Forty patients with the acquired immunodeficiency syndrome (AIDS) and their first episodes of Pneumocystis carinii pneumonia were assigned at random to receive either trimethoprim-sulfamethoxazole or pentamidine isethionate. The two groups did not differ significantly in the severity of pulmonary or systemic processes at enrollment. Five patients treated initially with trimethoprim-sulfamethoxazole and one patient treated initially with pentamidine died during the 21-day treatment period (p = 0.09, Fisher's exact test). No significant differences were seen between groups in rates of improvement, pulmonary function tests, or 67Ga uptake by the lungs in the survivors at completion of therapy. Adverse reactions necessitated changing from the initial drug in 10 patients in the trimethoprim-sulfamethoxazole group and 11 in the pentamidine group. Minor reactions occurred in all patients. In patients with AIDS, trimethoprim-sulfamethoxazole and pentamidine do not have statistically significant differences in efficacy or frequency of adverse reactions.

The effects of ex-vivo depletion of T lymphocytes from donor bone marrow using a monoclonal anti-T-cell antibody (CT-2) and complement on the outcome of allogeneic bone marrow transplantation was evaluated in a prospective, randomized, double-blind study of 40 patients with leukemia. Patients receiving T-cell-depleted bone marrow had a lower incidence of acute graft-versus-host disease than control patients (3 of 20 compared with 13 of 20; p = 0.004), and mortality due to acute graft-versus-host disease was reduced. Five patients in the T-cell-depletion group developed graft failure; all control patients had sustained engraftment (p less than 0.05). Clinically apparent relapse of leukemia occurred in 7 patients from the T-cell-depletion group and in 2 controls (p, not significant). Cytogenetic evidence of residual leukemia was also detected in the 5 patients with graft failure without overt relapse. Infections and overall survival were similar in the two groups. The effects of T-cell depletion on engraftment and recurrence of leukemia require further evaluation.

In patients with stage IV Hodgkin's disease mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was randomly tested against MOPP alternated monthly with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). All 88 evaluable patients had not received chemotherapy and 25 had had a relapse after primary irradiation. The complete remission rate with MOPP/ABVD was 88.9% (40 of 45 patients), and with MOPP, 74.4% (32 of 43 patients). The 8-year results show that MOPP/ABVD was superior to MOPP in terms of freedom from progression (64.6% compared to 35.9%; p less than 0.005), relapse-free survival (72.6% compared to 45.1%; p less than 0.01), total survival (83.9% compared to 63.9%; p less than 0.06), and survival of complete responders (94.8% compared to 77.1%; p = 0.04). The delivery of MOPP/ABVD was not associated with an increased incidence of major toxicity. The early sequential rotation of two equally effective and non-cross-resistant drug combinations can substantially improve the likelihood of cure in patients with Hodgkin's disease.

In a randomized crossover study, 181 patients over the age of 65 with recurrent breast cancer received either tamoxifen or cyclophosphamide, methotrexate, and fluorouracil (CMF). After progression on tamoxifen, a hormone withdrawal period was required. Because of altered pharmacokinetics with aging, creatinine clearance was used in calculating the dose of CMF. Response rates were 45% on tamoxifen and 38% on CMF, with median durations of 10.4 and 7.9 months, respectively. Survival rates tended to favor tamoxifen as the initial treatment even in estrogen-receptor-negative patients. Additional disease control with hormone withdrawal occurred in 23% of patients, and this benefit was highly correlated with prior hormone response. We conclude that initiation of hormone therapy rather than CMF chemotherapy is justified in almost all situations in elderly patients, and combination chemotherapy, is safe and useful after hormone failure if modified on the basis of renal dysfunction.

The effect of an increasing serum ionized calcium concentration on blood pressure during hemodialysis was studied in a prospective cross-over trial. Twelve patients were dialyzed three times with a dialysate Ca concentration of 5.5 mg/dL and three times with one of 7.5 mg/dL. Dialysis with the high Ca dialysate was associated with less fall in the mean arterial pressure (p less than 0.001). No statistically significant changes occurred in serum osmolality, body weight, or heart rate after dialysis at the two dialysate Ca levels. Increasing the Ca concentration in dialysate may protect against intradialytic hypotension in some patients.

