In a previous comparison of persons between 14 and 62 years of age randomly assigned to receive care through a fee-for-service system (n = 784) or through a health maintenance organization (HMO) (n = 738) in Seattle, Washington, persons in the HMO had much lower hospital expenditures and admissions, more bed days, a higher prevalence of serious symptoms, and less satisfaction with care. We report an examination of 20 additional health status measures. Our results are consistent with a hypothesis of no differences in health status measures between the two systems. In addition, a comparison of nine health practices between the systems also indicated no overall differences. Most physiologic measures and health practices for a typical person were not affected by care received through the fee-for-service system or the HMO. However, we are less certain of this result in specific subgroups, such as persons of lower income initially at elevated risk, because confidence intervals are necessarily wider. We conclude that the cost savings achieved by this HMO through lower hospitalization rates were not reflected in lower levels of health status.

We evaluated the effect of norfloxacin, 400 mg given orally every 12 hours, on the prevention of bacterial infections in 68 adult patients who had acute leukemia throughout prolonged courses of granulocytopenia (median, 32 days). Gram-negative infections were documented in 13 of the 33 patients receiving placebo, but only in 4 of the 35 patients receiving norfloxacin; no effect on the frequency of gram-positive or fungal infections was noted. Norfloxacin administration resulted in the suppression of gastrointestinal tract colonization by aerobic bacteria without the development of norfloxacin resistance. Patients receiving norfloxacin developed first infectious fevers later than did those receiving placebo, had more rapid resolution of that fever after systemic antibiotic treatment, and spent less time febrile. Therefore, although no difference was seen in survival duration, we found that the prophylactic administration of oral norfloxacin led to decreases in overall morbidity and gram-negative infections, was well tolerated, and did not predispose to the development of multiply drug-resistant bacteria.

Fifty-six patients receiving remission induction treatment for acute leukemia were studied in a randomized trial comparing ciprofloxacin with trimethoprim-sulfamethoxazole plus colistin for prevention of infections. Both groups received amphotericin B for antifungal prophylaxis. Six major infections occurred in 28 patients receiving ciprofloxacin, and 11 major infections occurred in 28 patients receiving trimethoprim-sulfamethoxazole plus colistin. No infections caused by gram-negative bacilli were seen in the ciprofloxacin group (p less than 0.02). Ciprofloxacin prevented colonization with resistant gram-negative bacilli, but 12 resistant colonizing strains were isolated from 10 patients receiving trimethoprim-sulfamethoxazole plus colistin (p less than 0.01). Ciprofloxacin was better tolerated: 23 of 28 patients were highly compliant to the drug, compared with 15 of 28 patients in the trimethoprim-sulfamethoxazole group (p less than 0.05). These results suggest that ciprofloxacin is a promising drug for the prevention of infection in patients with granulocytopenia.

The effects of high doses of polyvalent intravenous immune globulin given for prophylaxis of cytomegalovirus infection and interstitial pneumonia in recipients of allogeneic marrow transplants were evaluated in a randomized controlled trial. Both symptomatic cytomegalovirus infection (21% compared with 46%, p = 0.03) and interstitial pneumonia (18% compared with 46%, p = 0.02) occurred less frequently in the recipients of intravenous immune globulin than in control patients. Prophylactic intravenous immune globulin was also associated with a lower incidence of graft-versus-host disease (34% in recipients compared with 65% in controls, p = 0.01), but its reduction in rates of interstitial pneumonia was independent of graft-versus-host disease and occurred in both patients with and without graft-versus-host disease. The high doses of immune globulin were well tolerated. Prophylactic intravenous immune globulin can modify the severity of cytomegalovirus infection and prevent interstitial pneumonia and possibly graft-versus-host disease in patients having allogeneic marrow transplantation.

In a double-blind, placebo-controlled trial, 225 patients with acute partial stable thrombotic stroke were randomly assigned to receive continuous intravenous heparin therapy or placebo for 7 days for the prevention of stroke progression or death. No statistically significant difference between the two groups was found in degree of neurologic change; incidence of stroke progression after 7 days; or functional activity level of survivors at 7 days, 3 months and at 1 year after treatment. Compared with controls, a statistically significant greater number of patients in the group receiving heparin died in the year after the stroke. These deaths occurred 3 to 12 months after the initial stroke and probably were not related to treatment. Results of this study do not support the use of intravenous heparin to treat patients who have had acute partial stroke.

