Losartan versus valsartan in the treatment of patients with mild to moderate essential hypertension: data from a multicenter, randomized, double-blind, 12-week trial.

BACKGROUND: Losartan, the first of the angiotensin II receptor blockers (ARBs) to be introduced, has been studied extensively in comparison with other classes of antihypertensive agents. Less research has been conducted on the efficacy and tolerability of losartan compared with that of other ARBs. OBJECTIVE: This randomized, multicenter, double-blind, parallel-group equivalence study was conducted to compare the antihypertensive efficacy and tolerability of a once-daily regimen of losartan with that of valsartan. METHODS: Patients > or = 21 years of age with mild to moderate hypertension, defined as a trough sitting diastolic blood pressure (SiDBP) between 95 and 115 mm Hg, were randomized to receive once-daily losartan (50 mg) or valsartan (80 mg) for 12 weeks. At the end of the sixth treatment week, patients in both groups with trough SiDBP > or = 90 mm Hg had their dose doubled for the remainder of the treatment period. Analysis of variance was used to compare treatment groups with respect to change in mean trough SiDBP from baseline to week 12. Within-treatment changes were analyzed using the paired t test. With at least 220 patients per treatment group, the study had 90% power to place a 90% CI on the difference between losartan and valsartan in SiDBP within the equivalence interval of +/- 2.5 mm Hg. RESULTS: A total of 495 patients were randomized, 247 to the losartan group and 248 to the valsartan group: 456 patients completed the study. Adjusted mean change from baseline values for trough SiDBP atthe end of 12 weeks of treatment were significantly different (P < 0.001) from zero in both the losartan group (-9.9 mm Hg) and the valsartan group (-10.1 mm Hg). At week 12, losartan was as effective as valsartan in lowering SiDBP, with a between-group difference of 0.2 mm Hg (90% CI, -1.3 to 1.7; P = 0.827). At week 6, the difference in SiDBP between groups was -1.3 mm Hg (90% CI, -2.7 to 0.0; P = 0.106). A similar pattern of results was obtained at weeks 6 and 12 for sitting systolic blood pressure. The percentage of patients reaching the SiDBP goal at week 6 (46% [112/2411 losartan; 42% [103/245] valsartan) and week 12 (57% [139/243] losartan; 59% [145/245] valsartan) was not significantly different between the treatment groups. Both losartan and valsartan were similarly well tolerated. Over the 12 weeks, the laboratory profiles of the 2 drugs were similar except for serum uric acid levels, which decreased from 6.0 to 5.7 mg/dL in the losartan group and increased from 5.9 to 6.0 mg/dL in the valsartan group (P = 0.001 for between-treatment difference). CONCLUSIONS: At starting and titrated doses, losartan and valsartan are similarly effective in reducing blood pressure in patients with mild to moderate hypertension. Losartan, but not valsartan, was associated with a decrease in serum uric acid levels.

Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients.

NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan -5.3 mm Hg, P:<0.001; captopril -5.6 mm Hg, P:<0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg, P:<0.05) and captopril (2.7 mm Hg, P:<0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00 AM to 11:00 PM) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 PM to 6:59 AM) was significantly attenuated in captopril-treated patients (2.0 mm Hg, P:<0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril.

Comparative effects of combination drug therapy regimens commencing with either losartan potassium, an angiotensin II receptor antagonist, or enalapril maleate for the treatment of severe hypertension.

OBJECTIVE: To compare the efficacy and safety of a regimen of losartan potassium (losartan) and a regimen of enalapril maleate (enalapril) in a randomized trial of patients with severe hypertension in which the initial treatments were blinded. DESIGN AND METHODS: Seventy-five patients, 23-74 years of age, with sitting diastolic blood pressure of 115-130mmHg, were enrolled in a 12-site multicenter study. The primary efficacy parameters were the change in trough systolic and diastolic blood pressure, as well as response to treatment in terms of categories of hypertensive response. RESULTS: A gradual reduction in mean sitting diastolic blood pressure was observed in all patients treated from week 1 to 12 (10-29mmHg for the losartan regimen and 14-32 mmHg for the enalapril regimen). At week 4, a substantial number of patients remained on monotherapy at either the initial dose or double the dose of losartan (52%) or enalapril (72%). The blood pressure curves for each treatment were parallel over time. The enalapril-based regimen elicited a statistically significantly greater reduction in blood pressure than the losartan-based regimen, although the mean differences in the blood pressure response between the two treatment groups was small. Based on sitting diastolic blood pressure < 90 mmHg or a reduction in blood pressure of at least 10 mmHg, 98% of the patients assigned to the losartan regimen and 100% of the patients assigned to the enalapril regimen had a satisfactory response with a regimen of one to three antihypertensive drugs. Headache was the most common adverse experience in both treatment groups (occurring in 22% of patients assigned to the losartan regimen and 20% of patients assigned to the enalapril regimen). CONCLUSIONS: In this study, the losartan-based regimen effectively lowered blood pressure, was generally well tolerated, and was generally similar to the enalapril-based regimen in the treatment of patients with severe hypertension.

Discriminable effects of phencyclidine analogs evaluated by multiple drug (PCP versus OTHER) discrimination training.

This study tested structural analogs of phencyclidine (PCP) using drug discrimination procedures to determine which analogs produced discriminable effects similar to those of PCP. It also tested the utility of multiple-drug discrimination training (PCP versus other drugs or saline) as a method for increasing the specificity produced by training. All discrimination training took place in two-lever operant compartments using FR-10 reinforcement of presses on the correct lever. During training, rats were required to concurrently discriminate PCP from one or more other drug conditions. Rats in group 1 discriminated PCP (lever 1) versus saline (lever 2). Rats in group 2 discriminated PCP (lever 1) versus saline, fentanyl, phenobarbital, amphetamine, or mescaline (lever 2). In both groups 1 and 2, the required discriminations were rapidly learned. The percentage of PCP choices and the ED50 doses obtained during tests for generalization did not differ significantly in groups 1 and 2. Drugs to which responding on the PCP lever generalized included 1-[1-(2-thienyl)cyclohexyl]piperidine, N-ethyl-1-phenylcyclohexylamine, 1-phenylcyclohexylamine, ketamine, 1-(1-phenylcyclohexyl)morpholine, 1-[1-(2-thienyl)cyclohexyl]morpholine, N,N-diethyl-1-phenylcyclohexylamine, N-(iso-propyl)-1-phenylcyclohexylamine, N-methyl-1-phenylcyclohexylamine, N-(n-propyl)-1-phenylcyclohexylamine, Dextrorphan, (dl)-N-allyl-N-normetazocine, N-N-dimethyl-1-phenylcyclohexylamine, N-(n-butyl)-1-phenylcyclohexylamine, 1-[1-(2-thienyl)cyclohexyl]pyrrolidine, and N-(s-butyl)-1-phenylcyclohexylamine, in agreement with previous reports. Rats in group 3 discriminated PCP (lever 1) versus saline, cyclazocine, dextrorphan, phenobarbital, or mescaline (lever 2).(ABSTRACT TRUNCATED AT 250 WORDS)