 v placebo) and atorvastatin alone (-2.8/3.8 mm Hg, P <.05 v placebo only for diastolic BP). The positive effect on fibrinolytic balance and BP control observed suggests that in hypertensive, hypercholesterolemic patients with impaired fibrinolysis, the combination of amlodipine and atorvastatin could be the treatment of choice.

Ambulatory versus clinic blood pressure for the assessment of anti hypertensive efficacy in clinical trials: insights from the Val-Syst study

Background: Several studies have found that measurement of blood pressure (BP) in the clinical setting may lead to overestimation of hypertension and may yield inaccurate assessments of the efficacy of antihypertensive treatment. Objective: The aim of this study was to determine whether the use of clinic BP in the Valsartan and Amlodipine for the Treatment of Isolated Systolic Hypertension in the Elderly (Val-Syst) study accurately identified those elderly outpatients with systolic hypertension who had true 24-hour elevations in BP, as well as those who required dose increases in antihypertensive therapy during follow-up. Methods: In Val-Syst, patients aged between 60 and 80 years with a clinic sitting systolic BP (SBP) of 160 to 220 mm Hg and a diastolic BP <90 mm Hg after a 2-week placebo washout period were randomized to receive valsartan 80 mg or amlodipine 5 mg once daily (level 1). In those with a trough SBP >-140 mm Hg after 8 weeks of double-blind treatment, doses were titrated upward to valsartan 160 mg or amlodipine 10 mg once daily (level 2). If clinic SBP was >-140 mm Hg after a further 8 weeks, hydrochlorothiazide 12.5 mg was added for an additional 8 weeks (level 3). Clinical decisions during the active-treatment period were based on clinic BP measurements. Thirteen of the 35 participating centers assessed ambulatory BP as well as clinic BP at baseline and the end of the treatment, making it possible to compare the results of the 2 modes of measurement. The Student test was used to compare drug-induced changes in clinic and ambulatory BP in individual patients. Differences between the decreases in clinic and ambulatory BP at the 3 treatment levels were tested using repeated-measures analysis of covariance (ANCOVA), with baseline as the covariate. Results: One hundred sixty-four elderly patients (age range, 60–80 years; 85 men, 79 women) were included in the study (79 valsartan, 85 amlodipine), and valsartan and amlodipine were reported to have comparable effects on the level and rhythm of 24-hour BP In the present study, 22 of 164 patients had white-coat hypertension at baseline (clinic SBP >-160 mm Hg and mean 24-hour SBP <130 mm Hg). For both treatments combined, the mean (SD) decreases in clinic SBP were inversely proportional to the treatment level (level 1 = −33.2 (7.9) mm Hg; level 2 = −31.6 (11.8) mm Hg; level 3 = −29.3 (11.6) mm Hg; P = 0.001, overall ANCOVA). In contrast, after adjusting for baseline values, the decreases in mean 24-hour SBP did not differ between treatment levels (level 1 = −10.8 [10.4] mm Hg; level 2 = −13.0 [11.2] mm Hg; level 3 = −16.4 [13.8] mm Hg). The decrease in clinic BP during therapy was similar in patients with white-coat hypertension and sustained hypertension (clinic SBP >-160 mm Hg and mean 24-hour SBP ≥130 mm Hg), whereas 24-hour and 8- to 9- am SBP decreased significantly only in patients with sustained hypertension ( P < 0.001). At the end of the study, mean 24-hour SBP continued to be uncontrolled (≥130 mm Hg) in 16 of 53 patients (30.2%) at treatment level 1, 27 of 62 (43.5%) at level 2, and 19 of 49 (38.8%) at level 3 ( P = NS). Conclusion: Based on the findings in this population of elderly patients with systolic hypertension, the management of hypertension may vary depending on whether decisions concerning the selection of patients for clinical trials and treatment adjustments during follow-up are made using clinic or ambulatory BP measurement.

Tic Reduction With Risperidone Versus Pimozide in a Randomized, Double-Blind, Crossover Trial

To compare the tic suppression, electrocardiogram (ECG) changes, weight gain, and side effect profiles of pimozide versus risperidone in children and adolescents with tic disorders. This was a randomized, double-blind, crossover (evaluable patient analysis) study. Nineteen children aged 7 to 17 years with Tourette's or chronic motor tic disorder were randomized to 4 weeks of treatment with pimozide or risperidone, followed by the alternate treatment after a 2-week placebo washout. The primary efficacy outcome measure was change in tic severity assessed by the Yale Global Tic Severity Scale (YGTSS). ECG results, weight gain, and side effects were also compared. Compared to pimozide treatment, risperidone treatment was associated with significantly lower tic severity scores (YGTSS: baseline 43.3 +/- 17.5, pimozide 34.2 +/- 14.2, risperidone 25.2 +/- 13.6; p =.05). Weight gain during the 4-week treatment periods was greater for risperidone (mean 1.9 kg) than pimozide (1.0 kg). No patient suffered a serious adverse event, but 6 of 19 subjects failed to complete the protocol. Neither medication was associated with ECG changes. In this study, risperidone appeared superior to pimozide for tic suppression but was associated with greater weight gain.

