We evaluated the long-term effects of a five to 15-week course of chlorambucil and prednisone in 59 children with idiopathic nephrotic syndrome who had previously received prednisone alone and had had frequent relapses or steroid dependency or resistance. By actuarial analysis of 65 courses of dual therapy followed up for one to 12 years (mean, 5.0), we found that 95 per cent of patients were in remission at one year and 85 per cent at four years. All but two had remissions lasting longer than those induced by steroids alone, and only eight others had one or more relapses after therapy. Life-table analysis of two dosage schedules of chlorambucil at four years showed that 91 per cent of patients on low doses and 80 per cent of those on high doses were still in remission. Although immediate complications were minimal, the potential for long-term toxicity still requires careful selection of patients who receive chlorambucil. Prolonged use of chlorambucil in daily doses above 0.3 mg per kilogram of body weight per day or cumulative doses above 14 mg per kilogram is no longer warranted. Measured in terms of both the immediate and long-term responses, chlorambucil appears to lower the frequency of relapses in idiopathic nephrotic syndrome.

Physical exercise is known to improve glucose tolerance and diminish insulin requirements in patients with well-controlled diabetes mellitus. To ascertain whether these effects of exercise are associated with alterations in insulin receptors, we studied [125I]insulin binding to erythrocytes and monocytes in athletically untrained young men with insulin-treated diabetes during three hours of postprandial bicycle exercise (nine patients) and two hours of exercise during fasting (eight patients). Compared with control periods, postprandial exercise, as well as exercise during fasting, significantly increased insulin binding to erythrocytes and monocytes at an insulin-tracer concentration of 34 pmol per liter. We suggest that similar changes occur in working muscle cells and contribute to the improved glucose tolerance induced by exercise.

We studied the antiarrhythmic effect of a range of oral doses of encainide in 11 patients with stable high-frequency ventricular arrhythmias. Total suppression of arrhythmia was documented in 10 patients at a wide range of doses and plasma concentrations, and the suppression was subsequently verified in a placebo-controlled crossover study. Drug elimination was rapid (the half-life was 1.9 to 3.8 hours), but the margin between efficacy and side effects was sufficiently wide for therapy every six to 12 hours to be feasible in all 10 patients, with continuing outpatient treatment at six to 12 months. Marked prolongation of PR (mean, 44 per cent) and QRS (mean, 47 per cent) durations coincided with abolition of arrhythmia, but no evidence that these effects were detrimental was observed in radionuclide ventriculograms, exercise testing, or prolonged monitoring. A single patient whose arrhythmia and electrocardiogram were unchanged during therapy eliminated the drug much more slowly than the others and was the only patient in whom no O-demethyl form could be detected in plasma, suggesting that this metabolite may be active. In this study, encainide was a highly effective, well-tolerated antiarrhythmic agent.

To examine the effects of the Leboyer method of delivery, we randomly assigned 56 women to either a Leboyer or a conventional delivery and used a variety of clinical and behavioral measures to assess the outcome in mother and child. No differences were noted in maternal or newborn morbidity, in infant behavior in the first hour of life, at 24 or 72 hours post partum, or at eight months of age; or in maternal perceptions of her infant and the experience of giving birth, except that eight months after delivery, mothers who had used the Leboyer method were more likely to say that the event had influenced their child's behavior (P = 0.05). Women who expected a Leboyer delivery had shorter active labors (P = 0.03), suggesting that psychologic factors (expectations) influence physical outcomes in perinatal medicine. Our results suggest that the Leboyer procedure has no advantage over a gentle, conventional delivery in influencing infant and maternal outcomes.

