We randomly assigned 230 patients in sinus rhythm with moderately severe heart failure to treatment with digoxin, milrinone, both, or placebo. The effects of each were compared during a 12-week, double-blind trial. Treatment with milrinone or digoxin significantly increased treadmill exercise time as compared with placebo (by 82 and 64 seconds respectively; 95 percent confidence limits, 44 and 123, and 30 and 100). Both treatments reduced the frequency of decompensation from heart failure, from 47 percent with placebo to 34 percent with milrinone (P less than 0.05; 95 percent confidence limits, 22 and 46) and 15 percent with digoxin (P less than 0.01; 95 percent confidence limits, 7 and 26). However, the clinical condition of 20 percent of the patients taking milrinone deteriorated within two weeks after treatment was begun, as compared with only 3 percent of those taking digoxin (P less than 0.05). The left ventricular ejection fraction at rest was not significantly changed by milrinone (+0.2 percent; 95 percent confidence limits, -1.5 and 1.9), but it was increased by digoxin (+1.7 percent; P less than 0.01; 95 percent confidence limits, -0.03 and 3.4) and decreased by placebo (-2.0 percent; 95 percent confidence limits, -3.8 and -0.1). Three-month survival was related inversely to the base-line ejection fraction. Analysis of mortality from all causes according to the intention to treat suggested an adverse effect of milrinone (P = 0.064). After adjustment for an excess of patients with lower ejection fractions randomly assigned to receive milrinone, this trend was not significant (P = 0.26). Increased ventricular arrhythmias occurred more frequently in patients who received milrinone than in those who did not (18 vs. 4 percent; P less than 0.03). We conclude that milrinone significantly increased exercise tolerance and reduced the frequency of worsened heart failure. However, in the population of patients studied, milrinone or the combination of milrinone and digoxin offered no advantage over digoxin alone. Furthermore, our data suggest that milrinone may aggravate ventricular arrhythmias.

We treated 3262 patients with intravenous recombinant tissue plasminogen activator (rt-PA) within four hours of the onset of chest pain thought to be caused by myocardial infarction. Of these patients, 1636 were then randomly assigned to treatment according to an invasive strategy consisting of coronary arteriography 18 to 48 hours after the administration of rt-PA, followed by prophylactic percutaneous transluminal coronary angioplasty (PTCA) if arteriography demonstrated suitable anatomy; 1626 patients were randomly assigned to treatment according to a conservative strategy, as part of which arteriography and PTCA were to be performed only in patients with spontaneous or exercise-induced ischemia. In the group assigned to the invasive strategy, PTCA was attempted in 928 of the 1636 patients (56.7 percent); the procedure was anatomically successful in 93.3 percent. In the group assigned to the conservative strategy, 216 patients (13.3 percent) underwent clinically indicated PTCA within 14 days of the onset of symptoms. Reinfarction or death within 42 days, the primary end point, occurred in 10.9 percent of the group assigned to the invasive strategy and in 9.7 percent of those assigned to the conservative strategy (P not significant). There were no significant differences between the two groups in the ejection fraction at rest or during exercise, either at hospital discharge or six weeks after randomization. Eleven of 582 patients (1.9 percent) who received 150 mg of rt-PA and 15 of 2952 patients (0.5 percent) who received 100 mg of rt-PA had intracranial hemorrhage. A subgroup of 1390 patients who were eligible for short-term intravenous beta-blockade were randomly assigned to receive 15 mg of intravenous metoprolol immediately, followed by oral metoprolol, or oral metoprolol begun on day 6. The ejection fraction and the incidence of death in the two groups were similar during the hospital period. Total mortality within the first 6 days and at 42 days was also similar. However, in the group that received intravenous metoprolol, 16 patients had nonfatal reinfarctions and 107 patients had recurrent ischemic episodes by six days after entry into the study, as compared with 31 and 147 patients, respectively, among those randomly assigned to deferred oral beta-blockade (P = 0.02 and P = 0.005, respectively); the latter comparison was considered statistically significant according to the study criteria.(ABSTRACT TRUNCATED AT 400 WORDS)