Comparison of candesartan and felodipine alone and combined in the treatment of hypertension: a single-center, double-blind, randomized, crossover trial

Background: In the past decade, many studies have indicated that the combination of low doses of different classes of antihypertensive agents may be more efficacious than monotherapy while minimizing the likelihood of dose-dependent adverse effects (AEs). Objective: The aim of this study was to determine whether combination therapy with lower doses of candesartan and a calcium antagonist, felodipine, would be more effective and tolerable in controlling mild to moderate hypertension compared with either drug used alone. Methods: In this 18-week, single-center, double-blind, crossover study, patients with mild to moderate essential hypertension were randomized to 1 of 2 treatment groups after a 2-week placebo washout period. Patients in group 1 received candesartan 16 mg once daily and patients in group 2 received felodipine 5 mg once daily, for 6 weeks. All patients then received half-dose combination therapy (candesartan 8 mg plus felodipine 2.5 mg, once daily) for 6 weeks. Finally, patients received 6 weeks of monotherapy with the alternate medication (group 1 received felodipine 5 mg once daily and group 2 received candesartan 16 mg once daily). Results: Thirty patients (18 men, 12 women; mean [SD] age, 54.0 [4.9] years; range, 39–62 years) were included in the study. During both monotherapy periods, candesartan and felodipine significantly reduced blood pressure (BP) (both P<0.001). BP further decreased with combination therapy ( P<0.001 in both groups). Overall, 90.0% (27/30) of the patients achieved the target BP at the end of combination therapy. The incidence of AEs was similar with combination therapy compared with either monotherapy. Conclusions: In this study population, candesartan and felodipine had additive effects when used in combination, even at low doses, in the treatment of hypertension. Therefore, the combination of candesartan and felodipine is an effective alternative to that of candesartan and hydrochlorothiazide.

Gepirone Extended-Release

To assess the efficacy and tolerability of the 5-HT(1A) agonist gepirone in extended-release formulation (gepirone-ER) versus placebo in patients with major depressive disorder. Patients aged 18 to 70 years were eligible if they satisfied DSM-IV criteria for moderate-to-severe major depressive disorder and had a baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) score > or = 20. After a 4- to 7-day placebo washout period, patients were randomly assigned to receive either placebo (N = 106) or gepirone-ER (20-80 mg/day) (N = 103) for 56 days. Assessments were done at weeks 1-4, 6, and 8. Mean change from baseline in HAM-D-17 score within the intent-to-treat group (gepirone, N = 101; placebo, N = 103) was significantly greater with gepirone-ER than placebo at weeks 3 (p =.013) and 8 (p =.018). Significantly (p <.05) more patients receiving gepirone-ER than placebo were HAM-D-17 responders at weeks 3 (33.7% vs. 18.8%, respectively) and 4 (38.6% vs. 24.8%, respectively) and HAM-D-17 remitters at weeks 6 (24.8% vs. 13.9%, respectively) and 8 (28.7% vs. 14.9%, respectively). Mean change from baseline for HAM-D-25 total score was significantly (p < pr =.05) greater with gepirone-ER at all assessments except week 6. The proportion of HAM-D-25 responders was significantly greater (p < or =.05) with gepirone-ER at weeks 3 and 8. Gepirone-ER was well tolerated: 9.8% of the gepirone-ER group and 2.8% of the placebo group discontinued due to adverse events. Common adverse events were considered mild and included dizziness, nausea, and insomnia. Gepirone-ER did not differ statistically compared with placebo in weight gain or sedation. Furthermore, preliminary evidence suggested that gepirone-ER may not be associated with sexual dysfunction. No serious adverse events occurred in gepirone-treated patients. Gepirone-ER is effective for the short-term treatment of major depressive disorder and is well tolerated.

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: A one-year, randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors

