Acyclovir, a new antiviral agent, was compared to a placebo in a randomized double-blind trial of treatment for culture-proven herpes simplex virus infection after marrow transplantation. Patients received either intravenous acyclovir at 750 mg/m2 body surface area per day or a placebo for 7 days. Thirteen of 17 patients given acyclovir had a beneficial response as compared with two of 17 given the placebo (p less than 0.01). The duration of positive cultures was shorter among acyclovir recipients (3 versus 17 days, p less than 0.00005). Also shorter were the median days to resolution of pain (10 versus 16 days, p = 0.03), to crusting of lesions (7 versus 14 days, p = 0.01), and to total healing (14 versus 28 days, p = 0.03). No acyclovir toxicity was observed. Recurrent infection was common. Acyclovir provided significant antiviral and clinical efficacy without toxicity in highly immunosuppressed patients but had no effect on virus latency.

Streptococcus pneumoniae causes substantial morbidity and mortality. Incidence and severity are increased among populations with some chronic diseases. The currently available polyvalent polysaccharide vaccine induces antibody production among immunologically competent recipients against the 14 serotypes responsible for 80% of pneumococcal bacteremia in the efficacious in clinical trials with healthy young men in epidemic conditions and in patient with sickle cell anemia. Similar trials in two other high-risk populations had inconclusive results. Decisions on vaccine use now largely rest on indirect evidence of efficacy derived from knowledge of disease incidence, severity, and antibody response to vaccination among patient groups. Findings of a literature review suggest vaccinating high-risk patients immunologically competent to produce homotypic antibodies in response to vaccination with polysaccharide antigen, while continuing investigation of disease incidence, severity, serotype distribution, and immunologic response among high-risk groups and postmarketing surveillance efforts among all vaccinated patients.

We compared a 2-week course of 32 mg/d methylprednisolone with placebo in a double-blind crossover trial in 46 well-characterized patients with stable chronic obstructive pulmonary disease. Placebo and steroid trials were separated by 2 weeks when no tablets were given. Response was assessed by measuring forced expiratory volume in 1 second (FEV1.0). Placebo responses were normally distributed (mean, 0.8% change in FEV1.0; range, -30% to 33%). Six patients showed a greater than 50% increase of FEV1.0 in response to steroid; a seventh showed a 36% increase and an eighth, a 29% increase. Because of these patients the group as a whole showed a significantly greater FEV1.0 after steroid than after placebo. The eight steroid responders did not differ from nonresponders in age, sex, smoking history, or duration and intensity of symptoms including wheeze. Baseline lung function and eosinophilia of blood or sputum did not differ between the two groups. Patients who responded to steroids also responded to inhaled beta agonists: Acute bronchodilator response averaged 25% in steroid responders and 13% in nonresponders, a difference that was statistically significant although there was overlap between the two groups.

Laboratory tests are purported to affect patients even if they have no diagnostic values. We tested this hypothesis by measuring clinical outcomes of 176 patients thought clinically to have nonspecific chest pain. They were randomly allocated either to have a routine electrocardiogram and serum creatine phosphokinase tests (test group) or to have all diagnostic tests withheld (no-test group). Fewer patients in the tests group (20%) reported short-term disability after the index visit than patients in the no-test group (46%) (p = 0.001). Logistic discriminant analysis confirmed that the use of diagnostic tests was an independent predictor of recovery. Patients in the test group felt that care was "better than usual" more often (57%) than patients in the no-test group (31%) (p = 0.001). After the index visit, the two groups were equally worried about serious disease and equally sparing in their use of other medial care for chest pain.

Interaction between cimetidine and theophylline was studied in six male volunteers, who were randomly divided into two groups to eliminate temporal effects. The effect of cimetidine on theophylline elimination was immediate and progressed as cimetidine treatment was continued. Cimetidine prolonged theophylline half-life compared to that in control periods an average of 36.2% (range, 0 to 103%) on the first day of cimetidine exposure (p less than 0.05). Theophylline clearance was decreased an average of 18.5% (range, 4.9% to 36%), whereas theophylline volume of distribution was unchanged by cimetidine. After 8 days of cimetidine treatment at the usually recommended dosage, theophylline half-life further increased to 64.3% (range, 9% to 128%) of control values, whereas clearance declined an average of 30% (range, 5% to 50%) (p less than 0.01). Theophylline volume of distribution remained unchanged. Although cimetidine-theophylline interaction needs confirmation in a patient population, we advise caution when these agents are coadministered. Some adjustment in theophylline dosage may be needed in treated patients who are also given cimetidine, and these patients who are also given cimetidine, and these patients should be studied closely with theophylline serum concentration measurements and careful clinical assessments.