A period of early, intensive insulin treatment is thought to improve subsequent beta-cell function in insulin-dependent diabetes mellitus (IDDM). To study this hypothesis, we randomly assigned adolescents with newly diagnosed IDDM to receive either conventional treatment (n = 14) (NPH insulin, 1 U per kilogram of body weight per day, in two divided doses) or an experimental treatment (n = 12) (a two-week hospitalization with maintenance of blood glucose levels between 3.3 and 4.4 mmol per liter by continuous insulin infusion delivered by an external artificial pancreas [Biostator]). During the two-week intervention, the experimental-therapy group received four times more insulin than the conventionally treated group, and their endogenous insulin secretion was more completely suppressed, as evidenced by a urinary C-peptide excretion rate one seventh that of the conventionally treated group. After the first two weeks, both groups were treated similarly and received similar amounts of insulin. At one year, the mean (+/- SEM) plasma level of C peptide was significantly higher after mixed-meal stimulation in the experimental-therapy group than in the conventionally treated group (0.51 +/- 0.07 vs. 0.27 +/- 0.06; P less than 0.01). The experimental-therapy group also had better metabolic control, as evidenced by lower glycohemoglobin values (7.2 +/- 0.7 vs. 10.8 +/- 1.2 percent; P less than 0.01). We conclude that suppression of endogenous insulin by intensive, continuous insulin treatment during the first two weeks after the diagnosis of IDDM may improve beta-cell function during the subsequent year.

We randomly assigned 536 women who had undergone either a modified radical mastectomy or a total mastectomy with low axillary-node dissection for potentially curable breast carcinoma to receive adjuvant chemotherapy or no-treatment observation. The patients were considered at high risk for recurrence because they had either an estrogen-receptor-negative tumor of any size or an estrogen-receptor-positive tumor at least 3 cm in diameter with no histopathological evidence of axillary-node involvement. The chemotherapy consisted of six four-week cycles of cyclophosphamide (100 mg per square meter of body-surface area orally on days 1 through 14), methotrexate (40 mg per square meter intravenously on days 1 and 8), fluorouracil (600 mg per square meter intravenously on days 1 and 8), and prednisone (40 mg per square meter orally on days 1 through 14). Treatments were balanced with respect to patients' characteristics. The analysis included 406 eligible patients who were entered in the study before October 1, 1987. The overall disease-free survival among patients treated with the four-drug regimen was 84 percent, as compared with 69 percent for the control group, at a median follow-up of three years (P = 0.0001). A treatment benefit was also observed in premenopausal and postmenopausal patients as well as in patients with estrogen-receptor-positive or with estrogen-receptor-negative tumors. Severe or life-threatening hematologic toxicity was encountered in 33 percent of the treated patients, with one death. Our results indicate that adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, fluorouracil, and prednisone is effective in improving three-year disease-free survival among high-risk patients with axillary-node-negative, operable breast cancer. An analysis of the effect of treatment on survival awaits a longer follow-up.

We compared a single perioperative cycle of adjuvant combination chemotherapy with no adjuvant treatment in a randomized trial (Ludwig Trial V) including 1275 patients with breast cancer who had no axillary-node metastases. The chemotherapy was administered on days 1 and 8, beginning within 36 hours after mastectomy, and consisted of cyclophosphamide, methotrexate, fluorouracil, and leucovorin. At a median follow-up of 42 months, the mean four-year disease-free survival (+/- SE) was 77 +/- 2 percent among the patients who received chemotherapy perioperatively, as compared with 73 +/- 2 percent among the patients who received no adjuvant treatment (hazard ratio, 0.77; 95 percent confidence interval, 0.61 to 0.98; P = 0.04). An advantage was observed for both premenopausal and postmenopausal women. The magnitude of the treatment effect was largest among patients with no or low estrogen-receptor content in the primary tumor. We conclude that chemotherapy modifies the post-operative course of node-negative breast cancer. Further trials to investigate an optimal selection of patients and treatments should be regarded as the best available therapeutic approach.

