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.

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.

A blood lipid-lipoprotein elevating effect of the diuretics hydrochlorothiazide and chlorthalidone in mildly hypertensive men has been established by a cross-over, randomized controlled trial, confirming previous clinical observations. Compared to baseline, plasma total cholesterol increased 6% and 8% and triglycerides 17% and 15% under treatment with hydrochlorothiazide and chlorthalidone, respectively. A cholesterol-lowering diet largely prevents this increase. Because these effects may be long-lasting and may cancel part of the potential benefit of blood pressure control in mildly hypertensive patients, with thiazide diuretics attention should be given to prescription of a cholesterol-lowering diet and to periodic monitoring of blood lipid levels. Different antihypertensive agents might be considered in patients with elevated blood lipid levels. Other antihypertensive agents currently in use need to be studied for potential effects on lipid metabolism.

Ten patients with rheumatoid arthritis unresponsive to conventional therapy participated in a double-blind cross-over trial in which they randomly received either a "pulse" or 1 g of methylprednisolone or placebo, intravenously, once a month for 6 months. Both the drug-first and placebo-first groups had the same mean American Rheumatism Association functional classification, 2.5. During the study patients on methylprednisolone "pulses," compared to placebo, showed significantly better mean tender-joint counts, walking times, and grip strength (p < 0.05). The drug-treated patients also had significantly lower levels of immune complexes (p < 0.01) and IgG (p < 0.01). Effects could still be measured an average of 2.9 +/- 0.4 months after the last dose of methylprednisolone. No significant side effects were noted during the therapy. Despite these findings, "pulse" methylprednisolone did not appear to significantly retard radiologic progression of the arthritis.

The effectiveness of verapamil in controlling ventricular rate was evaluated in 20 patients with atrial fibrillation or flutter with a rapid ventricular response (Group 1) and 30 patients with paroxysmal supraventricular tachycardia (Group 2). In Group 1 low-dose verapamil (0.075 mg/kg body weight) decreased the mean ventricular rate from 146 to 114 beats/min (p < 0.01) compared to a decrease of 145 to 132 beats/min (p < 0.01) after placebo. In Group 2, 14 of 29 patients converted to sinus rhythm after low-dose verapamil, nine of 15 after high-dose verapamil (0.15 mg/kg body weight), and one of 24 after placebo (p < 0.01). We conclude that verapamil results in a clinically significant slowing of the ventricular response in atrial fibrillation or atrial flutter and is superior to placebo for conversion of paroxysmal supraventricular tachycardia to sinus rhythm.

We ascertained the effectiveness of oral bethanechol on symptoms and endoscopic evaluation of reflux esophagitis in a double-blind controlled study. Forty-four patients were treated with either 25-mg bethanechol tablets or placebo, each given four times daily for 4 weeks, in addition to conventional medical therapy. Both therapies significantly decreased symptoms as well as endoscopic lesions; however, endoscopic improvement was significantly better in the bethanechol-treated group. Bethanechol therapy resulted in complete endoscopic healing in 10 of 22 cases, whereas only three of 22 patients in the control group had such healing. No worsening of endoscopic lesions was seen in either group. Our study indicates that bethanechol is an effective drug offering advantages over conventional antacid therapy in the treatment of reflux esophagitis.

Twelve patients with chronic mucocutaneous candidiasis were assigned by random allocation to a 6-month course of treatment with ketoconazole or placebo in a double-blind trial. All six recipients of ketoconazole had remission of symptoms and virtually complete regression of mucosal, skin, and nail lesions, whereas only two of the six receiving placebo had even temporary mucosal clearing, and none had improvement of skin or nail disease. The clinical outcome in the ketoconazole-treated group was significantly more favorable (p = 0.001) than in the placebo-treated group. The six patients receiving placebo in the controlled trial were then treated with ketoconazole in an open trial, and all responded favorably. Hepatitis, probably drug induced, developed in one patient after 6 months of treatment but proved to be mild and reversible. Oral ketoconazole is an effective treatment for chronic mucocutaneous candidiasis.

We evaluated efficacy and mechanisms of the antiarrhythmic action of verapamil in 20 patients with sustained supraventricular tachycardia. Two patients had sinus nodal re-entrant tachycardia, nine atrioventricular (AV) nodal re-entrant tachycardia, and nine AV reciprocating tachycardia associated with the Wolff-Parkinson-White syndrome. The study design comprised a double-blind, randomized, cross-over phase using a 0.075 mg/kg dose of verapamil versus placebo and an open-label phase using a 0.15 mg/kg dose of verapamil. The overall results of both phases showed that 15 of 19 patients converted to sinus rhythm with verapamil while only one of 16 converted to sinus rhythm with placebo. The effective plasma verapamil concentration measured 123 +/- 40 ng/mL (mean +/- SD). Verapamil suppressed sinus nodal and AV nodal re-entry but exerted no selective depression between fast and slow AV nodal pathways. It had no significant effect on accessory AV bypass tract but was effective in terminating AV reciprocating tachycardia by its depressive action on the AV node.

Patients randomized to receive or not to receive prophylactic leukocyte transfusions were evaluated prospectively for serologic, histologic, and cultural evidence of cytomegalovirus infection. Recipients of prophylactic leukocyte transfusions and control subjects were similar with regard to age, sex, underlying disease, immunosuppressive therapy, and number of other transfusions. The recipients of prophylactic leukocyte transfusions (mean, 23.1) had significantly more cytomegalovirus infections (19 of 31 versus seven of 27, p = 0.01) than did control patients receiving no leukocytes or only therapeutic leukocyte transfusions (mean, 3.8). Twenty-seven of 66 donors of leukocytes were seropositive for cytomegalovirus complement-fixation antibody, but cytomegalovirus was not isolated from any of 62 leukocyte transfusions cultured for virus. These results are consistent with the hypothesis that latent cytomegalovirus may be present in leukocytes of blood donors with previous cytomegalovirus infection and after transfusion may be activated to produce active cytomegalovirus infection.