Fifty-two patients with nonlymphocytic leukaemia were studied during remission induction treatment in a randomized trial to ascertain the effect of prophylactic oral trimethoprim-sulfamethoxazole on infection and fever rate. A decrease in the total number of acquired infections was found (16 infections in the group given trimethoprim-sulfamethoxazole versus 31 in the control group, p less than 0.01). The number of patients without any infection in the trimethoprim-sulfamethoxazole group was 13 compared to only three in the control group (p less than 0.01). Patients in the trimethoprim-sulfamethoxazole group needed parenteral antibiotics during 33% of the days they were granulocytopenic compared to 61% of these days for patients in the control group. However, six of nine bacteriologically documented infections in the trimethoprim-sulfamethoxazole group were caused by resistant microorganisms compared to two out of 20 in the control group.

We conducted a prospective, controlled, randomized trial of oral trimethoprim-sulfamethoxazole treatment in patients with acute leukemia receiving consolidation chemotherapy. We followed 14 treatment patients during 33 episodes and 15 control patients during 34 episodes of granulocytopenia (less than 1000 granulocytes/mm3). We found no significant difference in the incidence of febrile episodes (13 in treatment group versus 14 in control group), hospitalizations to treat fever or infection (10 versus 12), number of documented infections (eight versus 10), number of septicemias (one versus two), or mean duration of hospital stay to treat fever or infection (8.9 versus 9.2 days) in the two groups. There was little colonization with organisms resistant to trimethoprim-sulfamethoxazole, including Candida, in either group. Prophylactic trimethoprim-sulfamethoxazole did not significantly reduce the incidence of fever, hospitalization, or infection in granulocytopenic patients during consolidation chemotherapy.

Eighty-five patients with advanced squamous carcinoma or adenocarcinoma of the lung were randomly assigned to receive vindesine with either high dose (120 mg/m2 of body surface area) or low dose (60 mg/m2) cisplatin. All patients had measurable disease and had not previously received chemotherapy. The response rate was similar with both treatments (43% complete and partial remission rate), but the high dose cisplatin regimen was superior to the low dose in median duration of response (12 versus 5.5 months; p = 0.05) and in median survival for responding patients (21.7 versus 10 months; p = 0.02). Myelosuppression was generally not a treatment problem; peripheral neuropathy and moderate azotemia were the major dose-limiting toxicities. With improved survival and response rates over those reported for conventional regimens, this combination of new agents supports the approach of new drug investigation in patients with lung cancer and the importance of the incorporation of active new agents into initial chemotherapy regimens.

We treated 289 men who had nongonococcal urethritis with minocycline, 100 mg once or twice daily for 7 to 21 days. After 21 +/- 7 days, urethritis persisted or recurred in 31 (27%) of 114 given 7-day therapy and only nine (8%) of 110 given 21-day therapy (p = 0.0005). However, by 49 +/- 14 days, the cumulative percent rate of failure was 31% for 7-day and 30% for 21-day therapy. Thus, 21-day therapy only delayed recurrence. The higher daily dosage did not improve outcome. Urethritis persisted or recurred in 19% of men with initial Chlamydia trachomatis infection. Among men without C. trachomatis, urethritis persisted or recurred in 32% with and 52% without Ureaplasma urealyticum infection (p = 0.03). At follow-up, 79% of cases of persistent or recurrent urethritis were culture negative for C. trachomatis and U. urealyticum. The cause of C. trachomatis-negative, U. urealyticum-negative nongonococcal urethritis, which was least responsive to minocycline therapy, remains uncertain.

