Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: Recent surveys reveal continuing deficiencies in the awareness, treatment, and control of hypertension. In many cases, failure to achieve blood pressure targets may be attributable to the use of antihypertensive monotherapy. OBJECTIVES: This study was undertaken to identify combinations of telmisartan, a new oral angiotensin II type 1-receptor antagonist, and hydrochlorothiazide (HCTZ) that might provide greater antihypertensive efficacy than monotherapy with either agent in the treatment of mild to moderate hypertension. It also examined the dose-response surface for the 2 drugs alone and in combination. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study that employed all cells of a 4 x 5 factorial design. After a 4-week, single-blind, placebo run-in period, men and women between 18 and 80 years of age with mild to moderate hypertension (defined as mean supine diastolic blood pressure [DBP] between 95 and 114 mm Hg during the last 2 weeks of the placebo run-in period and systolic blood pressure [SBP] between 114 and 200 mm Hg immediately before randomization) were eligible to enter the 8-week, double-blind, double-dummy treatment period. Study comparisons were between once-daily telmisartan monotherapy (20, 40, 80, or 160 mg), HCTZ monotherapy (6.25, 12.5, or 25 mg), 12 combinations of these telmisartan/HCTZ doses, and placebo. The focus was on 2 combinations: telmisartan 40 mg/HCTZ 12.5 mg and telmisartan 80 mg/HCTZ 12.5 mg. The primary efficacy variable was change in supine trough DBP from baseline to the last evaluable measurement during double-blind treatment. Plasma renin activity and safety parameters, including treatment-emergent adverse events, physical findings, electrocardiograms, and serum electrolyte levels (which are known to increase with HCTZ treatment), were also assessed. RESULTS: Of 1293 patients screened, 818 (63.3%) were enrolled at 47 centers. Of these 818, 749 (91.6%) completed the study. The intent-to-treat population (randomized with > or = 1 postrandomization blood pressure measurement) consisted of 807 patients (98.7%). Telmisartan 80 mg/HCTZ 12.5 mg significantly decreased mean supine trough SBP/DBP by 23.9/14.9 mm Hg, a benefit of 8.5/3.4 mm Hg compared with telmisartan 80 mg and of 17.0/7.6 mm Hg compared with HCTZ 12.5 mg (both comparisons, P < 0.01). Telmisartan 40 mg/HCTZ 12.5 mg significantly reduced mean supine SBP by 18.8 mm Hg, a benefit of 6.6 mm Hg compared with telmisartan 40 mg and 11.9 mm Hg compared with HCTZ 12.5 mg (both, P < 0.01). This same combination significantly reduced mean supine DBP by 12.6 mm Hg, a benefit of 5.3 mm Hg compared with HCTZ 12.5 mg (P < 0.01), but was not significantly different from telmisartan 40 mg. Telmisartan 80 mg/HCTZ 12.5 mg was significantly more effective than telmisartan 40 mg/HCTZ 12.5 mg in reducing mean supine DBP and SBP (both, P < 0.05). The response surface and responder analyses confirmed the additive antihypertensive efficacy of the combination of telmisartan and HCTZ. All regimens were well tolerated. CONCLUSIONS: Once-daily telmisartan 80 mg/HCTZ 12.5 mg was effective and well tolerated when used to reduce SBP and DBP in patients with mild to moderate hypertension. In addition to enhancing efficacy, this combination protected against potassium depletion, a common side effect of thiazide monotherapy.     

A multicenter,randomized, double-blind,placebo-controlled, 8-week trial of the efficacy and tolerability of once-daily losartan 100 mg/hydrochlorothiazide 25 mg and losartan 50 mg/hydrochlorothiazide 12.5 mg in the treatment of moderate-to-severe essential hypertension

