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.

Calcium ions play an important role in the cardiovascular system. They are involved in electrophysiologic processes, link excitation to muscular contraction, control energy storage and utilization, and constrict vascular smooth muscle in coronary and systemic arteries. A new group of pharmacologic agents that block the passage of calcium ions across cell membranes has been developed. These agents act during the slow inward current of cellular depolarization. The most extensive clinical experience has been obtained with four of these agents: verapamil, nifedipine, perhexiline, and diltiazem. Verapamil, which has profound electrophysiologic effects on the slow inward current, is emerging as a valuable antiarrhythmic agent. Re-entrant supraventricular arrhythmias, such as paroxysmal supraventricular tachycardia, are particularly amenable to treatment with intravenous verapamil. Preliminary trials of long-term therapy with oral verapamil for control of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia suggest that this agent is effective for therapy of these arrhythmias.

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.

In eight patients with chronic portal-systemic encephalopathy who were symptomatic despite protein restriction and lactulose, a double-blind crossover comparison was conducted of branched-chain amino acids (68 mmol/d) versus ornithine salts of branched-chain ketoacids (34 mmol/d), both mixtures being administered orally for 7 to 10 days, after control periods, during a single hospitalization. Ornithine salts of branched-chain ketoacids markedly improved electroencephalographic abnormalities and clinical grade of encephalopathy; branched-chain amino acids had significantly lesser effects, which were of borderline statistical significance. To ascertain whether ornithine or branched-chain ketoacids were responsible for the improvement observed, we administered to six patients calcium salts of branched-chain ketoacids (34 mmol/d) after control periods; only slight improvement was seen.. Four patients received a daily dose of ornithine alpha-ketoglutarate containing the same quantity of ornithine; one did not change and three deteriorated rapidly. We conclude that the combination of ornithine and branched-chain ketoacids improves chronic portal-systemic encephalopathy more than its components given separately and more than branched-chain amino acids at twice the molar dose.

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 Epstein-Barr (EB) virus excretion and antibody in 41 renal transplant recipients enrolled in a placebo-controlled trial of human leukocyte interferon. Half the patients were also treated with antithymocyte globulin. Epstein-Barr virus excretion occurred more often in recipients of cadaver kidneys (P = 0.03) and those receiving antithymocyte globulin (P = 0.04) and less often in patients given interferon (P = 0.08). Antibody to viral capsid antigen increased fourfold or more in 12 of 22 patients treated with antithymocyte globulin and in none of the non-antithymocyte globulin-treated group (P = 0.0002). Antibody to the restricted component of early antigen rose fourfold or more in eight patients and appeared related to the occurrence of syndromes similar to those attributed to cytomegalovirus in transplant recipients. We conclude that increasing immunosuppression augments the rate of EB virus reactivation and that EB virus may be an important pathogen in heretofore ill-defined syndromes.

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.