Background: Repaglinide and glimepiride are relatively new oral hypoglycemic agents. Few data are available concerning their effects on metabolic parameters other than measures of glycemic control.Objectives: In addition to assessing the effects of repaglinide and glimepiride on glycemic control in patients with type 2 diabetes mellitus, this study also examined the effects of these agents on 3 metabolic parameters known to be cardiovascular risk factors—lipoprotein(a) (Lp[a]), plasminogen activator inhibitor-1 (PAI-1), and homocysteine (Hcy).Methods: This randomized, placebo-controlled, double-blind trial was conducted at a single center in Italy. Eligible patients were nonsmokers; had no hypertension or coronary heart disease; were taking no hypolipidemic drugs, diuretics, beta-blockers, or thyroxin; and had normal renal function. After an initial 4-week placebo washout period, patients were randomized to receive repaglinide 1 mg/d or glimepiride 1 mg/d. The dose of study drug was optimized over an 8-week titration period, which was followed by a 12-month treatment period. Measures of glycemic control (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG], fasting plasma insulin [FPI], postprandial plasma insulin [PPI] and the other metabolic parameters of interest were assessed after 6 and 12 months of treatment.Results: One hundred twenty-four patients (63 women, 61 men) completed the study, 62 in each treatment group. There were no significant differences in demographic characteristics between groups. After 6 and 12 months of treatment, FPG levels and HbA1c values were significantly reduced from baseline in both groups (6 months, P < 0.05; 12 months, P < 0.01). After 6 months, PPG levels were significantly decreased only in the repaglinide group (P < 0.05 vs baseline); at 12 months, however, PPG levels were significantly reduced from baseline in both groups (P < 0.01 repaglinide, P < 0.05 glimepiride). No significant changes from baseline in FPI or PPI levels were seen in either group at 6 months, although FPI levels were significantly increased in the repaglinide group at 12 months (P < 0.05). Repaglinide significantly lowered levels of Lp(a), PAI-1, and Hcy after 12 months (all, P < 0.05 vs baseline). Glimepride significantly lowered levels of Lp(a) and Hcy after 6 months (both, P < 0.05 vs baseline) and levels of Lp(a) (P < 0.01 vs baseline), Hcy (P < 0.01 vs baseline), and PAI-1 (P < 0.05 vs baseline) after 12 months.Conclusions: Repaglinide and glimepiride improved glycemic control and reduced levels of other metabolic parameters of interest in this population of patients with type 2 diabetes. It is possible that the reductions in Lp(a), PAI-1, and Hcy were the result of improved glucose metabolism; however, the possibility that repaglinide and glimepiride may have a direct effect on these parameters should not be excluded.

A Randomized Trial of Sertraline as a Cessation Aid for Smokers With a History of Major Depression

Evidence that major depression can be a significant hindrance to smoking cessation prompted this examination of the usefulness of sertraline as a cessation aid for smokers with a history of major depression. Specifically, sertraline's efficacy for smoking abstinence and its effects on withdrawal symptoms were evaluated. The study design included a 1-week placebo washout, a 9-week double-blind, placebo-controlled treatment phase followed by a 9-day taper period, and a 6-month drug-free follow-up. One hundred thirty-four smokers with a history of major depression were randomly assigned to receive sertraline (N=68) or matching placebo (N=66); all received intensive individual cessation counseling during nine clinic visits. Sertraline treatment produced a lower total withdrawal symptom score and less irritability, anxiety, craving, and restlessness than placebo. However, the abstinence rates did not significantly differ between treatment groups: 28.8% (19 of 66) for placebo and 33.8% (23 of 68) for sertraline at the end of treatment and 16.7% (11 of 66) for placebo and 11.8% (eight of 68) for sertraline at the 6-month follow-up. No moderating effects of single or recurrent major depression, depressed mood at baseline, nicotine dependence level, or gender were observed. Sertraline did not add to the efficacy of an intensive individual counseling program in a double-blind, placebo-controlled study. However, given that the end-of-treatment abstinence rate for the placebo group was much higher than expected, it is unclear whether a ceiling effect of the high level of psychological intervention received by all subjects prevented an adequate test of sertraline.

Losartan and perindopril effects on plasma plasminogen activator inhibitor-1 and fibrinogen in hypertensive type 2 diabetic patients

Background This study compared the effects of losartan and perindopril on plasma plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in hypertensive type 2 diabetic patients. Methods We studied 85 nonsmoking outpatients, aged 46 to 64 years, with mild to moderate essential hypertension (diastolic blood pressure [BP] >90 and <110 mm Hg) and well controlled type 2 diabetes mellitus. After a 4-week washout placebo period, patients were randomized to received perindopril 4 mg once daily ( n = 42) or losartan 50 mg once daily ( n = 43) for 12 weeks according to a double-blind, parallel-group design. At the end of the placebo and active treatment periods, BP was measured and plasma PAI-1 and fibrinogen were evaluated. Results Both perindopril and losartan reduced systolic and diastolic BP values (−16/15 mm Hg and −15/14, respectively; P < .001 v placebo), with no difference between the two treatments. Plasma PAI-1 was reduced by perindopril (−10 ng/dL, P = .028 v placebo) but not by losartan (+4 ng/dL, NS), the difference between the two treatments being statistically significant ( P < .01). Plasma fibrinogen showed no significant change with both drugs, although a decreasing trend was noted with perindopril. Conclusions: These findings indicate that perindopril but not losartan decreases PAI-1 in hypertensive type 2 diabetic patients, which suggests that the PAI-1 lowering effect is unrelated with AT 1 receptor blockade and could rather be due to the fact that the endothelial receptors that mediate PAI-1 expression in response to angiotensin II are not type 1 receptor subtypes. Different effects of the two drugs on the bradykinin system might also be implicated.