BACKGROUND: Many patients with moderate-to-severe hypertension require multiple drug therapy to achieve blood-pressure goals. Fixed-dose combination therapy with losartan and hydrochlorothiazide may be useful in this population. OBJECTIVE: This study was conducted to obtain additional data on the antihypertensive efficacy and tolerability of once-daily, fixed-dose combinations of losartan and hydrochlorothiazide. METHODS: This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Patients > or = 21 years of age with moderate-to-severe essential hypertension, defined as a mean trough sitting diastolic blood pressure (SiDBP) of 105 to 115 mm Hg, were randomly assigned in a 2:2:1 ratio to receive losartan 100 mg/hydrochlorothiazide 25 mg (L100/25), losartan 50 mg/hydrochlorothiazide 12.5 mg (L50/12.5), or placebo (PBO) once daily for 8 weeks. The primary efficacy measurement was the mean change from baseline in trough SiDBP in the L100/25 versus L50/12.5 treatment groups. Responders were defined as patients with mean trough SiDBP <90 mm Hg or a > or = 10-mm Hg decrease in mean trough SiDBP. RESULTS: A total of 446 patients were randomly assigned to receive L100/25 (n = 173), L50/12.5 (n = 184), or PBO (n = 89). At week 8, mean trough SiDBP was significantly lower than at baseline in the L100/25 (-17.5 mm Hg), L50/12.5 (-15.2 mm Hg), and PBO groups (-8.5 mm Hg) (all P < 0.001). The difference between the active-treatment groups was statistically significant (-2.2 mm Hg; 95% Cl, range -3.8 to -0.6) (P = 0.006), as was the difference between the L100/25 and PBO groups (-9.0 mm Hg; 95% CI, range -I1.0 to -7.0) (P < 0.001) and the L50/12.5 and PBO groups (-6.7 mm Hg; 95% CI, range -8.7 to -4.8) (P < 0.001). At week 8, the percentages of responders were 86.7% (144 of 166), 78.9% (142 of 180), and 50.0% (42 of 84) in the L100/25, L50/12.5, and PBO groups, respectively. The incidence of adverse experiences (AEs) was 34.7% (60 of 173) in the L100/25 group, 23.9% (44 of 184) in the L50/12.5 group, and 32.6% (29 of 89) in the PBO group. The incidence of drug-related AEs was similar among the treatment groups (L100/25, 7.5% [13 of 173]; L50/12.5, 7.1% [13 of 184]; and PBO, 11.2% [10 of 89]). CONCLUSIONS: This study demonstrates the antihypertensive efficacy and tolerability of the once-daily, fixed-dose combination L50/12.5 in patients with moderate-to-severe essential hypertension. In this study, L100/25 provided additional anti-hypertensive efficacy beyond that of L50/12.5 (and both were more efficacious than PBO). Approximately 4 of 5 patients (78.9%) treated with L50/12.5 responded to therapy, as did nearly 9 of 10 patients (86.7%) treated with L100/25. The tolerability profiles of L50/12.5 and L100/25 were similar to that of PBO.     

Insulin-glyburide combination therapy for non-insulin-dependent diabetes mellitus: a long-term double-blind, placebo-controlled trial

Sixty-four patients with non-insulin-dependent diabetes mellitus were treated with a combination of insulin and oral sulfonylurea therapy in a double-blind, placebo-controlled trial during a 12-month period. Combination therapy lowered fasting glucose levels significantly only at the third and fourth months of treatment. Glycohemoglobin levels were significantly lower than control at 3 and 6 months whereas C-peptide levels were significantly increased at 3 and 9 months. Responders exhibited as much as a 50% reduction in total insulin dose compared with nonresponders or control subjects. These results suggest that combination therapy affords transient metabolic improvement in certain patients with non-insulin-dependent diabetes. Improvement in fasting glucose levels appears to be mediated by enhanced insulin secretion. Combination therapy may increase the cost of treatment by nearly 50% and appears warranted only in selected patients.     

Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: the VAST study

BACKGROUND: Recent antihypertensive treatment guidelines recommend greater use of combination therapies. OBJECTIVES: The primary objective of this study was to determine whether combination therapy with valsartan 160 mg plus hydrochlorothiazide (HCTZ) 25 mg OD would be more effective than monotherapy with amlodipine 10 mg OD in reducing systolic blood pressure (SBP) in patients with moderate (stage II) hypertension and > or =1 other cardiovascular risk factor or concomitant condition. A secondary objective was to assess the effects of the study treatments on circulating markers of endothelial dysfunction and vascular inflammation. METHODS: This was a multicenter, randomized, double-blind, active-controlled, 24-week study. After a 2-week, single-blind, placebo run-in period, patients were randomized to 3 groups, 2 of them receiving valsartan 160 mg OD and 1 receiving amlodipine 5 mg OD. At week 4, HCTZ 12.5 mg OD was added to valsartan in one of the treatment groups (V+HCTZ12.5), HCTZ 25 mg OD was added to the other (V+HCTZ25), and the amlodipine dose was force-titrated to 10 mg OD (A10). The primary efficacy variable was change in mean sitting SBP at week 24. Other variables were changes in mean sitting diastolic blood pressure (DBP) and mean pulse pressure (PP) from baseline, and response rate (systolic response defined as mean sitting SBP <140 mm Hg or a reduction in mean sitting SBP of > or =20 mm Hg from baseline; diastolic response defined as mean sitting DBP <90 mm Hg or a reduction in mean sitting DBP of > or =10 mm Hg from baseline). Changes in the following markers of endothelial dysfunction were determined at baseline and weeks 4, 12, and 24 in all randomized patients from the participating European and South African centers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular tissue plasminogen activator (t-PA) antigen, and oxidized low-density lipoprotein (LDL). RESULTS: The study enrolled 1088 patients with moderate hypertension (mean age, 61 years; 82% white; 53% women). The intent-to-treat population consisted of 1079 patients: 357 in the V+HCTZ12.5 group, 363 in the V+HCTZ25 group, and 359 in the A10 group. At baseline, the groups were comparable in terms of blood pressure and most other characteristics; the only statistically significant difference between groups was in the proportion of patients aged > or =65 years, which was lower in the amlodipine group (P = 0.01). At the end of the study, the least squares mean (SD) changes from baseline in mean sitting SBP were 27.1 (13.7), 29.7 (13.7), and 27.6 (13.8) mm Hg in the V+HCTZ12.5, V+HCTZ25, and A10 groups, respectively, with corresponding percent changes of 16%, 18%, and 17% (P < 0.05, V+HCTZ25 vs A10). The changes in mean sitting DBP did not differ significantly between groups. The reductions in PP were 17.5 (11.3), 18.7 (11.3), and 16.9 (11.3) mm Hg, with percent changes of 24%, 26%, and 23% (P < 0.05, V+HCTZ25 vs A10). Significant reductions in t-PA antigen were observed in both combination-therapy groups compared with the amlodipine monotherapy group at week 12 (P < 0.05); the reductions remained significant through the end of the study in the V+HCTZ12.5 group. There was a significant reduction in IL-6 and hs-CRP at week 12 with V+HCTZ25 compared with A10 (P < 0.05). Oxidized LDL values were reduced by approximately 10% with all treatments. Rates of total adverse events were significantly lower with the valsartan-based treatments compared with amlodipine monotherapy (49.7%, 49.6%, and 67.5% with V+HCTZ12.5, V+HCTZ25, and A10, respectively; P < 0.05). Rates of total discontinuations were a respective 10.1%, 9.0%, and 24.5%, and discontinuation rates due to AEs were 4.2%, 3.5%, and 18.2%. Leg edema was more common with amlodipine monotherapy than with the valsartan-based combinations (P < 0.05). CONCLUSION: In this group of patients with moderate hypertension and > or =1 other cardiovascular risk factor or concomitant condition, similar and greater antihypertensive effects were seen with the fixed-dose combinations of valsartan 160 mg and HCTZ 12.5 and 25 mg OD, respectively, compared with amlodipine 10 mg OD, with significantly lower rates of treatment-related adverse events and possible beneficial effects on vascular markers.     

Aripiprazole monotherapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study

