In a multicenter prospective randomized trial, the efficacy and toxicity of low-dose (400 mg/d) and high-dose (800 mg/d) oral ketoconazole were compared in 80 patients with blastomycosis and in 54 with histoplasmosis. Among 65 patients with blastomycosis treated for 6 months or more, high-dose treatment was more effective (100% success rate compared with 79%; p = 0.001). Among 19 patients with chronic cavitary histoplasmosis treated for 6 months or more, both regimens were equally effective (overall success rate, 84%). In 20 patients with localized or disseminated histoplasmosis treated for 6 months or more, low-dose treatment was more effective (100% success rate compared with 57%; p = 0.03). The success rate for all patients with histoplasmosis treated for 6 months or more was 85%. Adverse effects occurred in 81 of 134 patients (60%) and were commoner with the high-dose regimen. Ketoconazole is effective for immunocompetent patients with non-life-threatening, nonmeningeal forms of blastomycosis and histoplasmosis. Because of the higher frequency of side effects associated with the high dose, ketoconazole therapy should be initiated with the low dose.

Twelve patients with refractory rheumatoid arthritis were treated with weekly pulse methotrexate in a double-blind, placebo-controlled, crossover study. After 13 weeks of therapy, patients receiving methotrexate showed greater improvement, judged by degree of joint swelling and tenderness, duration of morning stiffness, and subjective assessments of clinical condition, compared to those receiving placebo (p less than or equal to 0.002). This improvement was associated with a decrease in sedimentation rate and decreases in levels of IgG, IgM, and IgA; no changes were seen in serum rheumatoid factor titer or complement protein levels. Proportions of mononuclear cell subsets that were abnormal before treatment (decreased percentage of total T cells, increased percentage of monocytes) improved toward normal after therapy with methotrexate. However, no changes were seen in elevated pretreatment Leu-3/Leu-2 ratios, in in-vitro proliferative responses of lymphocytes to mitogens, or in immunoglobulin secretory responses to pokeweed mitogen. Weekly pulse methotrexate is effective in the short-term treatment of refractory rheumatoid arthritis. Little evidence for cellular immune suppression was associated with this clinical benefit.

Tocainide, a newly released class 1B antiarrhythmic agent, has membrane stabilizing and electrophysiologic characteristics similar to those of lidocaine, but it can be prescribed for oral administration. Investigational studies in both animals and humans have shown tocainide's effectiveness for the treatment of ventricular arrhythmias in chronic and acute settings. The drug has nearly 100% bioavailability after oral administration and an effective half-life of 9 to 37 hours (mean, 15 hours). Antiarrhythmic efficacy is similar to that of other class I medications currently in use. Serious side effects most frequently involve the central nervous or gastrointestinal system and occur in 10% to 20% of patients. Tocainide has minimal negative inotropic effects and a tendency to shorten effective refractory periods.

The use of pulmonary artery flow-directed catheters has assumed epidemic proportions without clinical trials establishing improved outcome as a result of their use. During the past 10 years, however, it has become clear that improved outcome is found only in small groups of patients and that use of these catheters is associated with considerable risks of morbidity and mortality. A clinical trial is urgently needed to assess the balance between risks and benefits. While awaiting such trials, physicians should limit catheter use to circumstances in which there is a large probability that the data will result in more effective management; the measurements should only be used to answer specific questions about patient therapy. This situation will occur in a relatively small number of patients.

One hundred seventy elderly women with stage II breast cancer, stratified on the basis of the number of positive axillary nodes and estrogen receptor status, were randomly assigned to receive tamoxifen or placebo for 24 months in a prospective, double-blind, adjuvant trial. The median age was 71 years with a range from 65 to 84 years. The overall percentage of patients disease-free at 4 years was 76% for those given tamoxifen and 52% for those given placebo (p = 0.0004). Benefit was seen in all subgroups of patients treated with tamoxifen. Two years of tamoxifen therapy represents an effective postoperative adjuvant treatment for elderly women with stage II breast cancer, resulting in improved time to relapse, statistically fewer distant first recurrences, and minimal toxicity. No improvement in overall survival has been seen yet.