We conducted a randomized, double-blind, placebo-controlled trial of postoperative therapy with tamoxifen (10 mg twice a day) in 2644 patients with breast cancer, histologically negative axillary nodes, and estrogen-receptor-positive (greater than or equal to 10 fmol) tumors. No survival advantage was observed during four years of follow-up (92 percent for placebo vs. 93 percent for tamoxifen; P = 0.3). There was a significant prolongation of disease-free survival among women treated with tamoxifen, as compared with those receiving placebo (83 percent vs. 77 percent; P less than 0.00001). This advantage was observed in both the patients less than or equal to 49 years old (P = 0.0005) and those greater than or equal to 50 (P = 0.0008), particularly in the former, among whom the rate of treatment failure was reduced by 44 percent. Multivariate analysis indicated that all subgroups of patients benefited. Tamoxifen significantly reduced the rate of treatment failure at local and distant sites, tumors in the opposite breast, and the incidence of tumor recurrence after lumpectomy and breast irradiation. The benefit was attained with a low incidence of clinically appreciable toxic effects. The magnitude of the improvement obtained does not preclude the need for future trials in which patients given tamoxifen could serve as the control group in an evaluation of potentially better therapies. Tamoxifen treatment is justified in patients who meet the eligibility criteria of the present study and who refuse to participate in those trials. Since patients with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not eligible for this study, no information is available to indicate that such patients should receive tamoxifen.

We evaluated the postoperative use of sequential methotrexate and fluorouracil followed by leucovorin in 679 patients with primary breast cancer, histologically negative axillary nodes, and estrogen-receptor-negative (less than 10 fmol) tumors. No survival advantage was observed with this therapy as compared with no postoperative therapy during four years of follow-up (87 percent vs. 86 percent; P = 0.8). However, there was a significant prolongation of disease-free survival among women who received this therapy as compared with those who did not (80 percent vs. 71 percent; P = 0.003). An advantage was observed in both the patients less than or equal to 49 years old and those greater than or equal to 50. At four years, treatment failure was reduced by 24 percent in the younger group and by 50 percent in the older group. The rates of both local and regional and distant metastases were decreased. These benefits, achieved without the use of an alkylating agent, were associated with tolerable side effects. Multivariate analysis testing for potential interactions failed to identify subgroups of patients who did not benefit from the therapy. These results, although promising, do not obviate the need for additional trials to evaluate potentially better regimens of therapy, but they do suggest that sequential methotrexate-fluorouracil should be used in the control arm in such studies. Their use is also justified for the treatment of patients who refuse to participate in clinical trials, provided the patients meet the eligibility criteria of the present study. Since women with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not included in this study, we do not recommend systemic treatment for them outside of a clinical trial.

To test the hypothesis that the vasoconstrictor thromboxane A2 may affect renal hemodynamics in lupus nephritis, we examined the short-term effects of a selective thromboxane-receptor antagonist, BM 13,177, and of low-dose aspirin. In a randomized, double-blind, crossover study, 10 patients with biopsy-proved lupus nephritis were given a 48-hour continuous infusion of BM 13,177 or placebo. At base line, seven patients had markedly elevated urinary levels of thromboxane B2, the breakdown product of thromboxane A2. During the infusion of BM 13,177, the inulin clearance rate, which was 68 ml per minute per 1.73 m2 of body-surface area at base line, increased by an average of 24 percent (range, 12 to 47 percent; P less than 0.01). Para-aminohippurate clearance was increased to the same extent, with no change in the filtration fraction. The bleeding time doubled, indicating an occupancy of platelet thromboxane receptors of more than 95 percent. The hemodynamic changes were associated with a significant increase in sodium excretion from 76 to 118 mmol per day (P less than 0.01) but with no change in arterial blood pressure. In another study, 10 additional patients with lupus nephritis were randomly assigned to receive either placebo or 20 mg of aspirin twice daily for four weeks. The aspirin regimen produced a selective, cumulative inhibition of platelet cyclooxygenase activity and a doubling of bleeding time. However, there was no change in the inulin clearance rate and no change in urinary levels of thromboxane B2 or 6-keto-prostaglandin F1 alpha, which are indicators of renal synthesis of thromboxane A2 and prostacyclin, respectively. We conclude that in lupus nephritis, impairment of renal function is at least in part mediated hemodynamically and is reversible with a thromboxane antagonist. Platelets, however, are not a major source of thromboxane A2 synthesis and action within the kidney.