Aims: Rapid‐cycling bipolar disorder is difficult to treat and associated with greater morbidity than non‐rapid‐cycling disease. This post hoc analysis evaluated 28 patients with rapid‐cycling bipolar I disorder from a 100‐week, double‐blind, placebo‐controlled study assessing long‐term efficacy, safety and tolerability of aripiprazole in patients with bipolar I disorder (most recently manic/mixed). Methods: Following ≥ 6 consecutive weeks’ stabilisation with open‐label aripiprazole, patients were randomised (1 : 1) to aripiprazole or placebo. Patients completing 26 weeks treatment without relapse could continue for a further 74 weeks. Primary end‐point was time to relapse for manic, mixed or depressive symptoms, defined as discontinuation due to lack of efficacy. Safety assessments included adverse event (AE) monitoring and changes in weight and lipid, glucose and prolactin levels. Results: Of the 28 patients (aripiprazole, n = 14; placebo, n = 14) with rapid‐cycling bipolar disorder, 12 (aripiprazole, n = 7; placebo, n = 5) completed the initial 26‐week treatment period and three (all aripiprazole treated) completed the 100‐week, double‐blind period. Time to relapse was significantly longer with aripiprazole vs. placebo at week 26 [log‐rank p = 0.033; 26‐week hazard ratio = 0.21 (95% CI: 0.04, 1.03)] and week 100 [log‐rank p = 0.017; 100‐week hazard ratio = 0.18 (95% CI: 0.04, 0.88)]. The most commonly reported AEs with aripiprazole during the 100 weeks (≥ 10% incidence and twice placebo) were anxiety (n = 4), sinusitis (n = 4), depression (n = 3) and upper respiratory infection (n = 3). One aripiprazole‐treated patient discontinued due to an AE (akathisia). There were no significant between‐group differences in mean changes in weight or metabolic parameters. Conclusion: In this small, post hoc subanalysis, aripiprazole maintained efficacy and was generally well tolerated in the long‐term treatment of rapid‐cycling bipolar disorder. Further research with prospectively designed and adequately powered trials is warranted.     

A randomized pilot study comparing combination therapy plus enfuvirtide versus a treatment interruption followed by combination therapy plus enfuvirtide

Most individuals with multidrug-resistant HIV who switch to a new therapeutic regimen containing a single fully effective agent experience incomplete viral suppression. We postulated that interruption of antiretroviral therapy prior to the introduction of such a regimen would improve long-term virological outcomes. Thirty, three-class experienced, enfuvirtide-naive individuals with detectable drug-resistant viraemia were randomized to an immediate enfuvirtide/optimized-background treatment regimen or a 16-week treatment interruption followed by enfuvirtide/optimized-background treatment regimen. The median CD4+ T-cell count and viral load at study entry were 39 cells/mm and 4.72 log10 copies RNA/ml, respectively. There was no evidence of any virological or immunological benefit associated with the interruption. In multivariate analysis, only the baseline phenotypic susceptibility score was predictive of treatment response at week 48 (P=0.009). Only 40% of individuals had evidence of a shift in drug-resistance genotype during the interruption. In summary, interrupting therapy prior to initiating salvage therapy in patients with advanced disease did not result in an improved virological response to enfuvirtide. The collective predictive activity of an enfuvirtide-containing regimen was important in predicting treatment response.     

Randomized, double-blinded trial evaluation of valsartan/hydrochlorothiazide combination therapy in mild to moderate essential hypertension in north-east China

In this randomized, double-blind study, 126 mild to moderate essential hypertensive patients from northern China were studied to determine the efficacy and safety of a combination therapy of valsartan and hydrochlorothiazide. Patients were randomized to the V80/H12.5 (80 mg valsartan/12.5 mg hydrochlorothiazide) group or the V80 (80 mg valsartan) group. Six weeks after treatment, the mean decrease from baseline in mean sitting systolic blood pressure (MSSBP) was significantly higher in the V80/H12.5 group than the V80 group, but there was no difference in the change of mean sitting diastolic blood pressure (MSDBP) in the two groups. Overall, 80.33% and 70.97% had a controlled response (normalized MSDBP), and 85.25% and 77.42% had a diastolic response (normalized MSDBP or > 10 mmHg reduction in MSDBP) in the V80/H12.5 and V80 groups, respectively (not significantly different). The incidence of adverse events was also similar between the two groups. The combination of 80 mg valsartan/12.5 mg hydrochlorothiazide was efficacious and well tolerated in mild and moderate essential hypertensive patients.     