A significantly greater prevalence of interstitial pulmonary infiltrates and Pneumocystis carinii pneumonitis occurred on one arm of a randomized study comparing ProMACE-CytaBOM (prednisone, methotrexate with leucovorin, doxorubicin, cyclophosphamide, etoposide; cytarabine, bleomycin, vincristine, methotrexate with leucovorin) to ProMACE-MOPP (ProMACE, mechlorethamine, vincristine, prednisone, procarbazine) chemotherapy in patients with lymphoma. Of the 37 patients receiving ProMACE-CytaBOM, 13 (35.1%) developed an interstitial pulmonary infiltrate compared with 3 of 32 (9.4%) patients receiving ProMACE-MOPP (p2 = 0.02). Of the 13 patients receiving ProMACE-CytaBOM who had infiltrates, open lung biopsy in 7 showed P. carinii; 5 others had clinically suspected P. carinii pneumonia, and 1 had blastomycosis. No patient receiving ProMACE-MOPP had documented or suspected P. carinii pneumonia. Of patients with infiltrates, 3 of 13 on ProMACE-CytaBOM but 0 of 3 on ProMACE-MOPP died. Two other patients on ProMACE-CytaBOM who had P. carinii pneumonia died. Groups did not differ in predisposing risk factors or patient history. The exact cause for the increased prevalence of P. carinii infection in patients receiving ProMACE-CytaBOM was not ascertained. These data emphasize that new drug regimens may lead to unanticipated complications.

To estimate the effect of cost sharing on seeking care for serious and minor symptoms, we analyzed data for 3539 persons aged 17 to 61 from the Rand Health Insurance Experiment. Participants were randomly assigned to a free-care group or to insurance plans requiring them to pay part of the costs (cost-sharing group). Annual surveys were administered to determine if participants had serious and minor symptoms during the preceding month and whether they saw a physician. Serious symptoms were judged by a panel of physicians to warrant care in most instances; minor symptoms were judged neither to be severe nor to warrant care in most instances. The cost-sharing group was nearly one third less likely than the free-care group to see a physician when they had minor symptoms (6.3% compared with 9.0%; p less than 0.04). The free-care and cost-sharing groups did not differ significantly in seeking care for serious symptoms (22.3% compared with 17.9%; p = 0.095). However, for participants with low socioeconomic status who began the study in poor health, the prevalence of serious symptoms was higher in the cost-sharing than the free-care group (29.1% compared with 23.8%, p less than 0.004).

We compared the effect of 50- or 100-mg doses of oral doxepin or a placebo on basal gastric acid secretion, salivary flow, and pulse rate in seven asymptomatic patients with chronic duodenal ulcer disease. Acid secretion and salivary flow were measured for four 1-hour periods beginning at 3.5, 5.5, 7.5, and 9.5 hours after medication, with plasma sampling for measurement of doxepin at the midpoint of each collection period. Compared to placebo, the 50- and 100-mg doses of doxepin reduced mean basal acid output by 46% and 37%, respectively. There was no significant difference in the effect of the 50- or 100-mg dose on acid secretion even though mean plasma concentrations of doxepin were higher with the 100-mg than with the 50-mg dose (p less than 0.01). Salivary flow was reduced by 62% and 84% with the 50- and 100-mg doses, respectively, whereas doxepin had no effect on mean pulse rate.

We studied cardiovascular effects related to ophthalmic timolol maleate, a beta-adrenergic blocker commonly used to treat chronic glaucoma. Twenty normal subjects were randomly assigned to two double-blind treatment groups each with ten subjects. One group received two drops of ophthalmic timolol (0.5%) twice daily for 4 weeks, and the other received two drops of placebo (artificial tears) twice daily for 4 weeks. Ophthalmic timolol significantly decreased resting and maximal exercise heart rate after the first dose and maximal exercise heart rate during chronic dosing. Chronic timolol administration reduced oxygen consumption at maximal exercise and blunted the augmentation in exercise capacity seen during chronic placebo therapy. Cardiac sympathetic tone and inotropy were reduced after ophthalmic timolol treatment. Despite the presence of drug-induced cardiovascular effects, the plasma levels of timolol were often undetectable and never exceeded 2.8 ng/mL.