We compared the effectiveness, safety, and costs of outpatient (n = 87) and inpatient (n = 77) detoxification from alcohol in a randomized, prospective trial involving 164 male veterans of low socioeconomic status. The outpatients were evaluated medically and psychiatrically and then were prescribed decreasing doses of oxazepam on the basis of daily clinic visits. The inpatient program combined comprehensive psychiatric and medical evaluation, detoxification with oxazepam, and the initiation of rehabilitation treatment. The mean duration of treatment was significantly shorter for outpatients (6.5 days) than for inpatients (9.2 days). On the other hand, significantly more inpatients (95 percent) than outpatient (72 percent) completed detoxification. There were no serious medical complications in either group. Outcome evaluations completed at one and six months for 93 and 85 percent of the patients, respectively, showed substantial improvement in both groups at both follow-up periods. At one month there were fewer alcohol-related problems among inpatients and fewer medical problems among outpatients. However, no group differences were found at the six-month follow-up, nor were differences found in the subsequent use of other alcoholism-treatment services. Costs were substantially greater for inpatients ($3,319 to $3,665 per patient) than for outpatients ($175 to $388). We conclude that outpatient medical detoxification is an effective, safe, and low-cost treatment for patients with mid-to-moderate symptoms of alcohol withdrawal.

We performed a double-blind randomized trial comparing high doses of subcutaneous heparin (12,500 units every 12 hours) with low doses (5000 units every 12 hours) for 10 days in the prevention of left ventricular mural thrombosis in 221 patients with acute anterior myocardial infarction. Left ventricular mural thrombosis was observed by two-dimensional echocardiography on the 10th day after infarction in 10 of 95 patients (11 percent) in the high-dose group and in 28 of 88 patients (32 percent) in the low-dose group (P = 0.0004). One patient in the high-dose group and four in the low-dose group had nonhemorrhagic strokes (P = 0.17). One patient in the low-dose group had a fatal pulmonary embolism. There was no difference in the frequency of hemorrhagic complications, which occurred in six patients in the high-dose group and four in the low-dose group. The mean (+/- SEM) plasma heparin concentration was 0.18 +/- 0.017 U per milliliter in the high-dose group and 0.01 +/- 0.005 U per milliliter in the low-dose group (P less than 0.0001). In the high-dose group, the mean plasma heparin concentration was 0.10 +/- 0.029 U per milliliter among patients with abnormal two-dimensional echocardiograms, as compared with 0.19 +/- 0.019 U per milliliter among patients with normal echocardiograms (P = 0.01). We conclude that heparin administered subcutaneously in a dosage of 12,500 units every 12 hours to patients with acute anterior transmural myocardial infarction is more effective than a lower dosage (5000 units every 12 hours) in preventing left ventricular mural thrombosis.

In 19 patients with severe Parkinson's disease, we replicated the surgical procedures developed by Madrazo et al. for transplantation of the adrenal medulla to the striatum, and followed them for six months after operation. We monitored their motor function with the use of standardized scales and determined the amount and quality of "on" and "off" time (the hours of the waking day when the antiparkinsonian medications were effective and ineffective, respectively). We found significant improvement in focal areas of motor function. The mean percentage of on time during the day increased from 47.6 percent to 75.0 percent (P = 0.012); the mean percentage of on time without chorea increased from 26.6 percent to 59.2 percent (P = 0.006); the mean severity of off time decreased as assessed by both the Activities of Daily Living subscale of the Unified Parkinson's Disease Scale (P = 0.002) and the Schwab and England scale (P = 0.037). In contrast to the finding of Madrazo et al., however, the dosages of antiparkinsonian medications could not be decreased and postoperative morbidity was substantial. Despite cautious optimism, we conclude that the widespread use of this procedure outside of research centers is premature, since the improvement we found was slighter than in the previous cases.