Comparison of inhibition of cutaneous histamine reaction of ebastine fast-dissolving tablet (20 mg) versus desloratadine capsule (5 mg): a randomized, double-blind, double-dummy, placebo-controlled, three-period crossover study in healthy, nonatopic adults

BACKGROUND: Ebastine is a long-acting, second-generation, selective histamine H1-receptor antagonist. A fast-dissolving tablet formulation of ebastine has been developed at 10- and 20-mg doses, with the intention of facilitating administration to patients experiencing problems with swallowing, including those confined to bed and elderly people, as well as those who may need to use ebastine when they do not have easy access to water to aid swallowing a tablet. OBJECTIVES: This study was conducted to assess the pharmacodynamic effects (ie, inhibition of wheal response to cutaneous histamine challenge, and subjective assessments of itching, flare, and pain) and tolerability of the fast-dissolving 20-mg ebastine tablet formulation compared with desloratadine 5-mg capsule and placebo. Acceptability and convenience of the fast-dissolving tablet were also evaluated. METHODS: This double-blind, double-dummy, randomized, placebo-controlled, 3-period crossover study was conducted at the Drug Research Centre, Department of Clinical Pharmacology, the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Healthy, nonatopic, white adults aged 18 to 40 years were randomly assigned to 1 of 6 study sequences: ABC, ACB, BAC, BCA, CBA, or CAB, where A was the ebastine fast-dissolving 20-mg tablet, B was the desloratadine 5-mg capsule, and C was placebo. All study drugs were given orally once daily (8-9 AM) on days 1 to 5 of each study period. Study periods were separated by a washout period of 7 to 10 days. Histamine skin-prick test (SPT) challenge was performed before study drug administration on day 1 of each period (baseline), and then every 20 minutes for 2 hours after administration and again after 24 hours. The final SPT was 24 hours after the day-5 dose was administered. The primary end point was inhibition o f the histamine response, defined as the percentage reduction from baseline wheal area 24 hours after 5 days of administration. Subjective symptoms (itching, flare, and pain) were assessed by subjects using visual analog scales every 20 minutes for 2 hours after administration on day 1. At study end, acceptability (taste, convenience, and overall preference) of the fast-dissolving tablet and capsule formulations were assessed using a questionnaire completed by subjects. Tolerability was assessed using physical examination, laboratory analysis, physician questioning, and spontaneous reporting. RESULTS: Thirty-six people were randomized (22 women, 14 men; mean [SD] age, 24.7 [4.1] years; mean [SD] weight, 63.2 [9.9] kg); 35 completed the study (1 subject was lost to follow-up after the second study period). Unadjusted mean (SD) wheal areas 24 hours after dose administration on day 5 were 72.9 (29.5), 115.0 (32.1), and 146.7 (32.2) mm(2), for ebastine, desloratadine, and placebo, respectively. Mean differences in reduction from baseline in wheal area were 29.0% for ebastine versus desloratadine and 43.7% for ebastine versus placebo (both, P < 0.001). Corresponding unadjusted mean (SD) wheal areas 24 hours after administration of the first dose on day 1 were 76.5 (22.5), 128.9 (24.0), and 140.5 (33.1) mm(2). Mean itching, flare, and pain ratings were not significantly different between study drugs. Results from the preference questionnaire indicated that the majority (80%) preferred the ebastine fast-dissolving tablet to the desloratadine capsule (and hypothetically also to tablets and oral solution, which were not tested in this study). Ninety-seven percent of subjects were of the opinion that compliance in the home setting would be facilitated by the fas-tdissolving tablet formulation. Fourteen adverse events (AEs) were reported in 9 (25%) volunteers; all AEs were of mild or moderate intensity. Five occurred with ebastine 20 mg (intermittent somnolence, back pain, pharyngolaryngeal pain, pyrexia, and oral pain [1 patient each]), 5 occurred with desloratadine 5 mg (asthenia [2 patients] and dry mouth, somnolence, and back pain [1 patient each]), and 4 occurred with placebo (diarrhea [2 patients] and somnolence and headache [1 patient each]). The relationship with the study drugs was considered unlikely in 6 cases and possible in the remaining 8 cases. An additional AE (back pain) occurred during a washout period. CONCLUSIONS: In this small study in healthy, nonatopic white subjects, inhibition of the response to histamine injection was significantly greater with the ebastine 20-mg fast-dissolving tablet compared with desloratadine 5-mg capsule and placebo after 1 and 5 days of administration. Most participants expressed an overall preference for the fast-dissolving tablet formulation over capsules. All study drugs were well tolerated.     

