In a prospective evaluation of antibiotic prophylaxis against gonorrhea, 1080 men were given 200 mg of oral minocycline or placebo after sexual intercourse with prostitutes in a Far Eastern port. Later, at sea, gonococcal infection was detected in 57 of 565 men given placebo and 24 of 515 men given minocycline (P less than 0.001). Minocycline prophylaxis completely prevented infection by gonococci susceptible to 0.75 microgram or less of tetracycline per milliliter, reduced the risk of infection or prolonged the incubation period in men exposed to gonococci susceptible to 1.0 to 2.0 micrograms per milliliter, but did not prevent infection or prolong incubation in men exposed to gonococci resistant to 2.0 micrograms. Minocycline did not increase the proportion of asymptomatic infections. Minocycline prophylaxis would probably have limited effectiveness as a public-health measure because of the tendency to select resistant gonococci.

We compared the immediate effects of five beta-adrenoreceptor-blocking agents in 16 patients with stable angina pectoris. Acute dose-response studies showed that all five drugs improved exercise tolerance and reduced ST-segment depression, heart rate and blood pressure by a similar degree in comparison with a placebo (P less than 0.01). Near maximum improvement in exercise tolerance occurred when the acute cumulative oral dose had reached 160 mg for propranolol and oxprenolol, 200 mg for metoprolol and tolamolol and 400 mg for practolol. When these drugs were administered as a single doses, increase in walking time before the development of angina and reduction in ST-segment depression, heart rate and systolic blood pressure all occurred within one hour and persisted for eight hours--effects markedly different from the response to a placebo (P less than 0.01). These data show that non-cardioselective agents (propranolol and oxprenolol), cardioselective agents (practolol, metoprolol and tolamolol), as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective in the treatment of angina pectoris.

Because high concentrations of ascorbic acid (0.57 mM) lower the free (nonprotein) cystine content of cultured cystinotic skin fibroblasts by over 50 per cent, we did a double-blind clinical trial to establish whether this drug would benefit cystinotic children. Sixty-four patients were randomized into the study; 32 received ascorbic acid (200 mg per kilogram of body weight per day), and 32 placebo. The study was terminated after approximately two years because there was no indication that vitamin C was beneficial and accumulating evidence that it might be harmful. Of 11 patients who left the study because of death or the requirement for dialysis or renal transplantation, eight were receiving ascorbic acid. The estimated relative risk (treatment vs. control) of an adverse event was R = 2.7, with a 90 per cent confidence interval of (0.8, 11.5). The serum creatinine concentration increased 0.53 mg per deciliter per year in patients receiving vitamin C and 0.24 mg per deciliter per year in patients receiving placebo (P = 0.08).

Penicillamine has an effect on immune complexes and immunoglobulins both in vivo and in vitro. We therefore studied the effect of penicillamine on immune complexes and immunoglobulins in primary biliary cirrhosis. Twenty-eight patients were randomly allocated into a treatment group receiving 600 to 900 mg of penicillamine, or a control group, and followed for a maximum of 24 months. After 12 and 24 months, serum immune complexes had fallen significantly in treated patients as compared to controls (P less than 0.05, P less than 0.01). Treatment reduced IgA, IgG and IgM concentrations, with IgM being significantly different from controls at six, 12 and 24 months (P less than 0.01). Over 24 months, serum aspartate transaminase levels fell in treated patients but rose in controls (P less than 0.01). Bilirubin concentrations increased at a slower rate in treated patients. Penicillamine may favorably influence the course of primary biliary cirrhosis by its immunologic action in addition to its copper-chelating action.

To evaluate the effects of coronary-artery bypass, 100 patients with stable, disabling angina were randomized to medical (49) or surgical (51) therapy. There was no statistical difference in major cardiac events after three years (death in five medical vs. four surgical, infarction in eight vs. 10, and unstable angina requiring operation or reoperation in eight vs. three cases). Surgical patients with three-vessel disease had fewer major events (P less than 0.05) than the comparable medical group and less unstable angina requiring operation (P less than 0.02). All unstable angina was less frequent in the surgical group (15 vs. six, P less than 0.01). Functional classification improved more in surgical patients at six months (P less than 0.01) and at late followup examination (P less than 0.05). After six months, surgical patients achieved significantly higher exercise work loads (P less than 0.01), exercise heart rates (P less than 0.05), maximum paced heart rates (P less than 0.01) and myocardial lactate extraction (P less than 0.01). On the basis of this interim report of a relatively small group of patients, we conclude that bypass results in greater functional improvement and less unstable angina than medical therapy. The likelihood of death and myocardial infarction is unchanged by operation.

