We compared the effects of initial electrical shocks using 175 and 320 J (joules) in 249 patients with ventricular fibrillation. Survival was unrelated to the energy level used for defibrillation. Reversion to an organized rhythm occurred in a similar proportion of both treatment groups after one or two shocks. The rhythm identified after the first shock was related to outcome (the survival rate was 42 per cent in patients with supraventricular rhythm, 30 per cent in persistent ventricular fibrillation, 26 per cent in idioventricular rhythm, and 14 per cent in asystole; P less than 0.02). Fibrillation recurred in 68 per cent of patients who had been initially defibrillated to an organized rhythm. Repeated shocks at the higher energy level resulted in a higher incidence of atrioventricular block after defibrillation (24 per cent of patients receiving 320 J and 9 per cent of those receiving shocks of lower energy; P less than 0.005). Patients who survived required fewer shocks than patients who later died in the hospital (2.6 shocks as compared with 3.6; P less than 0.005). We conclude that initial defibrillatory shocks using 175 J are as safe and effective as shocks of nearly twice that energy level.

We evaluated protriptyline, a nonsedating tricyclic antidepressant, as a treatment for obstructive sleep apnea in a double-blind crossover study of five men. After two weeks of treatment, with no change in body weight, daytime somnolence was markedly reduced and nocturnal oxygenation was improved, although apnea duration and frequency were not significantly decreased. Rapid-eye-movement (REM) stage time as a fraction of the total sleep time was reduced during treatment from 0.231 +/- 0.031 to 0.107 +/- 0.013 (mean +/- S.E.M.) (P less than 0.05). REM apnea time as a fraction of total sleep time was reduced from 0.145 +/- 0.022 to 0.054 +/- 0.006 (P less than 0.05). REM reduction during treatment with protriptyline can account for decreased REM apnea time. Similar decreases in REM stage time and REM apnea duration and similar improvement in oxygenation continued after six months of treatment. In addition, body weight, apnea, and arousal frequency were decreased at this time. Although the obstructive sleep apnea was not resolved, it was reduced. Protriptyline can be effective in patients with sleep apnea when the disorder is not life-threatening.

In the Hypertension Detection and Follow-up Program, 7825 (71.5 per cent) of the 10,940 participants had diastolic blood pressures averaging between 90 and 104 mm Hg on entry into the study and were designated Stratum 1. Half were referred to their usual source of care in the community (the referred-care group), and half were treated intensively in special clinics (the stepped-care group). Five-year mortality in the Stratum 1 patients given stepped care was 20.3 per cent lower than in those given referred care (P less than 0.01). Particularly noteworthy was the beneficial effect of stepped-care treatment on persons with diastolic pressures of 90 to 104 mm Hg who had no evidence of end-organ damage and were not receiving antihypertensive medication when they entered the study. This subgroup had 28.6 per cent fewer deaths at five years among those treated with stepped care than among those treated with referred care (P less than 0.01). These findings support a recommendation that in patients with mild hypertension, treatment should be considered early, before damage to end organs occurs.

In a randomized trial of adjuvant chemotherapy, immunotherapy, or immunochemotherapy, 761 evaluable patients with pathological Stage II cutaneous melanoma anywhere on the body or with pathological Stage I melanoma of the trunk (Clark's level 3 to 5) were studied by the World Health Organization International Melanoma Group. Wide local excision and excisional regional lymphadenectomy alone were performed in 185 patients and the results were compared with those of surgery plus chemotherapy with dacarbazine (in 192 patients), surgery plus immunotherapy with bacille Calmette-Guérin vaccine (in 203), and surgery plus chemotherapy combined with immunotherapy (in 181). The rates of disease-free survival and overall survival at 36 months were 30.4 +/- 8.3 per cent (mean +/- S.E.) and 41.6 +/- 10.0 per cent, respectively, after surgical treatment alone; 37.2 +/- 7.9 per cent and 46.5 +/- 8.3 per cent after surgery plus chemotherapy; 34.8 +/- 7.9 per cent and 48.7 +/- 8.7 per cent after surgery plus immunotherapy; and 33.6 +/- 7.9 per cent and 50.0 +/- 8.8 per cent after surgery plus a combination of chemotherapy and immunotherapy. None of the differences between groups was significant, and thus no effect of adjuvant therapy could be demonstrated in this study.