A multicenter, randomized, double-blind, parallel-group trial of the antihypertensive efficacy and tolerability of a combination of once-daily losartan 100 mg/hydrochlorothiazide 12.5 mg compared with losartan 100-mg monotherapy in the treatment of mild to severe essential hypertension

BACKGROUND: Because patients with hypertension may require >1 antihypertensive agent to control blood pressure (BP), physicians often prescribe a fixed combination of antihypertensive medications. OBJECTIVE: This study evaluated the effect of adding low-dose hydrochlorothiazide 12.5 mg (HCTZ12.5) to high-dose losartan 100 mg (L100) in patients with hypertension whose BP was inadequately controlled with L100 monotherapy. METHODS: Enrolled in this multicenter, randomized, double-blind, parallel-group, filter study were patients aged > or =18 years with a mean trough sitting diastolic BP (SiDBP) of 95 to 120 mm Hg. Patients were treated with L100 QD for 4 weeks. Patients who did not achieve adequate BP control were randomly assigned to receive L100/HCTZ12.5 or L100 QD for 6 weeks. The primary efficacy measure was the mean change in trough SiDBP from baseline in the 2 groups. Responders were defined as patients with a mean trough SiDBP of <90 mm Hg or patients who had a > or =10-mm Hg decrease in mean trough SiDBP. RESULTS: Demographic characteristics were similar between treatment groups. The patients randomized to the double-blind treatment period were mostly white (65.1%) and male (57.5%), with a mean age of 53.8 years. The mean (SD) duration of hypertension at baseline was 9.7 (8.5) years. The proportion of patients previously treated with antihypertensive therapy was 76.7%. Of the 367 patients enrolled in the L100 filter period, 292 patients had BP inadequately controlled with L100 monotherapy and were randomized to receive L100 (n = 145) or L100/HCTZ12.5 (n = 147). At week 6 after randomization, mean trough SiDBP was significantly lower in the L100/HCTZ12.5 group than in the L100 group (-8.3 vs -5.2, respectively; P < 0.001). The between-group difference was -3.0 mm Hg (95 % CI, -4.6 to -1.40; P < 0.001), and the proportion of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group (63.0% vs 44.4%; P < 0.001). The incidence of adverse events (AEs) occurring in >2% of patients during the double-blind period was similar for both groups. AEs occurring in the L100 group and the L100/HCTZ12.5 group included respiratory tract infection (6.2% vs 3.4%, respectively), dizziness (2.1% vs 0.7%), and headache (0.7% vs 3.4%). CONCLUSIONS: After 6 weeks of therapy, L100/HCTZ12.5 was associated with greater antihypertensive efficacy than L100, as measured by the change in mean trough SiDBP The percentage of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group.     

Troxerutin-carbazochrome combination versus placebo in the treatment of posthemorrhoidectomy symptoms: a single-center, randomized, double-blind, placebo-controlled study

Background: Flavonoids, such as troxerutin, have been shown to be safe and effective agents for the treatment of chronic venous insufficiency. The fixed combination of troxerutin 150 mg plus carbazochrome (an oxidation product of epinephrine that enhances the microcirculatory tone) 1.5 mg has been shown to have a good efficacy and tolerability profile in nonsurgical patients with acute, uncomplicated hemorrhoids. A previous pilot study we carried out in 30 posthemorrhoidectomy patients showed that this combination was also effective and well tolerated in improving posthemorrhoidectomy symptoms.Objective: This study compared the efficacy and tolerability of troxerutin-carbazochrome active combination with placebo in the treatment of posthemorrhoidectomy symptoms.Methods: In this single-center, randomized, double-blind, placebo-controlled study, patients scheduled for hemorrhoidectomy were randomized to receive 1 of 2 treatments: troxerutin 150 mg plus carbazochrome 1.5 mg active combination or placebo IM in 3-mL ampules BID for 5 consecutive days after surgery, starting on the day of surgery. Efficacy parameters were assessed at baseline (T1), after the first administration (T2; day of surgery), day 2 after surgery (T3), and day 5 after surgery (T4). Efficacy parameters assessed included hemorrhoidal symptoms based on a visual analog scale (VAS): pain, discharge, bleeding, inflammation, and pruritus; edema; analgesic intake, if any; time to restore physiologic defecation; photographs taken at T1 and T4 (in selected patients; not included here); and standard blood coagulation tests.Results: Sixty patients were enrolled (33 males, 27 females; mean age, 45.6 ± 7.4 years). Analysis between treatment groups revealed significant differences in mean total VAS scores at T3 and T4 (P = 0.01 and P = 0.001, respectively) in favor of the active-combination group. Statistically significant between-group differences in scores for bleeding and pruritus at T3 and for bleeding, pruritus, and edema at T4 in favor of the active-combination group also were found (P < 0.001 for all). No severe adverse events were reported in either group. Blood coagulation test results were unaffected in both groups.Conclusions: IM administration of troxerutin 150 mg plus carbazochrome 1.5 mg combination was effective, well tolerated, and superior to placebo in improving hemorrhoidal and postsurgical signs and symptoms in 5 days of treatment in this study population.     