The efficacy of cimetidine in the prevention and treatment of stress-induced gastroduodenal lesions was evaluated in a randomized, double-blind, placebo-controlled study in which serial endoscopy was used to examine patients without clinical evidence of bleeding who were admitted to a medical intensive care unit. Endoscopy showed that 14 of 21 patients treated with cimetidine, compared with 5 of 18 patients treated with placebo, had normal or improved gastroduodenal mucosa (p less than 0.05). Endoscopic signs of bleeding cleared or did not develop in 20 patients treated with cimetidine and in 11 patients treated with placebo (p less than 0.01). Significantly fewer blood transfusions were given to patients with endoscopic signs of bleeding in the cimetidine-treated group (0.5 +/- 0.3 [SE] units) than in placebo-treated patients (4.5 +/- 1.5 units; p less than 0.05). The mortality rate was not statistically different between treatment groups. By preventing established gastroduodenal stress lesions from progressing in severity, cimetidine diminished both bleeding and the need for transfusions.

In two phase I-II trials, 33 patients were given recombinant interferon alpha-2 daily at dosages of 3, 10, 30, 50, or 100 MU/d for up to 4 weeks by intramuscular or intravenous routes. Dose-limiting toxicities, including neutropenia, elevated hepatocellular enzyme levels, fatigue, and disturbed mentation, correlated with differing serum pharmacokinetics of interferon in the two trials. In the intramuscular study, dose-limiting toxicity occurred at all dosages greater than 10 MU/d, at a median of 6 to 9 days of treatment. In the intravenous dose-study, limiting toxicity was seen only at dosages of 100 MU/d, at a median of day 8. Twenty-three patients had metastatic melanoma and 4 had objective partial or complete responses at dosages of 10 to 50 MU/d in the first month. Two patients with complete responses are free of tumor after 2.5 years of follow-up. A fifth patient had delayed complete regression, requiring 1 year to achieve maximum response, but remains free of disease at 26 months since entry to the trial. Interferon had antitumor activity against melanoma by both routes tested, at dosages of 10 to 50 MU/d.

In a randomized, double-blinded, placebo-controlled trial, we compared the therapeutic effect of oral acyclovir (400 mg five times daily for 10 days) with that of placebo in patients with marrow transplants and culture-proven recurrent mucocutaneous herpes simplex. Twelve patients received acyclovir and nine received placebo. Acyclovir treatment significantly shortened the median duration of viral shedding, new lesion formation, and time to first decrease in pain, resolution of pain, 50% healing, and total healing. These results compared favorably with those previously obtained with intravenous or topical acyclovir preparations. Oral acyclovir is highly effective for the treatment of recurrent mucocutaneous infections caused by herpes simplex virus in immunocompromised patients.

A randomized controlled trial was done to assess the ability of continuing medical education to change physicians' knowledge and behavior in the care of patients with acute myocardial infarction. Patient care practices on eight objectives were audited 6 months before and after physicians completed a 2-hour educational program. Sixty-three physicians from eight randomly selected communities constituted the experimental group and 40 physicians from four similar communities served as controls. The average score for desired care practices over all objectives increased from 48.5% to 60% (p less than 0.001). Three objectives showed significantly greater gains for physicians in the experimental group. The generalizability of these effects was also studied in two additional educational contexts: a multitopic and a unitopic university-based continuing medical education program. Similar significant changes in behavior resulted in both contexts. Significant overall increases in knowledge occurred and persisted for all groups. Continuing medical education can effect changes in physicians' knowledge and care practices that can persist for at least 6 months.

Recently the Food and Drug Administration approved cimetidine for the treatment of benign gastric ulcer. Approval was based in part on the results of our large multicenter trial involving 172 patients with benign gastric ulcer between 0.5 and 2.5 cm in diameter: 87 were randomly assigned to receive cimetidine (300 mg four times daily) and 85 to receive placebo. Cimetidine treatment resulted in significantly more rapid healing than placebo; after 2 and 6 weeks of therapy, 10.0% and 44.8% of patients receiving placebo were healed, as compared to 22.6% and 65.1% receiving cimetidine. The results of our study were compared with the time-response curve previously published (0, 4, and 8 weeks of therapy). The combined data yielded linear healing rates for the first 8 weeks of therapy (r greater than 0.99 for both cimetidine and placebo). These studies can be used to define expectations for healing of benign gastric ulcer, and we recommend follow-up intervals of 8 and, if unhealed, 16 weeks.

