A multicenter trial compared intermittent positive pressure breathing (IPPB) therapy with compressor nebulizer therapy in 985 ambulatory patients with chronic obstructive pulmonary disease. A bronchodilator aerosol solution was administered with both treatments, the only difference being the positive pressure applied by IPPB. Patients were randomly assigned to treatment and closely followed by monthly home and quarterly clinic visits for an average of 33 months. Compliance with treatment, lung function, and quality of life were evaluated at regular intervals during follow-up, and records were kept of hospitalizations and vital status. Treatment compliance was disappointing; only half of the patients used their devices the prescribed amount of time. There was no statistically significant difference between the treatment groups in mortality, rate and duration of hospitalizations, or change in lung function or life quality with time, overall or for clinically relevant subgroups. We saw no advantage of IPPB over compressor nebulizer therapy in this large group of patients, and conclude that, if an advantage exists, it must be marginal.

The efficacy of corticosteroid treatment in the prophylaxis of the fat embolism syndrome was evaluated in a prospective, randomized, double-blind study of high-risk patients with long-bone fractures. Using a set of objective diagnostic criteria, we saw a significant difference in the incidence of the syndrome between corticosteroid- (0 of 21) and placebo-treated patients (9 of 41) (p less than 0.05). There were no complications related to corticosteroid treatment. No routine laboratory or physical findings reliably predicted the development of the fat embolism syndrome except petechial rash, which occurred only in 5 placebo-treated patients who developed the syndrome. Complement activation was present in all patients studied who had the syndrome (5 of 27) but also in many patients who did not meet our diagnostic criteria, suggesting a multifactorial cause. These data support the prophylactic value of corticosteroid treatment in patients at high risk for the fat embolism syndrome, particularly if several unfavorable predictors are present.

Sham and real trials of peritoneal dialysis were carried out in a double-blind crossover study design to test the efficacy of peritoneal dialysis as a treatment for psoriasis. The criteria for patients included having severe plaque-type psoriasis unresponsive to all conventional therapy including methotrexate. Patients were randomly assigned to 4 weeks of sham or real dialysis, 8 weeks of observation, 4 weeks of alternative real or sham dialysis and 8 weeks of observation. Topical therapy was continued during the trial. Real dialysis was done for 48 hours weekly with 1.5-hour cycle times and 2-litre exchanges by machine. Sham peritoneal dialysis was done recycling the same 2 litres of 1.5% continuous ambulatory peritoneal dialysis fluid with 1.5-hour cycle times for 48 hours weekly. After real dialysis, two patients completely cleared, two patients had greater than 75% clearing, and one patient had no substantial response. None of the five patients had a response to the sham dialysis procedure (p less than 0.01).

From 1969 to 1975, 53 patients with lupus nephritis took part in randomized trials comparing prednisone, oral azathioprine plus low-dose prednisone, and oral cyclophosphamide plus low-dose prednisone. After a mean follow-up of 85 months, cyclophosphamide appears marginally superior to prednisone for maintaining renal function (p = 0.03) and preventing end-stage renal failure (p = 0.07). Chronic change shown by renal biopsy assessed by a chronicity index was found useful in predicting renal function outcomes and response to immunosuppressive therapy. Three of 21 patients with a low chronicity index and 9 of 10 patients with a high chronicity index doubled their serum creatinine (p less than 0.00003). The probability of renal functional deterioration was not different among the treatments studied. However, in 14 patients with an intermediate chronicity index, 1 of 11 patients treated with azathioprine or cyclophosphamide doubled the serum creatinine level whereas all 3 patients treated with prednisone have progressed to end-stage renal failure (p = 0.005). The study suggests that single-drug oral immunosuppressive treatment combined with prednisone is most beneficial in lupus patients with intermediate chronic change shown by renal biopsy.