Efficacy of omalizumab in allergic asthma patients at high-risk for asthma-related death

Efficacy of omalizumab in allergic asthma patients at high-risk for asthma-related death

Efficacy of losartan, valsartan, and telmisartan in patients with mild to moderate hypertension: A double-blind, placebo-controlled, crossover study using ambulatory blood pressure monitoring

Background: The angiotensin II (AII) receptor antagonists are effective agents for the treatment of mild to moderate hypertension. Agents within this drug class differ with respect to their pharmacologic and pharmacokinetic properties, which may translate into differences in antihypertensive effect. Objective: The purpose of this study was to compare the antihypertensive efficacy of the AII receptor antagonists losartan, valsartan, and telmisartan using 24-hour ambulatory blood pressure monitoring (ABPM). Methods: Outpatients aged 40 to 60 years with mild to moderate hypertension (sitting diastolic blood pressure [DBP] ≥95 mm Hg and ≤115 mm Hg) were enrolled. After a 4-week placebo washout period, patients were randomized to receive losartan 50 mg, valsartan 80 mg, telmisartan 40 mg, or placebo once daily for 4 weeks according to a 4-period crossover design. Each treatment period was separated by a 2-week placebo washout period. Every 2 weeks, 24-hour ABPM was performed. To assess the homogeneity of blood pressure (BP) control, the trough-to-peak (T/P) ratio and the smoothness index (SI) for systolic blood pressure (SBP) and DBP were calculated. Results: After 2 and 4 weeks of treatment, all 3 agents produced significant reductions in 24-hour, daytime, and nighttime SBP and DBP, compared with placebo ( P < 0.001). Valsartan, however, induced significantly greater BP reductions than did losartan and telmisartan at 2 weeks ( P < 0.01) and after 4 weeks ( P < 0.05) of treatment. At 2 weeks, the T P ratio was significantly higher with valsartan and telmisartan than with losartan, whereas at 4 weeks all drugs resulted in a T P ratio >50%. The SI for SBP and DBP was significantly higher with valsartan than with losartan and telmisartan both at 2 weeks ( P < 0.001) and 4 weeks ( P < 0.01). A positive correlation between SI for SBP and SI for DBP was found at both 2 and 4 weeks with losartan and valsartan treatments, whereas for telmisartan this correlation was present only at 4 weeks. At 4 weeks, plasma active renin (PAR) levels increased significantly with all drugs compared with placebo ( P < 0.01 vs placebo), whereas at 2 weeks PAR levels increased significantly ( P < 0.05 vs placebo) only with losartan and valsartan. Conclusions: In the present study, treatment with valsartan resulted in an earlier, greater, and smoother antihypertensive effect compared with treatment with losartan or telmisartan; this differential effect was likely due to differences in the pharmacologic properties of these agents. Analysis of SI revealed a qualitative difference in the antihypertensive action of telmisartan at the beginning of treatment.

A multicenter, randomized, double-blind comparison of the efficacy and safety of irbesartan and enalapril in adults with mild to moderate essential hypertension, as assessed by ambulatory blood pressure monitoring: The MAPAVEL study

Background: When blood pressure (BP)—lowering efficacy is assessed by measurements taken in a clinic setting, angiotensin II—receptor antagonists show similar efficacy to angiotensin-converting enzyme inhibitors and better tolerability. A search of MEDLINE to date, however, reveals no randomized, double-blind studies using ambulatory BP monitoring (ABPM) to compare the BP-lowering efficacy of irbesartan and enalapril in a large number of patients (>200) with essential hypertension. Objective: This study compared 24-hour BP reduction and BP control, as assessed by ABPM, in patients with mild to moderate essential hypertension treated with irbesartan or enalapril. The relative tolerability of the 2 treatments was also evaluated. Methods: This was a multicenter, randomized, double-blind study in patients with mild to moderate essential hypertension (office diastolic BP [DBP] 90–109 mm Hg or systolic BP [SBP] 140–179 mm Hg). After a 3-week, single-blind placebo washout phase, patients with a mean daytime DBP ≥85 mm Hg, as measured by ABPM between 10 am and 8 pm, were randomized to 12 weeks of active treatment with irbesartan or enalapril. Starting doses were 150 and 10 mg/d, respectively, with titration to 300 or 20 mg/d if clinic DBP was ≥90 mm Hg at week 4 or 8. Based on clinic measurements, BP control was defined as a BP reading <140/90 mm Hg after 12 weeks of treatment; patients achieving a reduction in DBP of ≥10 mm Hg at 12 weeks were considered responders. The ABPM criterion for BP control, independent of clinic values, was achievement of a daytime BP <130/85 mm Hg after 12 weeks of treatment; patients achieving a reduction in 24-hour DBP ≥5 mm Hg at 12 weeks were considered responders, independent of clinic values. Results: A total of 238 patients were randomized to treatment, 115 to irbesartan and 123 to enalapril. The study population was ∼52.0% female and 48.0% male, with a mean (±SD) age of 52.7 ± 10.6 years. The study was completed by 111 patients in the irbesartan group (dose titrated to 300 mg/d in 72.0% of patients) and 115 patients in the enalapril group (dose titrated to 20 mg/d in 76.5% of patients). BP reductions were similar in the 2 groups, both as measured in the clinic (DBP, 12.7 ± 8.8 mm Hg irbesartan vs 12.4 ± 7.4 mm Hg enalapril; SBP, 19.0 ± 14.1 mm Hg vs 17.5 ± 14.0 mm Hg) and by 24-hour ABPM (DBP, 9.4 ± 8.5 mm Hg vs 8.8 ± 8.5 mm Hg; SBP, 14.7 ± 14.7 mm Hg vs 12.6 ± 13.1 mm Hg). As assessed by ABPM, rates of BP control were 40.5% (45/111) for irbesartan and 33.9% (39/115) for enalapril, and the response rates were a respective 71.2% (79/111) and 71.3% (82/115). The overall incidence of adverse events (40.0% irbesartan, 51.2% enalapril) was not statistically different between groups, although the incidence of adverse events considered probably related to antihypertensive treatment was significantly higher with enalapril than with irbesartan (24.6% vs 9.2%, respectively; P = 0.026), essentially because of the higher incidence of cough (8.1% vs 0.9%). Conclusions: As assessed by ABPM, irbesartan 150 to 300 mg/d was as effective in lowering BP and achieving BP control as enalapril 10 to 20 mg/d. Based on the number of treatment-related adverse events, irbesartan was better tolerated than enalapril.