We conducted a prospective randomized study in which patients with biopsy-confirmed idiopathic membranous nephropathy were assigned to receive either a six-month course of prednisone given on alternate days (45 mg per square meter of body-surface area; n = 81) or no specific treatment (n = 77). The mean duration of follow-up was 48 months. Patients in the prednisone group (median age, 46 years) entered with a mean disease duration of 15 months, a median creatinine clearance of 1.2 ml per second per 1.73 m2 (range, 0.25 to 2.6), and a median rate of urinary protein excretion of 6.8 g per day (0.3 to 26). The annual change in the corrected creatinine clearance at six months did not differ between the prednisone group and the control group (0.10 vs. 0.06 ml per second; P = 0.8), or at the last follow-up evaluation (-0.07 vs. -0.02 ml per second; P = 0.2; 95 percent confidence interval on the difference, -0.03 to 0.13). The proportion of patients with complete remission of proteinuria was also similar in the groups at 6 and 12 months and after a mean of 48 months. Outcomes were similar in the two groups with respect to progression to renal failure (3 vs. 4 patients), death (3 vs. 1 patient), complete remission of proteinuria at 36 months (16 vs. 19 patients), and a decline of 25 percent or more in the creatinine clearance at 60 months (32 vs. 25 percent of patients). A multivariate analysis, which adjusted for differences at entry in sex distribution, urinary protein excretion, and creatinine concentration, as well as other prognostic variables, failed to provide an explanation for the lack of effect of prednisone. We conclude that a six-month course of therapy in which prednisone is given on alternate days is of no benefit to patients with idiopathic membranous nephropathy.

Experimental studies have suggested that nonionic contrast agents are less nephrotoxic than ionic contrast agents. To examine the relative nephrotoxicity of the two types of agents, we randomly assigned 443 patients to receive either iopamidol (nonionic) or diatrizoate (ionic) for cardiac catheterization. The patients were stratified into low-risk (n = 283) or high-risk (n = 160) groups, on the basis of the presence of diabetes mellitus, heart failure, or preexisting renal insufficiency (base-line serum creatinine level, greater than 133 mumol per liter). Serum and urine analyses were performed at base line and 24 and 48 hours after the infusion of contrast material. Nephrotoxicity was defined as an increase in the serum creatinine level within 48 hours of at least 44 mumol per liter. The median maximal rise in the serum creatinine level was 18 mumol per liter in both the diatrizoate group (n = 235) and the iopamidol group (n = 208) (P not significant; power to detect a difference greater than 9 mumol per liter, greater than 90 percent). Creatinine levels increased by at least 44 mumol per liter (0.5 mg per deciliter) in 10.2 percent of the patients receiving diatrizoate and 8.2 percent of the patients receiving iopamidol (P not significant). Among the high-risk patients, creatinine levels increased by at least 44 mumol per liter in 17 percent of the patients in the diatrizoate group, as compared with 15 percent of the patients in the iopamidol group (P not significant). We were unable to demonstrate a difference in the incidence of nephrotoxicity between patients receiving a non-ionic contrast agent and those receiving an ionic contrast agent.

