Twenty-four depressed patients with heart disease were treated for four weeks in a double-blind trial of imipramine, doxepin, or placebo to assess the effects of tricyclic antidepressants on ventricular function and rhythm. The tricyclic antidepressants had no effect on left ventricular ejection fraction at rest or during maximal exercise, as measured by radionuclide ventriculograms obtained before and after treatment. Premature ventricular contractions were reduced by imipramine but were not consistently changed by doxepin or placebo. Treatment with imipramine and doxepin, but not placebo, was associated with significant improvement (P less than 0.001) in standard ratings of depression. Our findings underscore the need for a reappraisal of the cardiovascular risks of tricyclic antidepressants and suggest that in the absence of severe impairment of myocardial performance, depressed patients with preexisting heart disease can be effectively treated with these agents without an adverse effect on ventricular rhythm or hemodynamic function.

Hypoglycemia (blood glucose less than 45 mg per deciliter [less than 2.5 mmol per liter]) occurred in seven of 19 healthy men who exercised to exhaustion on a cycle ergometer at 60 to 65 per cent of maximal aerobic power. The hypoglycemic subjects exercised for 15 to 70 minutes despite blood glucose levels of 25 to 48 mg per deciliter (1.4 to 2.7 mmol per liter), and their exhaustion time (mean +/- S.E.M., 142 +/- 15 minutes) was not significantly different from that of the euglycemic group (165 +/- 11). Plasma epinephrine was inversely related to blood glucose (P less than 0.01) and was three times higher in the hypoglycemic subjects (P less than 0.05). Glucose ingestion (40 or 80 g per hour) prevented the hypoglycemia and resulted in a smaller rise in plasma epinephrine but did not alter perceived exertion or consistently delay exhaustion. We conclude that hypoglycemia occurs in normal subjects during prolonged exercise and results in an exaggerated rise in plasma epinephrine. However, hypoglycemia fails to effect endurance, and its prevention does not consistently delay exhaustion.

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.

Beta-blocking drugs are increasingly prescribed in coronary heart disease, but controversy surrounds the hemodynamic relevance of their ancillary pharmacologic properties--cardioselectivity and intrinsic sympathomimetic activity. We therefore compared the effects of four intravenous beta-adrenoreceptor antagonists with different ancillary properties on left ventricular function in 24 patients with coronary heart disease. All four drugs depressed the relation between left ventricular filling pressure and cardiac output at rest and during exercise. However, practolol and oxprenolol, which have intrinsic sympathomimetic activity, induced significantly less depression of left ventricular function than either propranolol or metoprolol, which do not have this activity. Cardioselectivity, a property of both practolol and metoprolol, had no discernible hemodynamic advantage. Beta-blocking drugs that have intrinsic sympathomimetic activity appear to be more effective in maintaining cardiac function than drugs without this property, when given intravenously to patients with coronary heart disease.

To determine whether continuing medical education affects the quality of clinical care, we randomly allocated 16 Ontario family physicians to receive or not receive continuing-education packages covering clinical problems commonly confronted in general practice. Over 4500 episodes of care, provided before and after study physicians received continuing education, were compared with preset clinical criteria and classified according to quality. Although objective tests confirmed that the study physicians learned from the packages, there was little effect on the overall quality of care. When the topics were of relatively great interest to the physicians, the control group (who did not receive the packages) showed as much improvement as did the study group. When the topics were not preferred, however, the documented quality of care provided by study physicians rose (P less than 0.05) and differed from that provided by control physicians (P = 0.01). Finally, there was no spillover effect on clinical problems not directly covered by the program. In view of the trend toward mandatory continuing education and the resources expended, it is time to reconsider whether it works.

We performed a double-blind, controlled study of prophylactic indomethacin therapy in 47 premature infants (less than 1700 g) who had subclinical patent ductus arteriosus. They received either indomethacin or placebo at a mean age of 2.9 days. Among the 25 infants weighing more than 1000 g, a hemodynamically important ductus shunt developed in only four of the 14 given placebo. The incidence of important shunts, the number of surgical ligations, and the duration of oxygen therapy were not appreciably different between the study groups. In contrast, among the 22 infants who weighed 1000 g or less, a major ductus shunt developed in 10 of the 12 given placebo. In the smaller infants indomethacin therapy was associated with a significantly lower incidence of major shunts, fewer surgical ligations, a decreased duration of oxygen therapy, and fewer days necessary to regain birth weight. We conclude that prophylactic indomethacin therapy in infants weighing under 1000 g prevents the later development of large ductus shunts and decreases morbidity.

In a prospective, controlled study, 50 children with frequently relapsing nephrotic syndrome who had steroid toxicity were treated for eight weeks with either cyclophosphamide (2 mg per kilogram of body weight per day) or chlorambucil (0.15 mg per kilogram per day), in combination with prednisone in tapering doses. Of the 34 children shows relapses had tended to occur after the prednisone dosage had been reduced or immediately after the drug was discontinued (the steroid-dependent group), 22 also had early relapses after cytotoxic-drug treatment. In contrast, cytotoxic drug treatment produced long-lasting remissions in 12 of the 16 children whose relapses usually occurred after prednisone treatment had been interrupted for more than 14 days (the non-steroid-dependent group). The difference in response between the two groups was highly significant (P less than 0.001). We conclude that patients with frequent relapses without steroid dependence can be treated successfully with an eight-week course of cytotoxic drugs, whereas those with steroid-dependent nephrotic syndrome do not profit from cytotoxic drugs in the low doses used.

We assessed the rates of vertebral fracture in patients with postmenopausal osteoporosis. Forty-five patients were not treated (91 person-years of observation); 59 were treated conventionally, with calcium (alone or combined with estrogen) or vitamin D or both (218 years); and 61 were treated with sodium fluoride combined with conventional therapy (251 years). The fracture rate (per thousand person-years) was 834 in untreated patients, 419 in those given calcium with or without vitamin D, 304 in those given fluoride and calcium with or without vitamin D, 181 in those given estrogen and calcium with or without vitamin D, and 53 in those given fluoride, estrogen, and calcium with or without vitamin D. It was reduced in all treatment groups (P less than 0.001 for calcium and P less than 1 x 10(-6) for other combinations); fluoride (one years of treatment) and estrogen (but not vitamin D) independently reduced the rate from that observed with calcium alone (P less than 0.001). The combination of calcium fluoride, and estrogen was more effective than any other combination (P less than 0.001). These results provide grounds for optimism about the efficacy of combinations of available agents with sodium fluoride for fracture in postmenopausal osteoporosis.

Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 per cent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants.

We evaluated D-penicillamine in the treatment of primary biliary cirrhosis. In a prospective double-blind trial, 26 patients received D-penicillamine (250 mg four times a day), and 26 received an identical placebo. Although the desired urinary excretion of copper was achieved in patients taking D-penicillamine, there was no improvement in survival or symptoms after 28 months. Serum bilirubin and alkaline phosphatase increased equally in both groups. Alanine and aspartate aminotransferases were lower in the D-penicillamine group, but serum albumin was also lower in this group. Liver histology worsened equally in both groups. Major side effects, some appearing more than 24 months after the start of treatment, occurred in 31 per cent of the patients receiving D-penicillamine. Less serious side effects occurred in an additional 46 per cent. We conclude that D-penicillamine at the dosage we used is not effective in the treatment of primary biliary cirrhosis and is associated with a high incidence of serious side effects.