Differential effects of raloxifene and continuous combined hormone replacement therapy on biochemical markers of cardiovascular risk: results from the Euralox 1 study

Objective To compare the effects of the selective estrogen receptor modulator (SERM) raloxifene (Evista®) and a continuous combined hormone replacement therapy (ccHRT) formulation containing estradiol and norethisterone acetate (Kliogest®) on lipid and fibrinogen levels of postmenopausal women. Methods Euralox 1 was a prospective, randomized, double-blind trial. After a placebo wash-out, healthy postmenopausal women (n = 1008, average age 56.1 ± 4.9 years) with a health risk profile that suggested a potential benefit from either treatment were randomly assigned to either 60 mg raloxifene or ccHRT consisting of 2 mg estradiol and 1 mg norethisterone acetate (NETA) per day for 6 months. Measurements Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol with its fractions HDL2 and HDL3, the LDL/HDL ratio, triglycerides and fibrinogen were asessed at baseline and after 6 months or on early drop-out. Results Baseline values were comparable between the two groups. Blood samples of 841 women (83.4%) were available at baseline and endpoint. Total and LDL cholesterol decreased statistically significantly from baseline to endpoint in both treatment arms (by 7.2% and 3.8% with raloxifene and by 13.0% and 8.9% with ccHRT, respectively). Raloxifene produced a statistically significant increase in HDL cholesterol by 4.2%, while ccHRT induced a decline by 9.5%. Triglycerides were moderately suppressed with raloxifene and ccHRT, by 3.6 and 5.4%, respectively. Fibrinogen fell by 7.0% with raloxifene and rose by 3.6% with ccHRT. Conclusions Continuous combined HRT was associated with decreases in total cholesterol and LDL cholesterol about twice as large as with raloxifene, but also with a decrease in HDL cholesterol. The smaller decreases in total cholesterol and LDL cholesterol associated with raloxifene were accompanied by an increase in HDL cholesterol and a decrease in fibrinogen. In conclusion, raloxifene affects fibrinogen concentrations and the overall cholesterol profile more favorably than ccHRT; these differences may have important implications for the reduction of cardiovascular disease.