We conducted a double-blind treatment study of 110 adults from the United States who were attending summer classes in Guadalajara, Mexico, and had diarrhea (four or more unformed stools in 24 hours, or three or more unformed stools per eight-hour period plus one or more additional clinical indicators of enteric infection). Thirty-seven patients received trimethoprim/sulfamethoxazole (TMP/SMX) (160 mg of TMP and 800 mg of SMX), 38 were given TMP alone (200 mg), and 35 took a placebo twice daily for five days. By the end of the first 24 hours of treatment, patients taking either TMP/SMX or TMP alone passed fewer unformed stools than did patients given placebo (P = 0.0002 and P = 0.01, respectively). Abdominal pain and nausea were reduced in both treatment groups. The beneficial effect was seen in treatment of Escherichia coli-induced diarrhea, shigellosis, and diarrhea not associated with an enteropathogen. Five per cent of patients given TMP/SMX, 8 per cent of those given TMP, and 49 per cent of those given placebo were considered treatment failures (P less than 0.001 for both active drugs as compared with placebo). Early treatment with TMP/SMX or TMP is an alternative to prophylactic use of drugs for travelers' diarrhea.

Zomepirac sodium was compared with placebo for relief of primary dysmenorrhea syndrome in a double-blind, crossover study of 47 patients. The agents were taken in three separate crossovers during six menstrual periods. Abdominal cramping and 25 other symptoms of dysmenorrhea syndrome were evaluated daily. Zomepirac was significantly more effective than placebo in relieving 12 of 13 primary symptoms and 6 of 13 associated symptoms (P less than or equal to 0.05). While taking zomepirac, patients were able to continue normal activities on a significantly higher proportion of days (P less than 0.001) and required supplemental analgesics significantly less often (P less than 0.001). Zomepirac was well tolerated by these patients. Gastrointestinal disturbances accounted for the largest proportion of adverse effects from either agent. These results indicate that zomepirac gave excellent relief of the symptoms of dysmenorrhea in this study population.

Although neither aspirin nor oral anticoagulants have been conclusively shown to reduce mortality in patients surviving myocardial infarction, both have been widely used for that purpose. In the present clinical trial we compared the effects of aspirin (0.5 g given three times a day) and oral-anticoagulant therapy. Of 6908 patients considered for entry, 1303 were randomized to anticoagulant (652) or aspirin (651) an average of 11.4 days after the onset of myocardial infarction and were followed for 6 to 59 months (mean, 29 months). There were 65 deaths in the anticoagulant group and 72 in the aspirin group. The number of patients with reinfarctions was higher in the aspirin group (33 vs. 20). None of these differences were statistically significant. Almost twice as many patients were withdrawn from therapy in the aspirin group. There were 54 per cent more patients with gastrointestinal events in the aspirin group and four times more patients with episodes of severe bleeding in the anticoagulant group. We conclude that aspirin in the dosage used in probably not different from oral anticoagulants in affecting mortality and morbidity after a myocardial infarction. However, this study does not consider the effectiveness of either agent in comparison to no antithrombotic therapy -- an issue that remains unsettled.

We investigated the effect of multiple oral doses of activated charcoal on the pharmacokinetics of intravenously administered phenobarbital in a randomized crossover trial. Six healthy men volunteered to take 200 mg of phenobarbital sodium per 70 kg of body weight intravenously on two separate occasions. On one occasion, each subject received oral activated charcoal (180 g) in divided doses over three days after the infusion of phenobarbital. Serum levels of phenobarbital were measured in all subjects up to 96 hours after the infusion, and urinary excretion of phenobarbital was measured in two subjects 24 to 96 hours after the infusion. A pharmacokinetic analysis showed that the charcoal decreased the serum half-life of phenobarbital form 110 +/- 8 to 45 +/- 6 hours (S.E.M.) (P less than 0.01), increased the total body clearance of phenobarbital from 4.4 +/- 0.2 to 12.0 +/- 1.6 ml per kilogram per hour (P less than 0.01), and increased the nonrenal clearance from 52 to 80 per cent of the total body clearance. We conclude that oral administration of activated charcoal enhances the nonrenal clearance of phenobarbital.

Four hundred fifty volunteers participated in a placebo-controlled, double-blind, randomized trial of the prophylactic effects of rimantadine and amantadine during an outbreak of influenza A. The subjects received drugs orally at a dose of 100 mg twice a day for six weeks. Influenza-like illness occurred in 41 per cent of the subjects receiving placebo but in only 14 per cent of those receiving rimantadine and 9 per cent of these receiving amantadine (P less than 0.001 for either drug vs. placebo). Laboratory-documented influenza occurred in 21 per cent of placebo recipients, 3 per cent of rimantadine recipients, and 2 per cent of amantadine recipients (P less than 0.001). These findings represent efficacy rates of 85 per cent for rimantadine and 91 per cent for amantadine, as compared with placebo. More recipients of amantadine (13 per cent) than recipients of rimantadine (6 per cent; P less than 0.05) or placebo (4 per cent; P less than 0.01) withdrew from the study because of central-nervous-system side effects. On the basis of this study, rimantadine appears to be the drug of choice for the prophylaxis of influenza A.

