The effects of amiloride hydrochloride on thiazide-induced hypokalemia were evaluated. In metabolic balance studies, amiloride reversed thiazide-induced urinary potassium loss, restored plasma bicarbonate concentration and pH to pretreatment levels, and produced further increases in aldosterone secretion. Effects of long-term administration of hydrochlorothiazide and an amiloride-hydrochlorothiazide combination were compared in outpatients who had experienced thiazide-induced hypokalemia while receiving oral potassium supplements. After eight weeks, those given hydrochlorothiazide alone had an average serum potassium level of 3.01 +/- 0.08 mEq/L). Those given the amiloride-hydrochlorothiazide combination had an average serum potassium level of 3.75 +/- 0.008 mEq/L, not significantly different from the control value (3.82 +/- 0.08 mEq/L). Both groups had increased plasma aldosterone concentrations and plasma renin activity. The potassium-conserving effect of amiloride persisted with extended therapy.

To evaluate the short-term effects of an intervention that consists of stress management training and dietary changes in patients with ischemic heart disease (IHD), we compared the cardiovascular status of 23 patients who received this intervention with a randomized control group of 23 patient who did not. After 24 days, patients in the experimental group demonstrated a 44% mean increase in duration of exercise, a 55% mean increase in total work performed, somewhat improved left ventricular regional wall motion during peak exercise, and a net change in the left ventricular ejection fraction from rest to maximum exercise of +6.4%. Also, we measured a 20.5% mean decrease in plasma cholesterol levels and a 91.0% mean reduction in frequency of anginal episodes. In this selected sample, short-term improvements in cardiovascular status seem to result from these adjuncts to conventional treatments of IHD.

Reserpine in different doses was assigned in random, double-blind fashion to 329 patients with mild to moderate hypertension who had not achieved normotension with chlorthalidone therapy alone. The additional reduction of BP averaged 11.0/10.4 mm Hg with chlorthalidone, 50 mg, plus reserpine, 0.25 mg (C 50+R 0.25); 9.5/9.4 mm Hg with C 50+R 0.125; 6.4/8.5 mm Hg with C 50+R 0.05; and 9.9/9.6 mm Hg with C 25+R 0.125. The percentage of patients in whom control was achieved at diastolic BP less than 90 mm Hg and at least 5 mm Hg below baseline with either chorthalidone alone or with reserpine added was 65% with C 50+R 0.25, 69% with C 50+R 0.125, 58% with C 50+R 0.05, and 56% with C 25+R 0.125. Side effects of lethargy and impotence noted by patients with the 0.05-mg dose of reserpine were only one third of those noted with the 0.25-mg dose, although the incidence of other side effects did not differ. These results indicate that hypertension in many persons can be controlled by less than customary doses of reserpine in combination with a diuretic.

As described in the preceding communication, either propranolol hydrochloride or hydrochlorothiazide were randomly allocated in a double-blind manner to 683 patients with initial diastolic BP in the range of 95 to 114 mm Hg. Of this number, 394 entered the long-term treatment phase. During the subsequent 12 months of long-term treatment, hydrochlorothiazide was more effective than propranolol in controlling BP (mean reductions, -17.5/-13.1 mm Hg with hydrochlorothiazide compared with -8.3/-11.3 with propranolol. After treatment with hydrochlorothiazide, a greater percentage of patients achieved the goal diastolic BP of less than 90 mm Hg (65.5% compared with 52.8% taking propranolol). Also during treatment, fewer patients receiving hydrochlorothiazide required termination as compared with those receiving propranolol; comparative dosage requirements were lower; additional titration during long-term treatment was required less often, and BP remained lower after withdrawal of the active drugs. However, biochemical abnormalities were greater with hydrochlorothiazide. Although not statistically significant, the antihypertensive effects of hydrochlorothiazide were greater in blacks than in whites. Whites, on the other hand, had a greater response to propranolol than blacks, although it was still less than the response of the whites to hydrochlorothiazide.