THE EFFICACY AND SAFETY OF ORAL DESMOPRESSIN IN CHILDREN WITH PRIMARY NOCTURNAL ENURESIS

We confirmed findings that oral desmopressin safely decreases the number of wet nights in children with enuresis and identified doses at which acceptable responses can be obtained. We evaluated the safety and efficacy of oral desmopressin in a double-blind, placebo controlled, parallel group, randomized, multicenter trial of 193 children 6 to 16 years old with documented primary nocturnal enuresis. The study was conducted in 2 phases: 1) a 2-week dose ranging phase in which children received desmopressin (0.2, 0.4 or 0.6 mg.) or placebo at bedtime and 2) an 8-week dose titration phase that followed a 2-week placebo washout. Patients received 0.2 mg. desmopressin or placebo for the first 2 weeks and then the dose was increased in 0.2 mg. increments at 2-week intervals until the patient was completely dry or was receiving 0.6 mg. Patients were instructed to limit fluid intake. Mean decrease from baseline in the number of wet nights, percentage of responding patients and safety were assessed at 2-week intervals. There was a statistically significant linear response to oral desmopressin at doses from 0.2 to 0.6 mg. during the dose ranging phase (p < or =0.05). The decrease in wet nights after 2 weeks of treatment with desmopressin was 27%, 30% and 40% at 0.2, 0.4 and 0.6 mg. doses, respectively, compared to 10% with placebo. All doses were statistically significantly different from placebo (p < or =0.05). During the dose titration phase all placebo treated and 87% of desmopressin treated patients were receiving the maximum dose of 3 tablets nightly because they had not been completely dry in the previous 2 weeks. Nevertheless, 44% of desmopressin treated patients had achieved at least a 50% reduction from baseline in the number of wet nights per 2 weeks at the lower doses of 0.2 and 0.4 mg. Most adverse events (rhinitis, pharyngitis, headache and increased cough) were mild to moderate in severity, unrelated to treatment and resolved before the study was completed. Oral desmopressin administered at bedtime to children with primary nocturnal enuresis was significantly better than placebo for decreasing episodes of bed-wetting (p <0.05). A linear dose-response relationship was observed (p <0.05). An acceptable response to treatment (50% or greater reduction from baseline in wet nights per 2 weeks) was seen at all doses of desmopressin. Oral desmopressin, up to 0.6 mg. for 8 weeks, was well tolerated.

Dose-Response Relationship and Reproducibility of the Fall in Exhaled Nitric Oxide After Inhaled Beclomethasone Dipropionate Therapy in Asthma Patients

The fractional concentration of exhaled nitric oxide (FENO) is a marker of asthmatic airway inflammation. We determined the dose response and the reproducibility of the FENO fall following inhaled beclomethasone dipropionate (iBDP) therapy in nonsteroid-treated asthmatic patients. Study A: For four 1-week periods (period 1 to period 4), the following regimens were administered in sequential order to 15 nonsteroid-treated asthmatic patients: period 1, placebo; period 2, 100 microg/d of iBDP; period 3, 400 microg/D of iBDP; and period 4, 800 microg/d of iBDP. Spirometry, FENO, and provocative concentration of methacholine resulting in a 20% fall in FEV(1) (PC(20)) were measured at each of five visits (visit 1 to visit 5). Study B: During four periods, 12 nonsteroid-treated asthmatic patients received placebo treatment for 7 days (period 1), 200 microg/d of iBDP for 14 days (period 2), washout on placebo treatment until the FENO was within 15% of baseline (period 3), and 200 microg/d of iBDP for 14 days (period 4). Study A: Mean FEV(1) rose progressively from 3.10 L (visit 1) to 3.41 L (visit 5; p = 0.001). All iBDP doses caused a significant FEV(1) rise compared to placebo treatment, but with no significant separation of doses using FEV(1). FENO geometric mean (95% confidence limits) fell progressively from 103.5 parts per billion (ppb) (78.5 to 136.7) to 37.4 ppb (29.1 to 48.0) from visit 1 to visit 5 (p = 0.001). All doses of iBDP resulted in a significant change in FENO from placebo treatment, but with significant separation of only the 100-microg and 800-microg doses by FENO. Geometric mean (95% confidence limits) PC(20) rose progressively from 0.01 mg/mL (0.00 to 0.19) to 0.48 mg/mL (0.01 to 8.1) from visit 1 to visit 5 (p = 0.002). All doses of iBDP resulted in a significant change in PC(20) from baseline or placebo treatment, but with no significant separation of active iBDP doses using PC(20). Study B: FENO fell from 111.56 ppb (80.3 to 155.1) to 66.3 ppb (49.2 to 89.5; p < 0.001) from period 1 to period 2, and from 110.2 ppb (79.3 to 153.1) to 61.7 ppb (42.9 to 88.8; p < 0.001) from period 3 to period 4. There were no significant differences between FENO in period 1 and period 3 (p = 0.83) or between period 2 and period 4 (p = 0.220). FENO was superior to FEV(1) and PC(20) in separating doses of iBDP. The fall in FENO after two identical administrations of iBDP separated by placebo washout was highly reproducible.

Valsartan improves vascular endothelial dysfunction in essential hypertension

Vascular endothelial dysfunction can be demonstrated in essential hypertension, and reversing this abnormality is an attractive therapeutic objective. We tested whether this could be achieved by blocking the AT1 receptor and compared this with calcium channel blockade. 12 hypertensives [mean age 60 (SD 8) years] with a mean ambulatory blood pressure of 154(10)/97(6) mmHg were randomized following a 2-week placebo (baseline) run-in period in a single blind crossover fashion to 8 week treatment period with either valsartan or amlodipine, separated by 2-week placebo washout period. Forearm venous occlusion plethysmography and intra-arterial infusions of acetylcholine (ACh) and NG-monomethyl-L-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide (NO) release, respectively. Sodium nitroprusside (SNP) was used as endothelium-independent NO (control vasodilator). Valsartan and amlodipine each lowered the clinic blood pressure to the same extent (Table). The vasodilatory response to ACh was significantly increased with valsartan but remained unchanged with amlodipine. The response to SNP was not different between treatments suggesting that the endothelium-independent pathway was unaffected. Valsartan and amlodipine similarly increased the vasoconstrictive response to L-NMMA (Table). p<0.05 versus baseline; p<0.001 versus baseline.[table] p<0.05 versus baseline; p<0.001 versus baseline.[table] Valsartan, an AT1 receptor antagonist, increased both stimulated and basal endothelial nitric oxide release whereas for the same degree of blood pressure control, amlodipine had no effect on stimulated NO release. Thus, AT1 receptor blockade may offer superior vascular protection in hypertension. Table legend: SBP/DBP systolic and diastolic blood pressure (SD); FBF=Forearm Blood Flow (SEM)