Thirty-one patients with first episodes of genital herpes were randomized in a double-blind fashion to intravenous treatment with saline placebo or acyclovir, 5 mg/kg body weight at 8-hour intervals, for 5 days. The median duration of viral shedding from genital lesions after the onset of therapy was significantly shorter for patients given acyclovir (2 days) than for those given placebo (13 days), p less than 0.001. Viral shedding from the pharynx, cervix, urethra, and urine were also shorter in acyclovir-treated patients. (p less than or equal to 0.01 for each comparison). Local and systemic symptoms were shortened by a mean of 5 days and healing of genital lesions by a mean of 12 days in acyclovir-treated patients. (p less than 0.01). Complications during treatment, such as extragenital lesions or urinary retention requiring catheterization, developed in four patients given placebo and in none given acyclovir. (p less than 0.05). Intravenous acyclovir substantially decreases the symptoms, duration of lesions, and complications of primary genital herpes.

The clinical efficacy of clindamycin was compared with that of penicillin in a randomized study of the treatment of community-acquired putrid lung abscess. After starting therapy, patients treated with clindamycin had a shorter febrile period and fewer days of fetid sputum than patients treated with penicillin (mean 4.4 versus 7.6 days and 4.2 versus 8.0 days, respectively, p less than 0.05). Four of 20 patients treated with penicillin had clinically significant pulmonary or pleural extension of their infection within 10 days after starting therapy; this was not found in any of 19 patients treated with clindamycin (p less than 0.05). Penicillin treatment failed in two additional patients after 20 days of therapy. Within 1 month after treatment, 1 of 4 patients given penicillin for 3 weeks had relapse, but none of the 13 patients given clindamycin for 3 or 6 weeks, and none of the 5 patients given penicillin for 6 weeks had relapse. Overall, only 8 of 15 patients treated with penicillin who could be followed to the end of the study were cured, whereas all 13 patients treated with clindamycin who could be followed were cured (p less than 0.01). These results suggest that penicillin may not be optimal therapy for anaerobic lung abscess.

In a randomized placebo-controlled double-blind trial, we compared flecainide to quinidine for treatment of ventricular ectopic depolarizations in 19 patients. The mean percent suppression of total ventricular ectopic depolarizations was 95% for flecainide and 56% for quinidine (p less than 0.05). A greater than 80% reduction of total ventricular ectopic depolarizations was obtained in eight of nine patients given flecainide and in five of ten patients given quinidine (p = 0.09). After the randomized protocol, the patients who had received quinidine were given flecainide; 9 of the 10 patients had greater than 80% reduction of total ventricular ectopic depolarizations. Flecainide produced 100% suppression of nonsustained ventricular tachycardia and 99.5% suppression of paired ventricular depolarizations. Flecainide prolonged the PR and QRS intervals; quinidine prolonged the PR and JTC intervals. Side effects were commoner with quinidine than flecainide (p = 0.06). Three other patients failed to complete the protocol because of serious adverse experiences.

In an effort to prevent cytomegalovirus infection among seronegative patients having marrow transplants, a globulin with high antibody levels against cytomegalovirus was given before and for 11 weeks after transplantation in a randomized trial. Among 36 patients who received no prophylactic granulocyte transfusions, globulin recipients had significantly fewer infections than controls (2 of 17 versus 8 of 19, p = 0.05 by Fisher's exact test and p = 0.03 by Mantel-Cox test). Conversely, infection rates were high and unchanged by globulin use among patients who received granulocytes from seropositive donors (7 of 8 recipients versus 6 of 7 controls). The lack of effect of the globulin among patients receiving transfusions of granulocytes from seropositive donors may suggest that the dose of antibody was insufficient or that antibody is ineffective against virus transmitted in granulocytes. We conclude that cytomegalovirus infection can be prevented by immunoprophylaxis in seronegative patients having marrow transplants who are not given granulocyte transfusions.