We compared hydrochlorothiazide and propranolol hydrochloride for monotherapy of hypertension by a double-blind study of 683 men who were titrated to less than 90 mm Hg diastolic BP or to 640 mg of propranolol or 200 mg of hydrochlorothiazide. Propranolol reduced systolic BP from 146.0 +/- 14.4 (SD) to 134.8 +/- 16.3 mm Hg and diastolic BP from 101.6 +/- 4.6 to 90.5 +/- 7.5 mm Hg. Hydrochlorothiazide lowered both systolic BP more effectively from 146.5 +/- 15.8 to 128.8 +/- 12.2 mm Hg and diastolic BP from 101.3 +/- 4.5 to 89.4 +/- 6.5 mm Hg. In blacks, hydrochlorothiazide lowered systolic BP 20.3 +/- 14.3 mm Hg v 8.2 +/- 12.2 mm Hg for propranolol; hydrochlorothiazide reduced diastolic BP 13.0 +/- 7.0 mm Hg v 9.5 +/- 7.0 for propranolol. In whites, the systolic BP reductions were 15.3 +/- 12.0 mm Hg for hydrochlorothiazide v 13.2 +/- 13.1 mmn Hg for propranolol; diastolic BPs were 10.9 +/- 5.7 mm Hg for hydrochlorothiazide and 12.6 +/- 6.6 mm Hg for propranolol. In blacks treated with hydrochlorothiazide, 71.3% achieved diastolic BP of less than 90 mm Hg, v 53.5% with propranolol. There was no racial difference in dose response to propranolol, but blacks required much less hydrochlorothiazide to achieve control. We conclude that in this short-term study propranolol was as efficacious as hydrochlorothiazide in whites, but the latter was more effective than propranolol in blacks.

The Multiple Risk Factor Intervention Trial was a randomized primary prevention trial to test the effect of a multifactor intervention program on mortality from coronary heart disease (CHD) in 12,866 high-risk men aged 35 to 57 years. Men were randomly assigned either to a special intervention (SI) program consisting of stepped-care treatment for hypertension, counseling for cigarette smoking, and dietary advice for lowering blood cholesterol levels, or to their usual sources of health care in the community (UC). Over an average follow-up period of seven years, risk factor levels declined in both groups, but to a greater degree for the SI men. Mortality from CHD was 17.9 deaths per 1,000 in the SI group and 19.3 per 1,000 in the UC group, a statistically nonsignificant difference of 7.1% (90% confidence interval, -15% to 25). Total mortality rates were 41.2 per 1,000 (SI) and 40.4 per 1,000 (UC). Three possible explanations for these findings are considered: (1) the overall intervention program, under these circumstances, does not affect CHD mortality; (2) the intervention used does affect CHD mortality, but the benefit was not observed in this trial of seven years' average duration, with lower-than-expected mortality and with considerable risk factor change in the UC group; and (3) measures to reduce cigarette smoking and to lower blood cholesterol levels may have reduced CHD mortality within subgroups of the SI cohort, with a possibly unfavorable response to antihypertensive drug therapy in certain but not all hypertensive subjects. This last possibility was considered most likely, needs further investigation, and lends support to some preventive measures while requiring reassessment of others.

The efficacy and toxicity of topical applications of 30% idoxuridine in dimethyl sulfoxide, dimethyl sulfoxide alone, or saline in 96 recurrent and 39 first episodes of genital herpes simplex virus (HSV) infection were compared. Drug was applied to lesions four times daily for seven days. In recurrent episodes, the duration of viral shedding after beginning idoxuridine in dimethyl sulfoxide use was significantly shorter (0.6 days) than with dimethyl sulfoxide (1.4 days) or saline (2.0 days) (P less than .05). In primary episodes, viral shedding lasted 2.6 days with idoxuridine in dimethyl sulfoxide and 8.4 days with dimethyl sulfoxide or saline. Idoxuridine in dimethyl sulfoxide had no effect in recurrent or primary HSV on duration of symptoms, new lesion formation, healing time, or risk of subsequent recurrence. Complications in patients given idoxuridine in dimethyl sulfoxide included local burning, generalized contact dermatitis, and vulvar carcinoma in situ. Thirty percent idoxuridine in dimethyl sulfoxide has no effect on clinical manifestations of genital HSV infection and may be hazardous.

This study explores whether home BP self-determination can be used to assess the effect of treatment in patients with borderline hypertension. Sixteen untreated patients underwent a double-blind trial of propranolol hydrochloride (average dose, 105 mg), clonidine hydrochloride (0.24 mg), and placebo. Home BP readings decreased with both active compounds (-8/-5 with propranolol and -11/-7 with clonidine). During placebo, the readings increased to levels identical to untreated values. This study demonstrates that patients with borderline hypertension are consistently capable of detecting small average changes in home BP. It is also shown that sympatholytic monotherapy can be effectively used to lower the BP in such patients.