Evaluation of Salmeterol or Montelukast as Second-Line Therapy for Asthma Not Controlled With Inhaled Corticosteroids

To assess the addition of a leukotriene receptor antagonist and a long-acting beta(2)-agonist as second-line therapy in asthma. Placebo-controlled, double-dummy, crossover study. Outpatient clinic. Twenty patients with persistent asthma not controlled with inhaled corticosteroid therapy. Montelukast 10 mg once daily, or salmeterol, 50 microg bid, each for 2 weeks with 1-week run-in and washout placebo periods. Adenosine monophosphate (AMP) bronchial challenge, blood eosinophil count (EOS), exhaled nitric oxide, and lung function after both placebo periods and after the first and last doses of each active treatment. Patients recorded their domiciliary peak expiratory flow (PEF), asthma symptoms, and rescue bronchodilator requirement (RES) twice daily throughout the study. For the primary end point of the provocative concentration of AMP causing a 20% fall in FEV(1), compared to placebo (47.5 +/- 13.0 mg/mL), there were significant differences with the first (114.1 +/- 36.9 mg/mL) and last (94.2 +/- 30.4 mg/mL) doses of montelukast as well as the first (160.1 +/- 64.5 mg/mL) but not the last (70.1 +/- 23.7 mg/mL) dose of salmeterol. Only montelukast produced significant suppression of the EOS. Neither drug affected exhaled nitric oxide levels. There were significant improvements with the first doses of salmeterol for all parameters of lung function. After 2 weeks of treatment, there were significant improvements with both drugs for RES and morning PEF. There were no significant differences between drugs for any end points except EOS. Montelukast and salmeterol exhibited significant improvements in asthma control when given as second-line therapy. Montelukast also produced significant effects on AMP challenge and EOS suggesting anti-inflammatory activity.

Differential effects of raloxifene and continuous combined hormone replacement therapy on biochemical markers of cardiovascular risk: results from the Euralox 1 study

Objective To compare the effects of the selective estrogen receptor modulator (SERM) raloxifene (Evista®) and a continuous combined hormone replacement therapy (ccHRT) formulationcontaining estradiol and norethisterone acetate (Kliogest®) on lipid and fibrinogen levels of postmenopausal women.Methods Euralox 1 was a prospective, randomized, double-blindtrial. After a placebo wash-out, healthy postmenopausal women (n = 1008, average age 56.1 ± 4.9 years) with a health risk profile that suggested a potential benefit from either treatment wererandomly assigned to either 60 mg raloxifene or ccHRT consisting of 2 mg estradiol and 1 mg norethisterone acetate (NETA) per day for 6 months.Measurements Total cholesterol, low-density lipoprotein(LDL) cholesterol, high-density lipoprotein (HDL) cholesterol with its fractions HDL2 and HDL3, the LDL/HDL ratio, triglycerides and fibrinogen were asessed at baseline and after 6 months or on early drop-out.Results Baseline values were comparable between the two groups. Blood samples of 841 women (83.4%) were available at baseline and endpoint. Total and LDL cholesterol decreased statistically significantlyfrom baseline to endpoint in both treatment arms (by 7.2% and 3.8% with raloxifene and by 13.0% and 8.9% with ccHRT, respectively). Raloxifene produced a statistically significant increase in HDL cholesterolby 4.2%, while ccHRT induced a decline by 9.5%. Triglycerides were moderately suppressed with raloxifene and ccHRT, by 3.6 and 5.4%, respectively. Fibrinogen fell by 7.0% with raloxifene and rose by 3.6%with ccHRT.Conclusions Continuous combined HRT was associated with decreases in total cholesterol and LDL cholesterol about twice as large as with raloxifene, but also with a decrease in HDLcholesterol. The smaller decreases in total cholesterol and LDL cholesterol associated with raloxifene were accompanied by an increase in HDL cholesterol and a decrease in fibrinogen. In conclusion, raloxifeneaffects fibrinogen concentrations and the overall cholesterol profile more favorably than ccHRT; these differences may have important implications for the reduction of cardiovascular disease.