From a group of 108 female patients with measurable and/or evaluable metastatic breast carcinoma, 52 were randomized to receive tamoxifen and 56 to receive tamoxifen and fluoxymesterone. The fluoxymesterone dose, given orally twice a day, was 7 mg/m2 body surface area. The tamoxifen dose per patient, also given orally twice a day, ranged from 2 to 100 mg/m2 body surface area. Eighty-five percent of the patients had received previous chemotherapy and 60% previous hormone therapy. The complete and partial remission rate was better with the tamoxifen and fluoxymesterone regimen (p = 0.016), with remission rates of 15% for tamoxifen alone and 38% for the combination. The tamoxifen and fluoxymesterone regimen appeared to have higher remission rates in all subsets of pretreatment variables. Duration of remission with each regimen was similar, but the overall time to treatment failure for tamoxifen and fluoxymesterone was longer than for tamoxifen alone (180 versus 64 days, p = 0.01). Median survival with the combination was 380 days compared to 330 days for tamoxifen. No significant dose-response relationships emerged. Side effects were not different between dose levels or regimens except for the androgen effects in the tamoxifen and fluoxymesterone combination. These results suggest that there is no major dose-response effect for doses ranging from 2 to 100 mg/m2 body surface area given twice daily in this largely (94%) postmenopausal pretreated patient group, and that the tamoxifen and fluoxymesterone regimen is superior to tamoxifen alone.

The efficacy of bicozamycin, a poorly absorbable antibiotic, in the treatment of acute diarrhea was assessed in a prospective, double-blind study of 140 adults from the United States visiting Guadalajara, Mexico. Patients randomly received bicozamycin (500 mg orally four times daily) or placebo for 3 days. The mean duration of illness was shorter in the bicozamycin than the placebo treatment groups for patients with diarrhea due to Shigella (37 versus 96 hours; p = 0.01), toxigenic Escherichia coli (31 versus 60 hours; p = 0.003), and unknown pathogens (18 versus 41 hours; p = 0.02). Cramps were significantly relieved by bicozamycin in all patients. Treatment failed in significantly fewer patients treated with bicozamycin than those treated with placebo when diarrhea was associated with Shigella, Salmonella or toxigenic E. coli. Bicozamycin was well tolerated and appears to be effective therapy for acute travelers' diarrhea of diverse causes. These data show the value of an antibiotic in the therapy of toxigenic E. coli infection and indicate a need to reevaluate the clinical dictum that nonabsorbable antibiotics are ineffective against invasive enteropathogens.

We assessed serially the bone mineral loss in 37 premenopausal women for 24 months after oophorectomy and determined the dose-response for conjugated estrogen therapy in preventing this loss. Spinal cancellous bone was measured by quantitative computed tomography and measurement of appendicular cortical bone by radial photon absorptiometry and metacarpal radiogrammetry. For the placebo and low-dose treatment groups, the mean annual bone mineral losses were 7% to 9% from the vertebral spongiosum and 1% to 3% from the peripheral cortex. The correlation between axial and appendicular loss was weak (r = 0.581), precluding a reliable estimate of spinal loss from peripheral measurements. For the maximal-dose group (0.6 mg/d), the mean annual bone mineral losses were less than 0.5% from the axial and appendicular sites, and were not significant. The results indicate that spinal quantitative computed tomography provides a highly sensitive measurement of bone mineral loss after oophorectomy, that bone mineral loss is five- to sevenfold greater from the spinal spongiosum than from the appendicular cortex, and that conjugated estrogen in doses of less than 0.6 mg/d are inadequate to prevent the vertebral mineral loss.

Patients with granulocytopenia (granulocyte count less than 0.5 x 10(9)/L) and a documented infection were randomized to receive or not to receive daily granulocyte transfusions in addition to antimicrobial therapy. Thirty-four of 47 control patients responded to therapy compared to 30 of 48 transfused patients (type 2 error, pneumonia, or a soft tissue infection, respective response rates for the control and transfused patients were 11 of 11 and 11 of 16 (Yates' corrected chi-squared test, p = 0.12). Response rates for patients with gram-negative septicemia were lower but were influenced by recovery of bone marrow function. Eleven of 12 control patients and seven of seven transfused patients with recovery of marrow function survived the gram-negative septicemia. In contrast, 12 of 24 control patients and 12 of 25 transfused patients survived gram-negative septicemia and persistent granulocytopenia (type 2 error p = 0.13). Two thirds of all fatal infections were associated with an underlying disease refractory to medical therapy. Therapeutic granulocyte transfusions had no substantial benefit over optimal antimicrobial therapy alone in managing infected patients with granulocytopenia.