The effect of digoxin on the right and left ventricular ejection fractions in 15 patients with pulmonary heart disease caused by severe chronic airflow obstruction was studied in a double-blind, randomized, placebo-controlled trial. All patients were ambulatory and had clinical features of right but not left ventricular dysfunction. Equilibrium radionuclide angiography showed reduced right ventricular ejection fraction in all patients and reduced left ventricular ejection fraction in four. After 8 weeks of digoxin treatment, the abnormal left ventricular ejection fractions were normal; right ventricular ejection fractions increased only in those patients who had had abnormal left ventricular ejection fractions. We conclude that in patients with pulmonary heart disease, the right ventricular ejection fraction is abnormal and improves with digoxin treatment only when the left ventricular ejection fraction also is initially abnormal.

A double-masked study was conducted to determine the efficacy and safety of randomly allocated chenodiol (chenodeoxycholic acid, 750 mg/d or 350 mg/d) or placebo administered for 2 years to 916 patients for dissolution of radiolucent gallstones. There was confirmed complete dissolution in 13.5% of patients (750 mg/d), 5.2% (375 mg/d), and 0.8% (placebo), p less than 0.0001. Partial (over 50%) or complete dissolution (by validated roentgenographic metrology) occurred in 40.8% (750 mg/d), 23.6% (375 mg/d), and 11.0% (placebo), p less than 0.0001. Dissolution occurred more frequently in women, thin patients, or patients with small or floating gallstones or serum cholesterol greater than or equal to 227 mg/dL. Clinically significant hepatotoxicity occurred in 3% of patients (750 mg/d), 0.4% (375 mg/d), and 0.4% (placebo), p less than 0.007, and always was reversible biochemically. Elevations of 10% or more of serum cholesterol, mostly low-density lipoproteins, occurred in 85.2% of patients (750 mg/d), 82.8% (375 mg/d), and 67.0% (placebo), p less than 0.001. Chenodiol, 750 mg/d for up to 2 years, is appropriate therapy for dissolution of gallstones in selected patients who are informed of the risks and benefits.

A randomized, double-blind trial of a psyllium preparation was initiated in 77 patients with painful irritable bowel syndrome. Sixty-patients finished and submitted symptom data for 8 weeks while taking placebo (n = 34) or psyllium (n = 26). Increase in normal stools and decrease in pain severity (p less than 0.05) occurred equally in both groups. Subjective improvement was reported by 24 of 34 patients on placebo and 20 or 26 on psyllium (p greater than 0.05). Five symptom variables were significantly correlated (p less than 0.05) with patient's subjective global assessment (R = 0.64). Discriminant analysis of Minnesota Multiphasic Personality Inventory variables yielded overall rates of correct prediction of 66.1% for whether patients got "much better" and 77.9% for whether they voluntarily dropped from the study. A major placebo effect occurs in patients with painful irritable bowel syndrome and is probably responsible for the efficacy of psyllium. Personality factors influence the magnitude of therapeutic response and whether patients discontinue treatment within 8 weeks.

Dichloromethylene diphosphonate (Cl2MDP), an inhibitor of osteoclast function, was evaluated for its ability to lower the serum and urinary calcium in 14 patients with primary hyperparathyroidism. The study was double-blind, placebo-controlled, and cross-over in design. All patients received 12 weeks of Cl2MDP (1600 mg daily) and 12 weeks of placebo in a randomized sequence. The average serum calcium was lowered by Cl2MDP from 11.5 +/- 0.1 mg/dL to 10.8 +/- 0.2 mg/dL (p less than 0.001). In the 3-month follow-up after drug administration, the average serum calcium (11.0 +/- 0.2 mg/dL) remained significantly below pretreatment levels (p less than 0.01). The reduction in serum calcium was accompanied by a significant decline in the urinary hydroxyproline excretion from 37 +/- 3 to 28 +/- 2 mg/g creatinine (p less than 0.01) and by a 40% reduction in the average urinary calcium excretion from 185 +/- 29 to 113 +/- 23 mg/g creatinine (p less than 0.01). Administration of Cl2MDP was not associated with any significant changes in parathyroid hormone levels or in urinary cyclic adenosine monophosphate excretion. No side effects were observed. We conclude that Cl2MDP lowers the serum and urinary calcium in patients with primary hyperparathyroidism.