Twenty-one adult patients with severe diabetic ketoacidosis entered a randomized prospective protocol in which variable doses of sodium bicarbonate, based on initial arterial pH (6.9 to 7.14), were administered to 10 patients (treatment group) and were withheld from 11 patients (control group). During treatment, there were no significant differences in the rate of decline of glucose or ketone levels or in the rate of increase in pH or bicarbonate levels in the blood or cerebrospinal fluid in either group. Similarly, there were no significant differences in the time required for the plasma glucose level to reach 250 mg/dL, blood pH to reach 7.3, or bicarbonate level to reach 15 meq/L. We conclude that in severe diabetic ketoacidosis (arterial pH 6.9 to 7.14), the administration of bicarbonate does not affect recovery outcome variables as compared with those in a control group.

To assess the antiarrhythmic efficacy of intravenous propafenone, 20 patients with inducible sustained supraventricular tachycardia received propafenone, 2 mg/kg body weight, or placebo in a double-blind, randomized, crossover study. Three patients had intra-atrial reentrant tachycardia, 3 had atrioventricular nodal reentrant tachycardia, and 14 had atrioventricular reciprocating tachycardia associated with the Wolff-Parkinson-White syndrome. Termination of supraventricular tachycardia occurred in 15 of the 20 patients receiving propafenone but 0 of the 11 patients receiving placebo (p less than 0.01). Propafenone prolonged refractoriness and slowed conduction of the atrium, the atrioventricular node, and accessory atrioventricular bypass tracts, and these effects provided antiarrhythmic action to halt tachycardia. No adverse effects were observed in any patient. We conclude that intravenous propafenone is safe and effective in the acute treatment of various forms of reentrant supraventricular tachycardia.

Ninety patients were entered into a randomized, controlled, double-blind trial lasting 12 months to compare auranofin (6 mg/d), and D-penicillamine (250 mg/d for 4 weeks, 500 mg/d for 4 weeks, then 750 mg/d thereafter) in the treatment of rheumatoid arthritis. Most patients in both groups completed the trial with significant improvement in all quantitative measures of efficacy. Patients treated with D-penicillamine were more likely to have "important improvement" in physician global assessment, swollen joint count, and score and grip strength. The overall frequency of side effects was similar between the two groups; however, more patients were withdrawn for adverse effects from the D-penicillamine group, and proteinuria (greater than or equal to 2+) and thrombocytopenia (less than 100 000 mm3) occurred significantly more frequently with D-penicillamine than auranofin (p = 0.028). These results suggest that in the dosage regimen used, auranofin is safer than D-penicillamine but that D-penicillamine tends to show greater clinical effectiveness in patients with rheumatoid arthritis.

We have evaluated the relation between alkylating agents and leukemic disorders in 3363 1-year survivors of ovarian cancer who were treated in five randomized clinical trials and at two large medical centers. Overall, 28 patients developed acute nonlymphocytic leukemia (expected, 1.2) and 7 developed preleukemia. A 93-fold increased risk for acute nonlymphocytic leukemia was seen in 1794 women treated with chemotherapy; the incidence of leukemic disorders was 7.7/1000 women per year. Risk was highest 5 to 6 years after the first treatment and appeared to decrease thereafter. The use of radiation therapy did not affect risk. The 10-year cumulative risk (mean +/- SE) of acquiring a leukemic disorder was 8.5% +/- 1.6% after treatment with any alkylating agent, 11.2% +/- 2.6% after treatment with melphalan, and 5.4% +/- 3.2% after cyclophosphamide treatment. A dose-response relationship was apparent in 605 women receiving melphalan and suggested in 333 women receiving cyclophosphamide. Women receiving melphalan were two to three times as likely to develop leukemic disorders than were women receiving cyclophosphamide. These data indicate that choice of chemotherapeutic agent and drug dosage may influence significantly the risk for long-term adverse effects of cancer therapy.

Eight patients with orthostatic hypotension were treated with subcutaneous dihydroergotamine. Two doses of the drug (6.5 and 13 micrograms/kg) or placebo were given in a random sequence at 0600 h, and blood pressures were measured hourly throughout the day with patients in both supine and upright positions. To assess the effect of postprandial hypotension on the therapeutic response to dihydroergotamine, we gave breakfast, lunch, and supper on a fixed schedule at 0900 h, 1200 h, and 1700 h. Dihydroergotamine had a pressor effect in seven of the eight patients during the fasting period (0600 h to 0900 h), but this agent did not counteract the hypotensive effect of eating. Concomitant administration of caffeine (250 mg, 30 minutes before breakfast), however, maintained the beneficial effect of dihydroergotamine during the postprandial period. The combination of subcutaneous dihydroergotamine and caffeine represents a new therapeutic option for patients with severe autonomic neuropathy.

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.