To prevent occlusion of aortocoronary-artery-bypass grafts, we conducted a prospective, randomized-double-blind trial comparing dipyridamole (instituted two days before operation) plus aspirin (added seven hours after operation) with placebo in 407 patients. Vein-graft angiography was performed in 360 patients (88 per cent) within six months of operation (median, eight days). Within one month of operation, 3 per cent of vein-graft distal anastomoses (10 of 351) were occluded in the treated patients, and 10 per cent (38 of 362) in the placebo group; the proportion of patients with one or more distal anastomoses occluded was 8 per cent (10 of 130) in the treated group and 21 per cent (27 of 130) in th placebo group. This benefit in graft patency persisted in each of over 50 subgroups. Early postoperative bleeding was similar in the two groups. In this trial dipyridamole and aspirin were effective in preventing graft occlusion early after operation.

Environmental stress has been implicated as an important factor in the relapse of schizophrenic patients receiving optimal drug therapy. In a randomized controlled study, we compared at-home family therapy with clinic-based individual supportive care in the community management of schizophrenia in 36 patients taking neuroleptic maintenance medications. The family-treatment approach sought to enhance the stress-reducing capacity of the patient and his or her family through improved understanding of the illness and training in behavioral methods of problem solving. The results at the end of nine months revealed the superiority of this approach in preventing major symptomatic exacerbations. Only one family-treated patient (6 per cent of all patients) was judged to have had a clinical relapse, as compared with eight patients (44 per cent) treated individually. Family-treated patients averaged 0.83 days in the hospital, as compared with 8.39 days for the comparison group. Significantly lower levels of schizophrenic symptomatology on blind rating-scale assessments supported these clinical observations of the superiority of family management.

Seventy-seven patients with first episodes of genital herpes and 111 with recurrent episodes were enrolled in a double-blind trial comparing topical acyclovir with a placebo (polyethylene glycol ointment). Among acyclovir-treated patients with first-episode primary genital herpes, the mean duration of viral shedding (4.1 days) and the time to complete crusting of lesions present at the initiation of therapy (7.1 days) were shorter than among placebo recipients (7.0 and 10.5 days, respectively) (P less than 0.05). Acyclovir-treated patients with recurrent herpes had a shorter duration of viral shedding than placebo recipients (0.95 vs. 1.90 days) (P = 0.03). Among the patients with recurrent herpes, acyclovir reduced the time to crusting of lesions in men but had no effect on the symptoms or healing times in women. Topical acyclovir shortens the duration of viral shedding and accelerates healing of some genital herpes simplex virus infections.

Eight hundred twelve men with presumed acute myocardial infarction and left ventricular filling pressure of at least 12 mm Hg participated in a randomized double-blind placebo-controlled trial to assess the efficacy of a 48-hour infusion of sodium nitroprusside. The mortality rates at 21 days (10.4 per cent in the placebo group and 11.5 per cent in the nitroprusside group) and at 13 weeks (19.0 per cent and 17.0 per cent, respectively) were not significantly affected by treatment. The efficacy of nitroprusside was related to the time of treatment: the drug had a deleterious effect in patients whose infusions were started within nine hours of the onset of pain (mortality at 13 weeks, 24.2 per cent vs. 12.7 per cent; P = 0.025) and a beneficial effect in those whose infusions were begun later (mortality at 13 weeks, 14.4 per cent vs. 22.3 per cent; P = 0.04). Nitroprusside should probably not be used routinely in patients with high left ventricular filling pressures after acute myocardial infarction. However, the results in the patients given late treatment suggest that those with persistent pump failure might receive sustained benefit from short-term nitroprusside therapy.

We gave sodium nitroprusside by intravenous infusion to 163 randomly selected patients during the first 24 hours after hospitalization for typical acute myocardial infarction, and we studied its effects on mortality at one week, on the incidence of cardiogenic shock, on clinical signs of left ventricular failure, and on peak levels of creatine kinase isoenzyme MB. A control group of 165 patients received standard medical treatment and infusion of 5 per cent glucose. The end point of the study was a significant reduction in mortality in the nitroprusside group; this was reached when five deaths had occurred in this group, as compared with 18 among the controls (P less than 0.05). The incidence of cardiogenic shock, clinical signs of left-heart failure, and mean peak levels of creatine kinase isoenzyme MB were all reduced (P less than 0.05). The results indicate that infusion of nitroprusside in the early phase of acute infarction limits complications, possibly by reducing infarct size. The drug was particularly effective in anterior-wall infarction.