A complete remission rate of 82% was obtained in a group of 68 patients with acute myelogenous leukemia treated with a high-dose induction chemotherapy (TAD) consisting of 7-day courses of 6-thioguanine, cytarabine, and daunorubicin. The patients who achieved remission received intensive consolidation chemotherapy and were randomized to receive maintenance chemotherapy with or without immunotherapy. Median remission duration was 13 months and median survival, 21 months. Neither central nervous system prophylaxis nor the addition of immunotherapy to the maintenance regimen prolonged remissions or improved survival. Age, sex, and subclassification of acute myelogenous leukemia had no effect on the remission rate or survival. These data indicate that a large proportion of patients with acute myelogenous leukemia can achieve remission with intensive induction chemotherapy. Attempts to prolong remission have been less successful.

Forty-six noninfected patients undergoing induction chemotherapy for acute nonlymphocytic leukemia were randomized to receive (25 patients) or not to receive (21 control patients) prophylactic granulocyte transfusions when their granulocyte count fell below 0.5 X 10(9)/L. Septicemia was less frequent in the patients who received transfusions (two in 25 patients) than in the control patients (five in 21 patients), but this difference was not statistically significant (p = 0.28). Moreover, pneumonia was more frequent among the transfused patients (12 in 25 patients versus two in 21 patients, p = 0.01). There were no significant differences between the two groups in the frequency of other documented infections, the achievement or duration of remission, or survival. Recipients of prophylactic granulocyte transfusions had a higher prevalence of cytomegalovirus infections (13 in 21 patients versus five in 19 patients, p = 0.03). These results suggest that prophylactic granulocyte transfusions have no statistically significant effect on the frequency of septicemia or other infections, do not enhance remission rates or survival, and are associated with an increased risk for pulmonary complications and cytomegalovirus infections.

To determine whether semiquantitative glucose measurements of spot urine specimens accurately reflect prevailing plasma glucose levels, we compared reported levels from 400 second-voided urines to simultaneous plasma determinations from 246 adult diabetics. Quantitative urine levels and plasma glucose levels correlated. However, when semiquantitative urinary determinations were compared to plasma glucose stratified into 0 to 149, 150 to 199, and greater than 200 mg/dL, 75% of the urine samples associated with plasma levels from 150 to 199 mg/dL were negative by Diastix, and 16.5% of samples negative by Diastix were in the 200+ mg/dL plasma range. Only 9% of samples from 0 to 149 mg/dL showed any positive Diastix readings. Because of the low sensitivity of semiquantitative methods, we fell that, except for detection of marked hyperglycemia, spot urine glucose determinations are inadequate as the sole means of clinical assessment for management of diabetic patients. Home glucose monitoring may be a better alternative for follow-up of these patients.

The judicial and executive branches of the federal government, motivated by emotionalism, political pressure, and a self-appointed need to placate the National Cancer Institute, have reached a decision on laetrile that weakens the legal protection of the general public. Recent approval of clinical trials of laetrile by the Food and Drug Administration was not consistent with policies adopted earlier, nor was it warranted by federal court decisions.

We treated 289 men with nongonococcal urethritis in a randomized, double-blind study with minocycline, 100 mg once or twice daily for 7 or 21 days. Ureaplasma urealyticum was isolated before treatment from 167 (58%). The pretherapy isolates from 82 men re-examined 6 to 8 days after initiation of treatment were viable. In six (7%) isolates were resistant to 256 microgram/mL or more of tetracycline. Tetracycline resistance was significantly correlated with persistence of U. urealyticum and persistence of nongonococcal urethritis during treatment. Recurrence of nongonococcal urethritis after initial resolution and recurrence of U. urealyticum after interim negative cultures were not correlated with tetracycline resistance of U. urealyticum. Thus tetracycline-resistant strains of U. urealyticum are a cause of persistent but not of recurrent nongonococcal urethritis.

Antimicrobial prophylaxis prevents recurrent urinary tract infections in susceptible women, but its cost effectiveness has not been studied. In a recent placebo-controlled trial of urinary prophylaxis, we also assessed cost effectiveness using a decision analysis model. In our hospital the direct cost of 1 patient year of urinary prophylaxis approximates the cost of treating one episode of cystitis. In women with a baseline infection rate of three per patient year, the annual cost of prophylaxis ($85.82) was less than treatment of acute episodes of infection ($392.30). Sensitivity analyses showed that in women with three infections per year, prophylaxis became cost effective when charges per episode exceeded $42.00. In women with frequent episodes of cystitis, prophylaxis will be cost effective in most practice settings.