We studied 170 premature infants with birth weights between 751 and 2000 g in a randomized sequential trial comparing "high" and "low" volumes of fluid intake. Beginning on the third day of life, the low-volume group received only enough water to meet average estimated requirements, and the high-volume group received an excess of at least 20 ml per kilogram of body weight per day (mean excess, 47 ml per kilogram per day). Sequential analysis showed that the risk of patent ductus arteriosus with congestive heart failure was greater in infants receiving the high-volume regimen. Thirty-five of 85 infants in the high-volume group acquired murmurs consistent with patent ductus arteriosus, and 11 of these 35 had congestive heart failure. Only nine of 85 infants in the low-volume group had murmurs consistent with patent ductus arteriosus, and two of these nine had congestive heart failure. More cases of necrotizing enterocolitis also occurred in the high-volume group. We conclude that limitation of fluid intake to amounts estimated to meet requirements for excretion, insensible loss, and growth can reduce the risks of patent ductus arteriosus and congestive heart failure in premature infants.

Over a 15-month period, 75 critically ill patients at risk of acute gastrointestinal bleeding were randomized into two groups: one group (38 patients) received the H2-blocker cimetidine intravenously at an initial dosage of 300 mg every six hours, and the other group (37 patients) received antacid (Mylanta II) through a nasogastric tube at an intial dosage of 30 ml every hour. Gastric pH was measured hourly and titrated above 3.5. Upper-gastrointestinal-tract bleeding occurred in seven of 38 cimetidine-treated patients but in none of 37 antacid-treated patients (P less than 0.01). When antacid titration was added to the cimetidine regimen in four of seven patients with bleeding, all four stopped bleeding. Renal failure, sepsis, peritonitis, hypotension, respiratory failure, jaundice, multiple trauma, and major operative procedures were associated with an increased incidence of bleeding. Cimetidine does not adequately protect seriously ill patients from acute upper-gastrointestinal-tract bleeding. Antacid is better for this purpose.

Dichloromethylene diphosphonate (Cl2MDP), an inhibitor of oestoclast activity, was evaluated for its ability to decrease the excessive mobilization of skeletal calcium that complicates multiple myeloma. Ten patients with active myeloma, wide-spread bone disease, and hypercalciuria were studied in a double-blind, placebo-controlled, crossover-designed trial in which they took Cl2MDP for eight weeks and placebos for eight weeks. Two patients died during the placebo phase; of eight patients who received Cl2MDP, seven had rapid, sustained, and highly significant (P less than 0.001) decreases in urinary excretion of calcium. Six also had significant decreases in hydroxyproline excretion, and five reported lessening of skeletal pain. On patient did not respond. Although the patients received concurrent chemotherapy during the study, concentrations of myeloma proteins actually increased or decreased only slightly, indicating the declines in hypercalciuria resulted from Cl2MDP and not from improvement in the underlying disease. We conclude that Cl2MDP is a potentially useful inhibitor of osteoclast-mediated bone erosion in multiple myeloma.

We report the results of a randomized double-blind, multicenter trial comparing sulfinpyrazone (200 mg four times a day) and a placebo in the prevention of cardiac mortality among 1558 patients followed for an average of 16 months, beginning 25 to 35 days after a documented myocardial infarction. All but one of the 106 deaths in the group were cardiac; 59 were sudden. The reduction in cardiac mortality at 24 months in the sulfinpyrazone group was 32 per cent (P = 0.058), and the reduction in sudden death was 43 per cent (P = 0.041). The benefit of sulfinpyrazone was attributable entirely to a reduction in sudden death during the second through seventh months after infarction, when there were 35 cardiac deaths in the placebo group and 17 in the sulfinpyrazone group (P = 0.021); of these deaths, 24 in the placebo group and six in the sulfinpyrazone group were sudden cardiac deaths -- a sulfinpyrazone-induced 74 per cent reduction in the calculated mortality rate (P = 0.003). We conclude that sulfinpyrazone prevents sudden cardiac death during the high-risk period shortly after an acute myocardial infarction, but that there is no further apparent effect beyond the seventh month after infarction.

