We evaluated the occurrence of acute nonlymphocytic leukemia (ANL) among 1399 women with ovarian cancer who were treated in five randomized clinical trials. Of the 1399 women, 998 had been treated with alkylating agents, and among these, 12 cases of ANL were observed; the expected number was 0.11. Ten patients with ANL had received melphalan, and two chlorambucil. ANL was not observed in 401 women who had been treated with surgery or radiation or both, without alkylating agents. The excess risk of ANL that was associated with alkylating-agent therapy was 5.8 cases per 1000 women per year, and the cumulative seven-year risk of ANL among patients who were treated with chemotherapy alone was indistinguishable from that observed in patients receiving both radiation and chemotherapy. A positive correlation between initial drug dose and the risk of ANL was suggested. These data underscore the need to assess other cytotoxic agents and regimens of drug administration to identify those that do not have harmful late effects.

It has been known for more than 25 years that certain plant foods, such as kidney beans and wheat, contain a substance that inhibits the activity of salivary and pancreatic amylase. More recently, this antiamylase has been purified and marketed for use in weight control under the generic name "starch blockers." Although this approach to weight control is highly popular, it has never been shown whether starch-blocker tablets actually reduce the absorption of calories from starch. Using a one-day calorie-balance technique and a high-starch (100 g) meal (spaghetti, tomato sauce, and bread), we measured the excretion of fecal calories after normal subjects had taken either placebo or starch-blocker tablets. If the starch-blocker tablets had prevented the digestion of starch, fecal calorie excretion should have increased by 400 kcal. However, fecal calorie excretion was the same on the two test days (mean +/- S.E.M., 80 +/- 4 as compared with 78 +/- 2). We conclude that starch-blocker tablets do not inhibit the digestion and absorption of starch calories in human beings.

Purified Fab fragments of digoxin-specific antibodies obtained from sheep were used to treat 26 patients with advanced, life-threatening digoxin (23 cases) or digitoxin (3 cases) toxicity. These patients had advanced cardiac arrhythmias, and in some cases hyperkalemia, which were resistant to conventional treatment. All patients had an initial favorable response to doses of Fab fragments calculated (in most cases) to be equivalent, on a molar basis, to the amount of cardiac glycoside in the patient's body. In four patients treated after prolonged hypotension and low cardiac output, death ensued from cerebral or myocardial hypoperfusion. In one case the available Fab fragment supply was inadequate to reverse a massive suicidal ingestion of digoxin, and the patient died after recurrent ventricular arrhythmias. In the remaining 21 patients, cardiac rhythm disturbances and hyperkalemia were rapidly reversed, and full recovery ensued. There were no adverse reactions to the treatment. We conclude that the use of purified digoxin-specific Fab fragments is a safe and effective means to reverse advanced, life-threatening digitalis intoxication.

We carried out a randomized double-blind controlled secondary-prevention trial of oxprenolol over seven years. Forty milligrams of oxprenolol or placebo was given twice daily to 1103 men 35 to 65 years old who had an acute myocardial infarction between 1 and 90 months previously. Overall, there was no difference in mortality or cardiac events between the placebo and oxprenolol groups. The major influence on prognosis was the time at which treatment was started after infarction. In 417 patients in whom treatment was started within four months of infarction oxprenolol increased the six-year cumulative survival rate from 77 to 95 per cent (P less than 0.001). In 274 patients with treatment starting between 5 and 12 months of infarction the survival rate was similar in the two groups, but in 412 patients entered between 1 and 7 1/2 years after their first infarction oxprenolol reduced the six-year survival rate from 92 to 79 per cent (P = 0.002). The increased mortality in this latter group mainly occurred late after withdrawal from active treatment. The value of low-dose oxprenolol in secondary prevention appears to be confined to patients treated relatively soon after myocardial infarction.

In an effort to decrease deaths from gram-negative bacteremia and endotoxin shock, we treated bacteremic patients with human antiserum to endotoxin (lipopolysaccharide) core. Antiserum was prepared by vaccinating healthy men with heat-killed Escherichia coli J5; this mutant lacks lipopolysaccharide oligosaccharide side chains, so that the core, which is nearly identical to that of most other gram-negative bacteria, is exposed for antibody formation. In a randomized controlled trial, patients were given either J5 antiserum or preimmune control serum intravenously, near the onset of illness. The number of deaths in the bacteremic patients was 42 of 109 (39 per cent) in controls and 23 of 103 (22 per cent) in recipients of J5 antiserum (P = 0.011). In those with profound shock, mortality was 30 of 39 (77 per cent) in controls and 18 of 41 (44 per cent) in recipients of J5 antiserum (P = 0.003). We conclude that human antiserum to the lipopolysaccharide core can substantially reduce deaths from gram-negative bacteremia.

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.

We conducted a double-blind, placebo-controlled trial to assess the value of vidarabine therapy for the prevention of complications from herpes zoster in immunocompromised patients. Of 121 patients with localized herpes zoster of 72 hours duration or less, 63 received vidarabine and 58 received the placebo. Populations were matched for pertinent characteristics. Therapy accelerated cutaneous healing and decreased the rates of cutaneous dissemination (from 24 per cent [14 patients] to 8 per cent [5 patients]) (P = 0.014); and of zoster-related visceral complications (from 19 per cent [11 patients] to 5 per cent [3 patients]) (P = 0.015). therapy also decreased the total duration of post-herpetic neuralgia (P = 0.047). Patients with lymphoproliferative cancers and those 38 years of age or older were at greatest risk for complications and benefited most from therapy. There was no serious drug toxicity. We conclude that vidarabine therapy, when started within the first three days, is valuable for the reduction of complications related to herpes zoster.

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.