Although oral glucose-electrolyte solutions containing 90 mmol of sodium per liter have been widely used in the treatment of acute diarrhea among under-nourished children in the developing world, they have rarely been studied in well-nourished children. We therefore conducted a controlled randomized study among well-nourished children three months to two years who were hospitalized with acute diarrhea (52 in the United States, and 94 in Panama), to compare the efficacy of this solution with that of one containing 50 mmol of sodium per liter and with standard intravenous therapy. Oral rehydration with both solutions according to protocol was successful in 97 of 98 children (one required unscheduled intravenous therapy), and in 87 (89 per cent) no intravenous therapy was required. All of six children admitted with hypernatremia were successfully treated with oral therapy alone. We conclude that glucose-electrolyte oral solutions containing either 50 or 90 mmol of sodium per liter are effective and safe in the treatment of well-nourished children hospitalized with acute diarrhea, and that they may completely replace the intravenous fluids in the majority of such children.

We assessed the efficacy of adding nifedipine to the conventional treatment of unstable angina in 138 patients in a prospective, double-blind, randomized, placebo-controlled trial. There was no difference between the two groups in the dose of conventional antianginal medication or in age, prior myocardial infarction, ejection fraction, or other risk factors. Failure of medical treatment (defined as sudden death, myocardial infarction, or bypass surgery within four months) occurred in 43 of 70 patients given placebo and in 30 of 68 given nifedipine. Kaplan-Meier survival-curve analysis of the number and time dependence of treatment failures demonstrated a benefit of nifedipine over placebo (P = 0.03). The benefit was particularly marked in patients with ST-segment elevation during angina (P = 0.02). Side effects (transient hypotension or diarrhea) required withdrawal of the drug from four patients given nifedipine and from one given placebo. We conclude that the addition of nifedipine to conventional therapy is safe and effective in unstable angina.

Of 75 consecutive patients with Stage IV Hodgkin's disease, we assigned 38 to receive MOPP alone (mechlorethamine, vincristine, procarbazine, and prednisone) and 37 to receive MOPP alternating monthly with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) - a combination of drugs not cross-resistant with MOPP. Complete remission was documented in 71 percent of the patients receiving MOPP alone and in 92 per cent of those receiving the alternating regimen (P = 0.02). At five years, there was no progression of disease in 37 per cent of the MOPP group and in 70 per cent of the MOPP-plus-ABVD group (P less than 0.0001). After chemotherapy, the median relapse-free survival period was 20 months in the MOPP group and over 31 months in the MOPP-plus-ABVD group (P less than 0.01). Five-year survival with no evidence of disease was 84 per cent in patients given MOPP and ABVD and 54 per cent in those given MOPP alone (P less than 0.005). We conclude than alternating non-cross-resistant combinations appear promising in the management of advanced Hodgkin's disease and are worthy of trial in other malignant diseases.

Human leukocyte interferon was evaluated as a treatment for varicella in a randomized double-blind, placebo-controlled study carried out in two phases. A total of 44 children being treated for cancer were enrolled within 72 hours of the appearance of the exanthem. The mean number of days of new lesion formation was 3.8 +/- 1.89 (+/- S.D.) in the interferon recipients and 5.3 +/- 2.56 in the placebo recipients (P less than 0.05). Eighty-one per cent of the interferon recipients had had no new lesions for 24 hours by Day 7, as compared with 56 per cent of the placebo recipients (P less than 0.025). In the second, higher-dose phase of the study 92 per cent of the interferon recipients had had no new lesions for 24 hours by Day 6, as compared with 45 per cent of the placebo recipients (P less than 0.025). Three of 21 placebo recipients died of progressive varicella. Two of the 23 interferon recipients died two to three weeks after the onset of varicella; viral cultures were negative in one of these patients, and the second had recurrent viremia at the end of the treatment period. Among the survivors, treatment with interferon reduced the number of patients who had life-threatening dissemination (none of 21 vs. three of 18; P = 0.053). We conclude that interferon had an antiviral effect against varicella virus in immunocompromised patients.

The view that digitalis clinically benefits patients with heart failure and sinus rhythm lacks support from a well-controlled study. Using a randomized, double-blind, crossover protocol, we compared the effects of oral digoxin and placebo on the clinical courses of 25 outpatients without atrial fibrillation. According to a clinicoradiographic scoring system, the severity of heart failure was reduced by digoxin in 14 patients; in nine of these 14, improvement was confirmed by repeated trials (five patients) or right-heart catheterization (four patients). The other 11 patients had no detectable improvement from digoxin. Patients who responded to digoxin had more chronic and more severe heart failure, greater left ventricular dilation and ejection-fraction depression, and a third heart sound. Multivariate analysis showed that the third heart sound was the strongest correlate of the response to digoxin (P less than 0.0001). These data suggest that long-term digoxin therapy is clinically beneficial in patients with heart failure unaccompanied by atrial fibrillation whose failure persists despite diuretic treatment and who have a third heart sound.