Effects of four angiotensin II-receptor antagonists on fibrinolysis in postmenopausal women with hypertension

Background: Reduced fibrinolysis due to increased concentrations of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of endogenous fibrinolysis, is associated with an increased risk for cardiovascular events. Objective: This study was undertaken to compare the effects of 4 angiotensin II (AII)-receptor antagonists with different pharmacokinetic properties—losartan, valsartan, irbesartan, and candesartan—on levels of PAI-1 antigen in postmenopausal women with hypertension. Methods: Postmenopausal women aged 51 to 60 years with mild to moderate hypertension (diastolic blood pressure [DBP] > 90 mm Hg and ≤105 mm Hg) who were not taking any hormone replacement therapy were studied. Patients with diabetes or obesity and patients who smoked were excluded. After a 2-week placebo washout period, patients were assigned to receive losartan 50 mg, valsartan 80 mg, irbesartan 150 mg, candesartan 8 mg, or placebo for 12 weeks according to a double-blind, randomized, parallel-group design, with a titration for nonresponders after 6 weeks. At the end of the placebo period and 6 and 12 weeks after active treatment, blood pressure, PAI-1 antigen levels, heart rate, and body mass index were measured. Results: A total of 156 patients were randomized to receive losartan (n = 31), valsartan (n = 32), irbesartan (n = 31), candesartan (n = 32), or placebo (n = 30); of these, 140 completed the study. All 4 active treatments significantly reduced DBP and systolic blood pressure, with no significant differences in efficacy between groups. Plasma PAI-1 levels decreased slightly after treatment with losartan (−0.9%) and valsartan (−3.8%) and increased slightly with irbesartan (+10.1%), but these values were not significantly different from placebo. In contrast, candesartan significantly increased PAI-1 values by 33.3% ( P < 0.05 vs placebo). There were no significant changes in heart rate or body mass index in any group. Conclusions: These findings suggest that, despite a comparable antihypertensive efficacy, candesartan differs from the other AII-receptor antagonists studied in that it significantly increases PAI-1 antigen levels. This might be related to its specific pharmacologic characteristics, particularly its insurmountable antagonism of the AII AT1 receptor.

Comparison of valsartan and irbesartan in the treatment of mild to moderate hypertension: a randomized, open-label, crossover study

Background: Differences in the pharmacokinetic and pharmacodynamic variables of angiotensin II receptor blockers (ARBs) have been cited as potentially important causes of differential clinical efficacy with respect to the magnitude and duration of the antihypertensive response. Objective: The goal of this study was to compare the antihypertensive efficacy of valsartan versus irbesartan using 24-hour ambulatory blood pressure monitoring (ABPM) in the treatment of mild to moderate hypertension. Methods: After a 2-week placebo washout period, outpatients of both sexes aged 31 to 60 years with mild to moderate hypertension were randomly assigned to treatment with irbesartan 150 mg or valsartan 80 mg, both administered once daily, for 4 weeks. After another 2-week placebo washout period, patients were switched to the alternate regimen for an additional 4 weeks. Patients were assessed at the end of each placebo and active treatment period. At each visit, casual blood pressure (BP) and heart rate were measured and 24-hour ABPM was performed using a portable, noninvasive, fully automatic recorder. Recordings were excluded from analysis when >10% of all readings or >1 reading per hour was missing or incorrect. Trough/peak ratio was assessed in each treatment group, and the smoothness index was determined to quantify the homogeneity of the antihypertensive effect over 24 hours. Results: Forty patients (20 men and 20 women; mean age, 51 ± 7 years) were included in the study. One patient withdrew after randomization (lost at follow-up); the results are given for 39 patients. Both valsartan and irbesartan significantly lowered 24-hour, daytime, and nighttime BP values ( P < 0.001 vs placebo) without affecting the normal BP circadian profile. No significant differences in efficacy were found between the 2 drugs. Mean values for 24-hour, daytime, and nighttime heart rate, as well as the 24-hour heart rate profile, were not significantly affected by either drug. Both drugs had a trough/peak ratio >50% (valsartan, 0.65 ± 0.72 for systolic BP [SBP] and 0.62 ± 0.55 for diastolic BP [DBP]; irbesartan, 0.57 ± 0.58 for SBP and 0.69 ± 0.54 for DBP) and a similar smoothness index (valsartan, 1.26 ± 0.31 for SBP and 1.41 ± 0.17 for DBP; irbesartan, 1.32 ± 0.43 for SBP and 1.52 ± 0.43 for DBP), which suggests that their antihypertensive effect was homogeneous throughout the 24-hour period and lasted to the end of the dosing interval. Casual BP results confirmed that valsartan and irbesartan were equally effective in reducing SBP and DBP values. Conclusions: Valsartan and irbesartan are 2 ARBs with different pharmacologic properties. Valsartan is more selective for angiotensin type 1 receptors than is irbesartan; irbesartan has a longer half-life and demonstrates insurmountable antagonism. These distinct pharmacologic properties did not appear to result in different effects on the magnitude and duration of antihypertensive efficacy.