The effect of oral charcoal on idiopathic generalized pruritus in 11 stable patients undergoing maintenance hemodialysis was compared to that of placebo dextrose in a controlled, double-blind, cross-over study. Contrasted to placebo, charcoal, 6 g daily for 8 weeks, relieved pruritus subjectively in all but one patient (P = 0.01). Symptomatic relief from pruritus coincided with objective resolutions of active, scratch-induced skin lesions (P = 0.03). No significant alterations were noted in the serum concentrations of standard laboratory variables, including lipids, alkaline phosphatase, phosphorus, or calcium, during treatment with either charcoal or placebo. No adverse effects from the charcoal were noted during the study.

We tested the relative efficacy of bronchodilators delivered in aerosol and in oral form in 17 patients with asthma in a double-blind randomized sequence. Treatment consisted of a 20-mg tablet of metaproterenol sulfate, five puffs of metaproterenol aerosol (0.65 mg in each puff for a total of 3.25 mg) administered 20 minutes apart between puffs, a combination of both, and placebos. Bronchodilator response measured by forced expiratory volume in 1 second (FEV1) was significantly greater on the aerosol and the combined regimen than on the oral and placebo regimen. The combined regimen produced a greater bronchodilator response than the aerosol alone, but the difference was not significant. Side effects were frequent after oral medication but absent after the aerosol. Sequential inhalation of aerosol is the preferred route of administration of adrenergic bronchodilator drugs in asthma.

At six centers, 203 patients with hypoxemic chronic obstructive lung disease were randomly allocated to either continuous oxygen (O2) therapy or 12-hour nocturnal O2 therapy and followed for at least 12 months (mean, 19.3 months). The two groups were initially well matched in terms of physiological and neuropsychological function. Compliance with each oxygen regimen was good. Overall mortality in the nocturnal O2 therapy group was 1.94 times that in the continuous O2 therapy group (P = 0.01). This trend was striking in patients with carbon dioxide retention and also present in patients with relatively poor lung function, low mean nocturnal oxygen saturation, more severe brain dysfunction, and prominent mood disturbances. Continuous O2 therapy also appeared to benefit patients with low mean pulmonary artery pressure and pulmonary vascular resistance and those with relatively well-preserved exercise capacity. We conclude that in hypoxemic chronic obstructive lung disease, continuous O2 therapy is associated with a lower mortality than is nocturnal O2 therapy. The reason for this difference is not clear.

We studied ventilatory, hemodynamic, and subjective responses to different plasma theophylline concentrations in 10 patients with "irreversible" airflow obstruction. Subjects received theophylline at doses that produced low (9.0 to 12.5 micrograms/mL) and high (17 to 22 micrograms/mL) peak plasma concentrations; subjects also received placebo. A significant (P less than 0.05) dose-related difference in pulmonary function was observed between each treatment. The mean maximal increase in forced expiratory volume at 1 second over placebo was 21.3% for high-dose theophylline and 6.0% for low dose. Both treatments were well tolerated with respect to hemodynamic changes and other adverse effects. Despite improved findings in pulmonary function tests patients were unable to distinguish either treatment from placebo in terms of improvement in breathlessness.

To study once-daily antimicrobial prophylaxis of urinary tract infections, we gave trimethoprim-sulfamethoxazole (40 mg/200 mg), trimethoprim (100 mg), nitrofurantoin macrocrystals (100 mg), or placebo to 60 women for 6 months. During prophylaxis, infections per patient year were comparable in the groups receiving trimethoprim (0.0), nitrofurantoin (0.14), or trimethoprim-sulfamethoxazole (0.15) and occurred less frequently than in patients receiving placebo (2.8; P less than 0.001, placebo versus each drug regimen). The effectiveness of prophylaxis was limited to the 6 months that antimicrobials were given, and infections were more likely to develop after prophylaxis in women who had three or more infections in the year before prophylaxis (P less than 0.005). Further, women whose preprophylaxis infection was positive for antibody-coated bacteria were more likely to have same-strain relapse when infections recurred (P = 0.001). Emergence of trimethoprim-resistant Escherichia coli was rare, but non-E. coli infections occurred more often after prophylaxis (P less than 0.05). Prophylaxis with these drugs is effective, well tolerated, and did not produce emergence of resistant E. coli but may predispose to non-E. coli urinary tract infections after its discontinuation.

To evaluate the role of corticosteroids as treatment for acute exacerbations of chronic obstructive pulmonary disease, we conducted a double-blind, randomized, placebo-controlled trial in 44 consecutive patients with chronic bronchitis and severe airflow obstruction. All were hospitalized with acute respiratory insufficiency from acute bronchitis. Patients with asthma, atopy, or pneumonia were excluded. Treatment consisted of intravenous aminophylline, inhaled isoproterenol, antibiotics, and either methylprednisolone, 0.5 mg/kg of body weight, or placebo every 6 h intravenously for 72 h. Bedside spirometry was done before and after bronchodilator inhalation three times daily. The methylprednisolone-treated group had a greater improvement in both prebronchodilator and postbronchodilator forced expiratory volume in 1 second (P less than 0.001). More patients with large improvements in their prebronchodilator or postbronchodilator flow rates, or both (greater than or equal to 40% by 72 h), received methylprednisolone (P less than 0.01). Methylprednisolone improved airflow more than placebo when added to standard therapy in patients with chronic bronchitis and acute respiratory insufficiency.