Patients with long-term indwelling urethral catheters are subject to acute and long-term complications of bacteriuria. To evaluate the common practice of short-course antibiotic therapy in such patients, we performed a randomized controlled trial of ten-day courses of cephalexin monohydrate repeated whenever a susceptible bacteriuria was present. We observed 17 cephalexin group patients for 545 patient-weeks (160 cephalexin courses) and 18 control group patients for 477 patient-weeks. Throughout the study, the groups were comparable in regard to incidence and prevalence of bacteriuria, number of bacterial strains per weekly urine specimen, incidence of febrile days, and incidence of obstructed catheters. In the cephalexin group, the frequency of fever during periods when antibiotics were being used was similar to that during periods when antibiotics were not being used. More cephalexin-resistant bacteria were isolated from cephalexin group patients. Routine treatment with cephalexin of asymptomatic long-term catheterized patients, even for susceptible organisms, does not seem to be warranted.

Sixty-four climbers participated in a randomized clinical trial of acetazolamide prophylaxis for acute mountain sickness (AMS) during rapid, active ascent of MT Rainier. Twenty-nine (93.6%) of 31 climbers receiving acetazolamide and 25 (75.8%) of 33 receiving placebo attained the summit. Time spent ascending from sea level to the summit (4,394 m) averaged 33.5 hours (range, 23 to 48 hours). On the summit AMS was less common in climbers receiving acetazolamide, and they experienced less headache, nausea, drowsiness, shortness of breath, and dizziness and a greater sense of satisfaction and psychological well-being. Minute ventilation on the summit was significantly greater in subjects taking acetazolamide (24.9 +/- 2.0 L/min compared with 16.9 +/- 3.8 L/min). Expired vital capacity was also greater on the summit in the acetazolamide group (6.9 +/- 0.4 L compared with 5.8 +/- 0.4 L). We conclude that acetazolamide is effective in the prophylaxis of AMS for climbers attempting rapid, active ascent. Increased ventilation at altitude, producing an increased alveolar oxygen tension, may be related to the observed amelioration of symptoms.

The influence of cimetidine hydrochloride (300 mg four times daily for seven days) on plasma ethanol concentrations and the subjective assessment of intoxication after a single oral dose of ethanol (0.8 g/kg) were investigated in a randomized double-blind placebo controlled study in six volunteers. Compared with the placebo, cimetidine produced a small increase in both the peak plasma ethanol level (from 146 +/- 5.2 to 163 +/- 7.6 mg/dL, mean +/- SEM) and th area under the ethanol concentration time curve (from 717 +/- 17 to 771 +/- 44 mg/dLXhr). In addition, using a visual analogue scale, subjects rated themselves more intoxicated at their peak of intoxication while receiving cimetidine. These results suggest that cimetidine has a small effect on the handling of ethanol in humans.

Eighty-one healthy, sedentary men aged 30 to 55 years were randomly assigned to supervised running (n = 48) or to sedentary control groups (n = 33) and followed up in a one-year trial. Measurements of plasma lipoproteins, fitness, and percent body fat were made at three-month intervals. Results and conclusions from this study are (1) that cross-sectional studies of lipoprotein concentrations in exercisers may be biased by a self-selection effect, since study participants with initially higher high-density lipoprotein cholesterol (HDL-C) and lower triglyceride concentrations were more easily persuaded to run more miles; (2) that plasma concentrations of HDL-C and low-density lipoprotein cholesterol (LDL-C) generally did not begin to change until a threshold exercise level (ten miles run per week) was maintained for at least nine months; and (3) that fitness increased and percent body fat decreased sooner and at lower exercise levels than required for HDL-C and LDL-C concentration changes.

One hundred seventeen unselected women with symptoms of acute cystitis were randomized to groups for immediate therapy with one of the following four single-dose regimens: (1) 1 g of sulfisoxazole; (2) 2 g of sulfisoxazole; (3) a combination of trimethoprim, 160 mg, and sulfamethoxazole, 800 mg; and (4) a combination of trimethoprim, 320 mg, and sulfamethoxazole, 1,600 mg. Forty-one women were excluded, 13 did not return for follow-up, and 28 did not have significant bacteriuria in the pretherapy culture. Escherichia coli was isolated in 81% of infections. Antibacterial activity was significantly greater in urine collected during the 24 hours after therapy in those who received trimethoprim-sulfamethoxazole. However, overall cure varied from 85% to 95%, without any great differences between the regimens. The rate of cure of 69% in the 13 patients with presumptive evidence of renal infection (antibody-coated bacteria present) was significantly lower than the rate of cure of 95% in women without evidence of renal infection. Single-dose therapy with these regimens was safe and effective in adult women with symptoms of acute cystitis, regardless of the localization of the site of infection.