To determine the risk of nephrotoxicity induced by the infusion of radiographic contrast material, we undertook a prospective study of consecutive patients undergoing radiographic procedures with intravascular contrast material. There were three study groups: patients with diabetes mellitus and normal renal function (n = 85), patients with preexisting renal insufficiency (serum creatinine level, greater than or equal to 150 mumol per liter) without diabetes (n = 101), and patients with both diabetes and renal insufficiency (n = 34). The control group consisted of patients undergoing CT scanning or abdominal imaging procedures without the infusion of contrast material who had diabetes mellitus (n = 59), preexisting renal insufficiency (n = 145), or both (n = 64). Clinically important acute renal failure (defined as an increase of greater than 50 percent in the serum creatinine level) attributable to the contrast material did not occur in nondiabetic patients with preexisting renal insufficiency or in diabetics with normal renal function. The incidence of clinically important contrast-induced renal failure among the diabetic patients with preexisting renal insufficiency was 8.8 percent (95 percent confidence interval, 1.9 to 23.7 percent), as compared with 1.6 percent for the controls. The incidence of acute renal insufficiency, more broadly defined as an increase of greater than 25 percent in the serum creatinine level after the infusion of contrast material, was 11.8 percent among all patients with preexisting renal insufficiency. After the exclusion of patients whose acute renal insufficiency could be attributed to other causes, the incidence was 7.0 percent (95 percent confidence interval, 3.2 to 12.8 percent), as compared with 1.5 percent in the control group. The risk of acute renal insufficiency attributable to the contrast material was therefore 5.5 percent, and the relative risk associated with the infusion of contrast material was 4.7. These rates were similar whether the osmolarity of the contrast material was high or low. We conclude that there is little risk of clinically important nephrotoxicity attributable to contrast material for patients with diabetes and normal renal function or for nondiabetic patients with preexisting renal insufficiency. The risk for those with both diabetes and preexisting renal insufficiency is about 9 percent, which is lower than previously reported.

We conducted a multicenter randomized clinical trial to compare the efficacy and safety of high-frequency ventilation with that of conventional mechanical ventilation in the treatment of respiratory failure in preterm infants. Of 673 preterm infants weighing between 750 and 2000 g, 346 were assigned to receive conventional mechanical ventilation and 327 to receive high-frequency oscillatory ventilation. The incidence of bronchopulmonary dysplasia was similar in the two groups (high-frequency ventilation, 40 percent; conventional mechanical ventilation, 41 percent; P = 0.79). High-frequency ventilation did not reduce mortality (18 percent, vs. 17 percent with conventional ventilation; P = 0.73) or the level of ventilatory support during the first 28 days. The crossover rate from high-frequency ventilation to conventional mechanical ventilation was greater than the crossover rate from mechanical to high-frequency ventilation (26 vs. 17 percent; P = 0.01). High-frequency ventilation, as compared with conventional mechanical ventilation, was associated with an increased incidence of pneumoperitoneum of pulmonary origin (3 vs. 1 percent; P = 0.05), grades 3 and 4 intracranial hemorrhage (26 vs. 18 percent; P = 0.02), and periventricular leukomalacia (12 vs. 7 percent; P = 0.05). These results suggest that high-frequency oscillatory ventilation, as used in this trial, does not offer any advantage over conventional mechanical ventilation in the treatment of respiratory failure in preterm infants, and it may be associated with undesirable side effects.

Forty-seven patients thought to have dysfunction of the sphincter of Oddi were randomly assigned to undergo endoscopic sphincterotomy or sham sphincterotomy in a prospective double-blind study. All the patients had pain resembling biliary pain, had previously undergone a cholecystectomy, and had clinical characteristics suggesting biliary obstruction. The patients were randomly assigned to the treatment (n = 23) or nontreatment (n = 24) group before manometric examination of the sphincter of Oddi was performed. Sphincterotomy resulted in improvement in pain scores at one-year follow-up in 10 of 11 patients with elevated sphincter pressure. In contrast, there was improvement in only 3 of 12 patients with elevated basal sphincter pressures who underwent the sham procedure. In patients with normal sphincter pressure, pain scores were similar regardless of treatment. After one year, sphincterotomy was performed in 12 symptomatic patients who had undergone the sham procedure--7 with elevated sphincter pressures and 5 with normal sphincter pressures. Forty patients were followed for four years. Of the 23 patients with increased sphincter pressure, 10 of the original 11 who underwent sphincterotomy remained virtually free of pain; 7 others who subsequently underwent sphincterotomy also benefited from it. Thus, 17 of 18 patients with sphincter-of-Oddi dysfunction verified by manometry benefited from sphincterotomy. In patients with normal sphincter pressure, sphincterotomy was no more beneficial than sham therapy. Our observations suggest that endoscopic sphincterotomy offers long-term relief of pain in a group of patients with verified sphincter-of-Oddi dysfunction.