Daily doses of 20 mg of elemental iron compensate for iron loss in regular blood donors: a randomized, double-blind, placebo-controlled study

BACKGROUND: A considerable number of regular blood donors develops an iron deficiency, and the exact amount of iron required to compensate for the iron loss from whole-blood donation in males and females is still unknown. STUDY DESIGN AND METHODS: A total of 526 regular blood donors (289 male and 237 female) were randomly assigned to treatment with either 40 mg, 20 mg, or 0 mg per day of elemental iron as ferrous gluconate for a period of 6 months, during which one unit of whole blood was collected on four occasions (males) or three occasions (females). Hemoglobin level, serum ferritin, and soluble transferrin receptor levels were measured before each donation. RESULTS: Daily doses of either 40 mg or 20 mg of elemental iron adequately compensated for iron loss in males, who gave blood at 2-month intervals, but did not result in a positive iron balance or an increase in storage iron as reflected by the logarithm of the ratio of transferrin receptor to ferritin concentration. In females, who donated at 3-month intervals, the same daily doses not only restored the iron balance but also led to an increase in storage iron. The number of gastrointestinal side effects due to iron supplementation (12%) was only slightly higher in both iron groups than in the placebo group. CONCLUSION: The results of this study indicate that 20 mg of elemental iron per day can adequately compensate for iron loss in males and females who donate whole blood up to four (females) or six times per year (males).     

Results of long-term follow-up of HIV-infected patients treated with lamivudine monotherapy, followed by a combination of lamivudine and zidovudine

The objective of this study was to determine the efficacy and safety of adding zidovudine to continuous treatment with lamivudine in symptomatic human immunodeficiency virus type 1 (HIV-1)-infected patients. Forty patients were monitored throughout lamivudine monotherapy and subsequent combination therapy with lamivudine and zidovudine, which was initiated because of disease progression, declining CD4 cell counts or prolonged use of lamivudine. Eleven of these patients had been treated with zidovudine before the start of the study. The median CD4 cell count at the start of lamivudine monotherapy was 200 x 10(6) cells/l. After a median interval of 69 weeks (range 23-102 weeks), the median CD4 cell count had dropped to 110 x 10(6) cells/l. Initial improvements in all laboratory markers for antiretroviral efficacy were observed after the addition of zidovudine. The median CD4 cell count remained 18% above baseline after 48 weeks of treatment with lamivudine and zidovudine, however plasma HTV-1 RNA load and CD4 cell counts returned towards baseline during prolonged treatment in most patients. The combination was well tolerated, although anaemia was observed in nine patients. Repeated measures analysis of variance suggested a superior effect of lamivudine monotherapy in patients who had previously used zidovudine. In conclusion, zidovudine was found to be effective in patients who have been treated with lamivudine. The study stresses the need to further define the mechanisms underlying this prolonged antiviral effect.     