Single (nafcillin for 6 weeks) and combined (nafcillin for 6 weeks plus gentamicin for 2 weeks) drug regimens were compared in two separate multicenter prospective randomized trials. Forty-eight parenteral drug addicts and 30 nonaddicts with clinically and bacteriologically documented Staphylococcus aureus endocarditis were studied. In the addicts, combined therapy effected a more rapid mean clinical response (defervescence and normalization of leukocyte count) and a reduced duration of bacteremia in patients with right-sided endocarditis. In the nonaddicts, combined therapy effected more rapid clearance of bacteremia, but was associated with a higher incidence of azotemia. The addition of gentamicin did not alter morbidity or mortality in either group.

A randomized, double-blind, vaccine/placebo trial of the Merck 20-micrograms hepatitis B virus (HBV) vaccine was done among 1402 homosexual men attending venereal disease clinics in five American cities. Vaccination was followed by only minimal side effects. Two doses of vaccine induced antibody in 80% of vaccine recipients. A booster dose 6 months after the first dose induced antibody in 85% of recipients and markedly increased the proportion of recipients who produced high antibody titers. The incidence of HBV events was markedly less in the vaccine recipients compared to that in the placebo recipients (p = 0.0004). Between month 3 and 15 after the first dose, 56 more significant HBV events (hepatitis, or hepatitis B surface antigen positive, or both) occurred in the placebo group while only 11 occurred in the vaccine group. Ten of the 11 HBV events in the vaccine recipients occurred in hypo- or nonresponders to the vaccine. This vaccine appears to be safe, immunogenic, and efficacious in preventing infection with hepatitis B virus.

The treatment of cervical Chlamydia trachomatis infection in nonpregnant women was evaluated in a double-blind randomized study. Objective criteria were used to assess the response of cervicitis to therapy. Fifty patients were treated with tetracycline hydrochloride, 500 mg orally four times daily, and 50 patients were treated with rosaramicin, 250 mg orally four times daily, both for 7 days. Both agents were highly effective in eradicating C trachomatis. Both produced significant improvement in objective signs of cervicitis: eliminating mucopurulent endocervical discharge and edema of ectopy, and decreasing the clinical severity score of cervicitis. This trial shows that the 1-week course of tetracycline hydrochloride currently recommended for treatment of chlamydial urethritis in men is also highly effective for the treatment of chlamydial cervical infection in women. Rosaramicin, a macrolide antibiotic, was equally effective but produced a higher rate of gastrointestinal side effects.

We conducted a double-blind, randomized, placebo-controlled trial in 40 patients to evaluate the need for antibiotics in acute exacerbations of chronic bronchitis. All patients were sufficiently ill to require hospitalization although none needed ventilatory support; the presence of pneumonia was excluded. Treatment consisted of bronchodilators, corticosteroids, and either tetracycline, 500 mg, or placebo by mouth every 6 hours for 1 week. Arterial blood gases, spirometric tests, bacteriologic evaluation of sputum, and patient and physician evaluation of the severity of illness were assessed at the beginning and end of the study. All patients improved both symptomatically and by objective measures of lung function. At the end of the study period there were no differences between those patients receiving tetracycline and those receiving placebo. We conclude that antibiotic therapy is not needed in moderately ill patients with exacerbations of chronic bronchitis.