The beta-Blocker Heart Attack Trial (BHAT) was a National Heart, Lung, and Blood Institute-sponsored, multicenter, randomized, double-blind, and placebo-controlled trial designed to test whether the regular administration of propranolol hydrochloride to men and women who had experienced at least one myocardial infarction would result in a significant reduction in total mortality during a two- to four-year period. During a 27-month interval, 3,837 persons between the ages of 30 and 69 years were randomized to either propranolol (1,916 persons) or placebo (1,912 persons), five to 21 days after the infarction. Depending on serum drug levels, the prescribed maintenance dose of propranolol hydrochloride was either 180 or 240 mg/day. The trial was stopped nine months ahead of schedule. Total mortality during the average 24-month follow-up period was 7.2% in the propranolol group and 9.8% in the placebo group. Arteriosclerotic heart disease (ASHD) mortality was 6.2% in the propranolol group and 8.5% in the placebo group. Sudden cardiac death, a subset of ASHD mortality, was 3.3% among the propranolol patients and 4.6% among the placebo patients. Serious side effects were uncommon. Hypotension, gastrointestinal problems, tiredness, bronchospasm, and cold hands and feet occurred more frequently in the propranolol group. Based on the BHAT results, the use of propranolol in patients with no contraindications to beta-blockade who have had a recent myocardial infarction is recommended for at least three years.

Twenty-five patients with symptomatic osteoarthritis (OA) of the knee were treated topically for one week with either 10% trolamine salicylate cream or placebo cream in a randomized double-blind crossover study. No significant difference was found in subjective or objective measures of pain relief between the treatment and control groups. Eight patients preferred "active" test cream, six preferred placebo, and 11 had no preference. No side effects were reported. Topically applied 10% trolamine salicylate cream did not relieve the pain of OA of the knee any more than did placebo.

The relative effectiveness of six nonsteroidal anti-inflammatory agents was studied in 33 patients with rheumatoid arthritis and 32 patients with ankylosing spondylitis in a double-blind, randomized, prospective study employing a six-way multiple crossover design with six-week trials of each agent. In ankylosing spondylitis, naproxen, indomethacin, and fenoprofen calcium were the most effective agents. In rheumatoid arthritis, relatively little mean difference between drugs was found. Most of this difference could be attributed to compliance factors, which favored drugs that required only a small number of pills daily. Despite the small differences in effect, patients had strong preferences. More than 85% of patients were still taking their preferred medication after a mean follow-up period of one year.

Thirty-five men with chancroid were randomly treated with oral sulfisoxazole, sulfisoxazole and tetracycline, sulfamethoxazole-trimethoprim, or intramuscular streptomycin. The highest rate of cures were obtained in 13 of 13 patients treated with streptomycin and in ten of ten patients treated with sulfamethoxazole-trimethoprim. Only seven of nine patients treated with sulfisoxazole and five of eight treated with sulfisoxazole and tetracycline were cured. We conclude that the sulfamethoxazole-trimethoprim combination is as efficacious as streptomycin and probably superior to sulfisoxazole and tetracycline in the treatment of chancroid.

The effect of duration of orally administered penicillin V potassium on the bacteriologic and clinical cure of group A streptococcal pharyngitis was evaluated. One hundred ninety-one middle-class patients received either seven days (96 patients) or ten days (95 patients) of therapy. Compliance with taking penicillin was assessed by multiple methods, including penicillinuria. Throat cultures were obtained during therapy and three times in the three weeks after therapy. M-precipitin and T-agglutinin typing were done on paired isolates of group A streptococci from patients who had recurrences. Patients treated for seven days had a significantly greater failure rate (30/96 [31%]) compared with patients receiving ten days of penicillin (17/95 [18%]). Compliance rates were high; 66% to 81% of patients showed penicillinuria throughout the study period. Treatment failure was not a function of poor compliance in either treatment group. The data support the current recommendation for ten full days of penicillin therapy and suggest that persistence of streptococci in the throat after adequate therapy may be common.