Using patients with varying degrees of trauma as their own controls we compared three isocaloric regimens in three-day crossover studies; 9.4 g of nitrogen as l-amino acids was also given daily. The urea production rate was used as an index of protein breakdown. We found that in catabolic patients, insulin and glucose produced a strikingly greater inhibition of protein breakdown that glucose alone, and that glucose alone was marginally more protein sparing than a regimen containing mainly fat (intralipid and sorbitol). These differences were not seen in noncatabolic patients (urea production rate less than 15 g daily). In the catabolic patients (urea production rate greater than 15 g daily) the protein-sparing effect of insulin was proportional to the initial urea production rate. We therefore concluded that insulin has important protein-sparing effects in severely ill traumatized patients, but little effect when there is no increased catabolic rate.

Our case-control study of the relation between estrogen use and endometrial cancer involved 451 cases and 888 controls. The overall risk of endometrial carcinoma was sixfold for estrogen users as compared with nonusers; long-term users (greater than five years) had a 15-fold risk. Excess risk was present for both diethylstilberstrol and conjugated estrogens. The risk associated with cyclic use was as great as that for continuous use. Increased risk was associated with estrogen use for all histologic grades of the tumor. The risk of advanced-stage carcinoma was fourfold for estrogen users, but rhe confidence interval was wide, and this question requires further study. Finally, this investigation contradicts the speculation that the association between this cancer and estrogen use can be explained by swifter diagnosis for estrogen users, misclassification of estrogen-related hyperplasia or treatment of early symptoms of the tumor with estrogen.

Two corticosteroid regimens, alternate-day prednisone and inhaled beclomethasone dipropionate, have been more acceptable than daily oral corticosteroids for treatment of chronic asthma. To compare the effect of these regimens on hypothalamic-pituitary-adrenal function, 20 children with asthma were evaluated while receiving 20 to 40 mg of prednisone on alternate mornings or 400 to 800 microgram per day of inhaled beclomethasone dipropionate in divided daily doses; seven children requiring only non-corticosteroid medication served as controls. Early-morning serum cortisol concentration, urinary free-cortisol excretion and the 11-desoxycortisol response to metyrapone were decreased to a similar degree among children receiving both corticosteroid regimens in comparison with the control patients and were lowest when alternate-day prednisone and inhaled beclomethasone dipropionate were given together. Thus, inhaled beclomethasone dipropionate appears similar to alternate-day prednisone in its effect on hypothalamic-pituitary-adrenal function when used alone; the effect is additive when the two are used together.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Twenty patients with chronic oral candidiasis were assigned by random allocation to a two-week course of either 10-mg clotrimazole buccal troches or placebo taken five times daily in a double-blind clinical trial. Each of the 10 recipients of clotrimazole had marked regression of symptoms and mucosal lesions, and in nine patients potassium hydroxide preparations and cultures of mucosal scrapings gave no evidence of candidiasis. In contrast, only one of the 10 patients receiving placebo showed any improvement. The clinical outcome in the clotrimazole-treated group was significantly more favorable (P less than 0.001) than in the group receiving placebo. No adverse reactions to the drug were observed. After the blind phase of their trial, 15 patients were treated with clotrimazole troches in an open trial. One to three troches per day were found adequate to sustain remissions. We conclude that clotrimazole is highly effective treatment for chronic oral candidiasis.

To evaluate the effectiveness of cyclophosphamide in the treatment of lupus nephritis, we designed a prospective study of patients with diffuse proliferative lupus nephritis. Twenty-six patients received prednisone (average dose, 40 mg per day) and 24 combined prednisone (average dose, 29 mg per day) and cyclophosphamide (average dose, 107 mg per day) for six months. Thereafter, all patients received maintenance doses of prednisone. Most of the patients improved (84 per cent) after six months of initial treatment with either program. Early progression of disease, ending mainly in end-stage renal disease, was equally frequent in the two treatment groups in patients with already advanced disease. In a four-year follow-up study there was a higher incidence (P approximately 0.04) and average rate (P approximately 0.02) of clinical recurrence of nephritis in the group initially given only steroid than in the group initially given both drugs. However, the proportion of patients alive after four years with stable or improved renal function was similar in the two treatment groups.