An intervention was developed to increase patient involvement in care. Using a treatment algorithm as a guide, patients were helped to read their medical record and coached to ask questions and negotiate medical decisions with their physicians during a 20-minute session before their regularly scheduled visit. In a randomized controlled trial we compared this intervention with a standard educational session of equal length in a clinic for patients with ulcer disease. Six to eight weeks after the trial, patients in the experimental group reported fewer limitations in physical and role-related activities (p less than 0.05), preferred a more active role in medical decision-making, and were as satisfied with their care as the control group. Analysis of audiotapes of physician-patient interactions showed that patients in the experimental group were twice as effective as control patients in obtaining information from physicians (p less than 0.05). Results of the intervention included increased involvement in the interaction with the physician, fewer limitations imposed by the disease on patients' functional ability, and increased preference for active involvement in medical decision-making.

Twenty-six patients participated in a randomized, double-blind study of the efficacy of total lymphoid irradiation in the treatment of intractable rheumatoid arthritis. All 26 patients, for whom therapy with gold compounds and penicillamine had failed, would ordinarily have been considered candidates for cytotoxic or antimetabolite drug therapy. Thirteen patients randomly assigned to receive full-dose total lymphoid irradiation (2000 rad) and 11 patients assigned to receive control low-dose total lymphoid irradiation (200 rad) completed radiotherapy. Alleviation of joint disease activity was significantly greater in the high-dose group as judged by morning stiffness, joint tenderness, and functional assessment (global composite score) at 3 and 6 months after radiotherapy. The high-dose group had a marked reduction in both T-lymphocyte function and numbers, but this finding was not observed in the low-dose group. Complications seen in the high-dose but not low-dose group included transient neutropenia, thrombocytopenia, pericarditis, and pleurisy.

Five intensively treated, insulin-dependent diabetics exercised for 45 minutes after fasting while receiving basal insulin injections. Plasma glucose concentrations remained stable during exercise but then declined, resulting in clinical hypoglycemia 1 to 2 hours later. Efficacies of three pre-exercise snacks in preventing the hypoglycemia were compared in a randomized crossover design. Orange juice, whole milk, and skim milk, each containing 13 g of carbohydrate, all prevented postexercise hypoglycemia. However, the more rapidly absorbed snacks, orange juice and skim milk, caused a greater increase in plasma glucose concentrations and the area under the glucose curve during exercise. From the recognized glucose profiles that occur after consumption of different carbohydrates, snacks as well as exercise and insulin can now be programmed for intensively treated, insulin-dependent diabetics. Because plasma glucose levels remain stable during exercise done after fasting and only fall late after exercise, a "lente" carbohydrate snack, such as whole milk, is an appropriate pre-exercise snack.

As more people with mild hypertension are treated, non-drug therapies should be used more frequently and effectively. These therapies include weight reduction; sodium restriction; potassium, calcium, and magnesium supplementation; other dietary changes; exercise; relaxation; and moderation of alcohol use. Such therapies have been inadequately used, in part because of a lack of confidence in their effectiveness and overconfidence in the effectiveness and safety of drug therapy. Evidence about the effectiveness, mode of action, safety, and patient acceptance of the various non-drug therapies is reviewed, and practical guidelines to their use are provided. Non-drug therapies may provide enough antihypertensive effect to lower blood pressure of many patients with mild hypertension to a safe level without the need for antihypertensive drugs.

In a prospective controlled trial, the relative effectiveness of allogeneic bone marrow transplantation and postremission chemotherapy was assessed for adult patients with acute myelogenous leukemia in first complete remission. Twenty-three patients, 15 to 45 years of age, who had an HLA-identical sibling donor were designated to receive bone marrow transplantation. Forty-four patients who either lacked an HLA-identical sibling or were over 45 years of age were designated to receive intensive consolidation chemotherapy. The actuarial rate of leukemia relapse was significantly lower in the transplantation group than in the chemotherapy group (40 +/- 25% [95% confidence interval] compared with 71 +/- 14%, p = 0.01). Actuarial survival at greater than 4 years was not significantly different (40 +/- 21% compared with 27 +/- 14%, p greater than 0.4). These data show that bone marrow transplantation is more effective than consolidation chemotherapy in preventing leukemia relapse, but overall survival was not improved in this study.