Omeprazole blocks the action of H+,K+-ATPase in the gastric mucosa and thus inhibits the secretion of hydrochloric acid. We conducted a double-blind multicenter study (45 centers in 13 countries) of 602 patients with benign gastric or prepyloric ulcers to compare the effectiveness of omeprazole (20 mg once daily, 203 patients, or 40 mg once daily, 194 patients) and ranitidine, an H2-receptor antagonist (150 mg twice daily, 205 patients) in promoting ulcer healing and to evaluate the pattern of ulcer relapse during a six-month follow-up. Healing occurred at four weeks in 80 percent of the patients receiving 40 mg of omeprazole, 69 percent of those receiving 20 mg of omeprazole, 69 percent of those receiving ranitidine. At eight weeks, the corresponding figures were 96, 89, and 85 percent. A multivariate analysis of ulcer healing showed that at four weeks the ulcers of significantly more patients receiving omeprazole had healed as compared with patients receiving ranitidine (omeprazole, 40 mg, vs. ranitidine, P less than 0.0005; omeprazole, 20 mg, vs. ranitidine, P = 0.01). At eight weeks, the 40-mg dose of omeprazole was significantly more effective than ranitidine (P = 0.001) or the 20-mg dose of omeprazole (P = 0.03). Ulcer symptoms were relieved faster with omeprazole. In 68 patients receiving concurrent nonsteroidal antiinflammatory drugs, the healing rates at four weeks were 81 percent in the group receiving 40 mg of omeprazole, 61 percent in the group receiving 20 mg, and 32 percent in the group receiving ranitidine; at eight weeks, the corresponding figures were 95, 82, and 53 percent. During the six-month follow-up period (without treatment), significantly more patients in the omeprazole groups were free of symptoms and ulcers than in the ranitidine group. We conclude that in the dose used, omeprazole is superior to ranitidine in the treatment of benign gastric ulcers.

We conducted a controlled trial to investigate the long-term effects of treatment with methylprednisolone and chlorambucil in patients with idiopathic membranous nephropathy. We have previously reported that after a mean of 31 months, treated patients did better. We now report the results of a longer follow-up. Eighty-one patients with proteinuria (greater than or equal to 3.5 g per day) and biopsy-proved membranous nephropathy were randomly assigned to receive either supportive therapy alone or a six-month course of corticosteroids alternated with chlorambucil (0.2 mg per kilogram of body weight per day) every other month. Methylprednisolone was first given intravenously in three pulses (1 g per day) and was then given orally (0.4 mg per kilogram per day) for 27 days. The patients were followed for 2 to 11 years (median, 5). Two patients in the control group and one in the treatment group died. At the last follow-up visit, 9 of 39 patients assigned to the control group (23 percent) and 28 of 42 patients assigned to the treatment group (67 percent) did not have the nephrotic syndrome. At five years there were more remissions of the nephrotic syndrome in treated patients than in controls (22 of 30 vs. 10 of 25; P = 0.026). Compared with base-line values, the mean reciprocal of the plasma creatinine level declined significantly in the control group (33 percent; P = 0.0002) but not in the treatment group (6 percent; P not significant). Plasma creatinine increased by 50 percent or more in 19 controls (49 percent) and in 4 treated patients (10 percent). We conclude that a six-month course of methylprednisolone and chlorambucil can bring about sustained remission of the nephrotic syndrome and help to preserve renal function in patients with idiopathic membranous nephropathy.