The effects of passive immunization on cytomegalovirus infection and interstitial pneumonia in marrow transplants were evaluated in a randomized, controlled trial. Twenty-four patients received cytomegalovirus immune plasma before and after transplantation, and 24 patients were controls. Although the incidence of cytomegalovirus infection was similar in the control and plasma groups, symptomatic infection (12 of 24 versus five of 24, p = 0.07) and interstitial pneumonia (11 of 24 versus five of 24, p = 0.12) occurred less frequently in the group receiving plasma. Cytomegalovirus infection occurred in 11 of 13 recipients of leukocyte transfusions and in 16 of 35 patients not given leukocyte transfusions (p = 0.02). Among patients not given leukocyte transfusions, the incidence of cytomegalovirus infection was similar in the control and plasma groups, but symptomatic infection (eight of 18 versus one of 17, p = 0.03) and interstitial pneumonia (nine of 18 versus one of 17, p = 0.01) were significantly less in the group receiving plasma. These results suggest that passive immunization modifies cytomegalovirus infection in humans and prevents interstitial pneumonia in marrow transplants especially when leukocyte transfusions are not used.

Forty-one patients with systemic lupus erythematosus and glomerulonephritis were studied in a randomized drug trial. Thirteen patients received prednisone only (Group 1), 16 received oral cyclophosphamide and oral azathioprine (1 mg/kg body weight . d of each initially) (Group 2), and 12 were given boluses of intravenous cyclophosphamide (0.5 to 1.0 g/m2 body surface area every 3 months) (Group 3). The mean observation period was 42 months (range 1 to 6.5 years). Renal function deteriorated in four of 12 patients in Group 1 and three of 27 patients in Groups 2 and 3 (p = 0.114). By life-table analysis, 86% of the entire group survived 5 years after entry to the study. Marked hypertension, fluctuating changes in serum creatinine, erratic changes in levels of antibody to DNA, reduced C3 levels, increasing proteinuria or sustained hematuria, and flares of extrarenal disease activity occurred more commonly in Group 1. Infectious complications were not commoner in Groups 2 and 3. We conclude that any marginal benefits produced by the programs tested cannot be shown in this class of patients without markedly increasing the sample size. Our current studies involve more vigorous treatment of patients with more acute disease and less treatment during prolonged periods of relatively good health.

Cimetidine reduced liver blood flow and the systemic clearance of drugs, such as propranolol, that are highly extracted by the liver. In a randomized placebo-controlled study, we examined the influence of cimetidine, 300 mg four times daily for 1 d, on the disposition of lidocaine, 1 mg/kg body weight by a 10-minute intravenous infusion. Cimetidine reduced the systemic clearance of lidocaine from 766 +/- 50 mL/min to 576 +/- 47 mL/min (p less than 0.05); the apparent volume of distribution at steady-state and the degree of plasma protein binding of lidocaine also were decreased. Five of the six subjects noted lidocaine toxicity during the cimetidine infusion in contrast to one subject on the placebo day. The peak lidocaine concentration (mean +/- SE) was 50% +/- 10% higher when subjects received cimetidine. This study provides additional evidence that the effect of cimetidine on the elimination of other drugs has multiple factors, and shows a previously unrecognized mechanism, involving altered initial drug distribution, whereby the interaction of cimetidine with other drugs may cause toxicity.

Ten patients with diabetic gastroparesis were selected for a randomized, double-blind, controlled trial of metoclopramide. Each patient had longstanding insulin-requiring diabetes mellitus and symptoms of gastric stasis. The patients were evaluated for the symptoms of gastric stasis and radionucleotide gastric emptying was measured before the patients entered the study and after they were given either metoclopramide or placebo treatment. Metoclopramide, 10 mg orally, stimulated an increase in the rate of gastric emptying (56.8% +/- 7.4%) in contrast to the response to placebo (37.6% +/- 7.7%) (p less than 0.01). The overall symptoms and symptoms of vomiting were markedly reduced during metoclopramide treatment in contrast to those during placebo treatment. Before the study five patients were constipated (less than three bowel movements per week); during metoclopramide treatment the patients' bowel habits were improved. There was a poor correlation between improved gastric emptying and decreased symptoms. Metoclopramide may improve symptoms of diabetic gastric stasis through two mechanisms: its peripheral effect on gastric smooth muscle, which increases gastric emptying; and its central effects on the chemoreceptor vomiting zone, which decrease nausea.