To investigate whether lithium ameliorates the infectious complications that accompany systemic chemotherapy, we studied 45 patients with small-cell bronchogenic carcinoma receiving combination chemotherapy and radiation therapy. Twenty received lithium carbonate, and 25 received no additional therapy. Control subjects experienced more days with neutropenia than the lithium-treated group (2.17 days per 100 patient-days vs. 0.29), more severe febrile episodes (seven patients vs. one patient), more days hospitalized with fever and neutropenia (1.92 per 100 patient-days vs. 0.18), and more infection-related deaths (five vs. none). Infection-free survival was significantly longer in the lithium-treated group than in controls (P less than 0.05). Delay in subsequent chemotherapy was longer (P less than 0.01) and the number of dose reductions greater (P less than 0.01) in the control group. For both leukocytes and neutrophils, the first cycle nadir, mean of all treatment nadirs, and the lowest nadir observed during treatment were significantly higher in the lithium group. Mean mid-cycle monocyte counts were greater in the lithium group (P less than 0.05) and correlated with concurrent serum lithium levels (rs = 0.74, P less than 0.05). We believe that lithium carbonate shows promise as a means of lowering the risk of infection among patients receiving cytotoxic therapy.

Delta-9-tetrahydrocannabinol (THC) is an effective antiemetic as compared with placebos in patients receiving chemotherapy for cancer. In this study we compared THC with prochlorperazine (compazine) in a randomized, double-blind, crossover trial with patients who had failed to benefit from standard antiemetic therapy. Regardless of the emetic activity of the chemotherapeutic agents, there were more complete responses to THC courses (in 36 of 79 courses) than to prochlorperazine (in 16 of 78 courses). Of 25 patients who were treated with both drugs and who expressed a preference, 20 preferred THC (P = 0.005). Among patients under 20 years of age there was a higher proportion of complete responses to THC courses (15 of 20) than among older patients (21 of 59 courses; P = 0.004). Increased food intake occurred more frequently with THC (P = 0.008) and was associated with the presence of a "high." Of 36 THC courses resulting in complete antiemetic responses, 32 were associated with a high. We conclude that THC is an effective antiemetic in many patients who receive chemotherapy for cancer and for whom other antiemetics are ineffective. (N Engl J Med 302:135--138, 1980).

Molsidomine, a new long-acting vasodilator, was administered intravenously (0.03 mg per kilogram of body weight) to two groups of six patients with stable anginapectoris. In the first group, studied during exercise-induced angina, the drug shortened the duration of pain and reduced electrocardiographically measured ST-segment depression, mean systemic arterial pressure, and mean pulmonary wedge pressure. Cardiac output and heart rate remained unchanged. In the second group, studied during pacing-induced angina, the drug reduced both left ventricular pressures and angiographically estimated ventricular volumes and improved the ejection fraction. In a double-blind crossover comparison with a placebo, molsidomine (2 mg three times daily) reduced the frequency of anginal attacks and the consumption of nitroglycerin tablets in 14 patients. During exercise testing on a treadmill a statistically significant reduction in ST-segment depression lasted for up to six hours. These studies suggest that molsidomine acts like nitroglycerin but its effects last longer. We conclude that molsidomine is effective in preventing the symptoms of angina pectoris. (N Engl J Med 302:1-6, 1980).

Seventy-two adults with the nephrotic syndrome without renal insufficiency had a membranous type of renal histology on biopsy. These patients were randomly allocated to at least eight weeks of alternate-day treatment with prednisone or placebo in a multicenter study. Deterioration of glomerular filtration rate was significantly more rapid in placebo-treated than in prednisone-treated patients, and ultimately 10 of 38 given placebo but only one of 34 given prednisone were in renal failure (creatinine more than 5 mg per deciliter [440 mumol per liter]) or dead (P less than 0.02). In male patients and in those with nonselective initial proteinuria, there was a trend (not reaching statistical significance) toward more rapid deterioration of renal function. Age, admission blood pressure, serum creatinine, daily total protein excretion, and severity of histologic changes did not predict the subsequent course. We conclude that a short course of alternate-day prednisone therapy was beneficial in our group of patients with idiopathic membranous nephropathy.