Ertapenem versus ceftriaxone followed by appropriate oral therapy for treatment of complicated urinary tract infections in adults: results of a prospective,randomized, double-blind multicenter study

The efficacy and safety of intravenous (i.v.) ertapenem (1 g once a day) with the option to switch to an oral agent for treatment of adults with complicated urinary tract infections (UTIs) were compared with that of i.v. ceftriaxone (1 g daily) with the same oral switch option in a multicenter, double-blind, prospective, randomized study. At entry, 592 patients were assigned to one of two strata: acute pyelonephritis or other complicated UTI without acute pyelonephritis. After a minimum of 3 days, patients could be switched to an oral antimicrobial agent. A total of 159 patients in the ertapenem group and 171 patients in the ceftriaxone group were microbiologically evaluable. Approximately 95% of patients in each treatment group were switched to oral therapy. The most common pathogens were Escherichia coli and Klebsiella pneumoniae. At the primary efficacy endpoint 5 to 9 days after treatment, 91.8% of patients who received ertapenem and 93.0% of those who received ceftriaxone had a favorable microbiological response (95% confidence interval for the difference, adjusting for strata, -7.6 to 5.1%), indicating that outcomes in the two treatment groups were equivalent. Microbiological success rates for the two treatment groups were similar when compared by stratum and also by severity of infection. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. In this study, ertapenem was as effective as ceftriaxone for the initial treatment of complicated UTIs in adults, was generally well tolerated, and had a similar overall safety profile.     

Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study

BACKGROUND: The goal of antihypertensive therapy is to provide good blood pressure (BP) control without eliciting adverse effects. OBJECTIVE: This study compared the risk-benefit profile of the angiotensin II receptor blocker valsartan with that of the angiotensin-converting enzyme inhibitor lisinopril in patients with mild to severe hypertension. The primary objective was to show that the equipotent BP-lowering effect of the valsartan-based treatment is accompanied by a better tolerability profile. METHODS: This 16-week, randomized, double-blind, parallel-group study was conducted at 88 outpatient centers across Italy. After a 2-week placebo run-in period, patients aged > or = 18 years with mild to severe hypertension (systolic BP [SBP], 160-220 mm Hg; diastolic BP [DBP], 95-110 mm Hg) were eligible. Patients were randomized to receive once-daily, oral, self-administered treatment with valsartan 160-mg capsules or lisinopril 20-mg capsules under double-blind conditions for 4 weeks. Responders continued monotherapy, whereas nonresponders had hydrochlorothiazide 12.5 mg added for the final 12 weeks of the study. The 2 primary variables used to assess the equivalence of therapeutic efficacy of the 2 regimens were sitting SBP and sitting DBP, which were measured at weeks 0 (baseline), 4, 8, and 16. The rate of drug-related adverse events (AEs) was used to assess whether 1 treatment had a better tolerability profile than the other. Tolerability was assessed by collecting information about AEs by means of questioning the patient or physical examination at each visit. RESULTS: A total of 1213 patients were enrolled (635 men, 578 women; mean [SD] age, 54.5 [10.1] years [range, 28-78 years]). The study was completed by 1100 patients (553 receiving valsartan and 547 receiving lisinopril). Fifty-one patients (8.4%) treated with valsartan and 62 (10.2%) [corrected] treated with lisinopril withdrew, mainly because of AEs (9 [1.5%] and 23 patients [3.8%], respectively). The valsartan- and lisinopril-based treatments were similarly effective in reducing sitting BP, with mean SBP/DBP reductions of 31.2/15.9 mm Hg and 31.4/15.9 mm Hg, respectively. At the end of the study, BP was controlled in 82.6% [corrected] of the patients receiving valsartan and 81.6% of those receiving lisinopril. AEs were experienced by 5.1% of the patients treated with valsartan and 10.7% of those treated with lisinopril (P=.0001), with dry cough observed in 1.0% and 7.2% of patients, respectively (P<0.001). CONCLUSIONS: Valsartan and lisinopril were both highly effective in controlling BP in these patients with mild to severe hypertension, but valsartan was associated with a significantly reduced risk for AEs, especially cough.     

Dexamethasone to prevent postextubation airway obstruction in adults: a prospective,randomized, double-blind,placebo-controlled study

Introduction  

Prophylactic steroid therapy to reduce the occurrence of postextubation laryngeal edema is controversial. Only a limited number of prospective trials involve adults in an intensive care unit. The purpose of this study was to ascertain whether administration of multiple doses of dexamethasone to critically ill, intubated patients reduces or prevents the occurrence of postextubation airway obstruction. Another specific objective of our study was to investigate whether an after-effect (that is, a transient lingering benefit) exists 24 hours after the discontinuation of dexamethasone.