Reflux esophagitis may be unresponsive to standard medical therapy with an H2-receptor antagonist drug. Twenty-five patients with chronic reflux esophagitis, refractory to cimetidine treatment alone, were randomly assigned in a double-blind design to receive cimetidine (1200 mg/d), in combination with metoclopramide (40 mg/d) or placebo. Nine of twelve patients receiving cimetidine with metoclopramide had significant symptomatic improvement at the end of the 8-week study period, compared with 3 of 12 patients receiving cimetidine with placebo (p less than 0.02). Endoscopic appearance improved in 9 patients receiving metoclopramide and in 4 patients receiving placebo (p less than 0.05). Neither group had significant improvement in lower esophageal sphincter pressure, 24-hour esophageal pH recordings, and esophageal histologic findings. Side effects were common with cimetidine and metoclopramide but were rarely disabling. This combination is efficacious in the management of chronic reflux esophagitis but, because of frequent side effects, should be reserved for patients refractory to treatment with cimetidine alone.

Fifteen patients with chronic type B hepatitis were treated with corticosteroids in a randomized, double-blind, placebo-controlled trial lasting 28 days. Ten patients received prednisolone, 60 mg/d for 2 weeks, then 30 mg/d for another 2 weeks; 5 patients received placebo. Serum aminotransferase levels decreased significantly during prednisolone therapy but 4 to 10 weeks after abrupt withdrawal of the drug, they rebounded to levels greater than those before treatment. This exacerbation of disease lasted for several months and was prolonged and symptomatic in 3 patients. Hepatitis B virus levels did not change substantially during treatment. Follow-up examinations showed no improvement in biochemical or serologic features of the disease in any of the 15 patients; follow-up liver biopsies showed a worsening in 4 of 7 treated patients but in 0 of 5 control patients. Thus, a 28-day course of prednisolone produced no beneficial effects in patients with mild-to-moderate chronic type B hepatitis; on the contrary, such treatment may be harmful.

In a randomized, double-blinded study, patients with chronic obstructive pulmonary disease and hypercapnia were fed low, moderate, and high carbohydrate diets to determine the effect on metabolic and ventilatory values. The low carbohydrate diet consisted of 28% carbohydrate calories and 55% fat calories and resulted in significantly lower production of CO2 (p less than 0.002), respiratory quotient (p less than 0.001), and arterial Pco2 (p less than 0.05). At the end of the 15-day study, both the forced vital capacity (p less than 0.05) and the forced expiratory volume in 1 second (p less than 0.05) had improved by 22% over baseline values. Total calories given surpassed daily caloric requirements. This approach, together with a low carbohydrate, high fat mixture, may be beneficial for such patients.

The blood pressure response of 48 hypertensive persons and 32 normotensive persons to elemental calcium (as the carbonate or citrate salt), 1000 mg/d for 8 weeks, was assessed in a randomized, double-blind, placebo-controlled, crossover trial. Compared with placebo, Ca2+ significantly lowered supine systolic blood pressure by 3.8 mm Hg, standing systolic blood pressure by 5.6 mm Hg (p less than 0.02), and supine diastolic blood pressure by 2.3 mm Hg (p less than 0.05) in hypertensive persons. The response in normotensive persons differed significantly from that in hypertensives (p less than 0.03) as their blood pressure was unchanged. Twenty-one (44%) hypertensive and 6 (19%) normotensive persons achieved a reduction in standing systolic arterial pressure of 10 mm Hg or greater. Reported adverse effects were similar between calcium and placebo phases and did not necessitate withdrawal of any patient from the trial. Treatment with 1000 mg/d of oral Ca2+ for 8 weeks represents a safe, well-tolerated, nonpharmacologic intervention that lowers blood pressure in selected patients with mild to moderate hypertension.

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.

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.