Evaluation of sorivudine (BV-araU) versus acyclovir in the treatment of acute localized herpes zoster in human immunodeficiency virus-infected adults. The Multinational Sorivudine Study Group.

The clinical efficacy and safety of sorivudine as treatment for acute cutaneous zoster in human immunodeficiency virus-infected adults was compared with that of acyclovir in a double-blinded randomized study. A total of 125 patients with laboratory-confirmed zoster rash present for < or =72 h were assigned treatment with either 40 mg of sorivudine once daily or 800 mg of acyclovir five times daily, both taken orally for 7 days. Patients were assessed daily until all lesions crusted and then monthly for 6 months for postherpetic neuralgia (PHN) and for 12 months for recurrent or new episodes of zoster. Sorivudine significantly shortened the median period of new vesicle formation from 3.0 to 4.0 days (log rank P = .0001). Sorivudine was effective regardless of duration of rash before treatment. Zoster recurrences and new episodes were experienced by fewer patients assigned sorivudine (11%) than acyclovir (26%, P = .037). No differences were seen in incidence, severity, or duration of either acute neuritis or PHN. Both treatments were well tolerated.

Switching from zidovudine to didanosine in patients with symptomatic HIV infection and disease progression. ddI Iberian Study Group.

This study evaluated the efficacy of switching to didanosine in patients who were clinically or immunologically progressing despite zidovudine therapy. This multicenter, open-label study involved 400 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), who had tolerated zidovudine for at least 12 weeks and had signs of clinical or immunological disease progression. They were randomly assigned to receive 600 mg/d of zidovudine (n=133), 500 mg/d of didanosine (n=131), or 200 mg/d of didanosine (n=136). The primary end point was a new AIDS-defining event or death. The study was prematurely terminated, after the first interim analysis, mainly owing to results of two controlled studies demonstrating that a change to didanosine was associated with an improved outcome in patients with advanced HIV-1 disease. The median duration of follow-up was 53 weeks. The primary end point rates were 41, 58, and 59 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups (zidovudine vs. didanosine 500 mg, relative risk 1.28, 95% confidence interval, 0.88-1.86, p = 0.19; didanosine 200 vs. 500 mg, relative risk 1.24, 95% confidence interval, 0.85-1.79, p = 0.26). In subjects with a baseline CD4 count of 100/mm3 or more, the primary end point rates were 8, 29, and 25 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups, respectively (zidovudine vs. didanosine 500 mg, relative risk 2.96, 95% confidence interval 0.91-9.62, p = 0.07). No difference was seen in survival. In the didanosine 500 mg group, more patients had a 50% increase in CD4 cells (10% vs. 1% in zidovudine group, p = 0.01) and an increase of > or = 2.5 kg in body weight (2% versus 3%). Fatal pancreatitis developed in one patient assigned to didanosine 500 mg and in one to zidovudine. Our data suggest that switching from zidovudine to currently recommended doses of didanosine in subjects with ARC or AIDS who show evidence of clinical and laboratory disease progression can be associated with improvements in clinical outcome as well as in surrogate markers of HIV disease progression. This effect tended to be greater among individuals with higher CD4 counts (>100/mm3).

Encainide--an updated safety profile.

The safety of encainide has been evaluated using retrospective analyses of the Bristol-Myers Supraventricular and Ventricular Arrhythmias data base and of the Post-Marketing Adverse Experience Report data and prospective analyses of the Cardiac Arrhythmia Suppression Trial (CAST), the Cardiac Arrhythmia Pilot Study (CAPS), and the Ventricular Tachycardia/Heart Disease and Boston studies. CAST, a randomized, placebo-controlled study in patients with a history of myocardial infarction with asymptomatic or minimally symptomatic ventricular arrhythmias, showed that sudden death or nonfatal cardiac arrest occurred more frequently on encainide (24/418, 5.7%) than on placebo (7/416, 1.7%). The highest sudden death/cardiac arrest rates were found in patients with a left ventricular ejection fraction of less than 0.30, those with a ventricular premature beat count of more than 50/hr and those with a myocardial infarction of more than 90 days. Similar sudden death/cardiac arrest rates were seen in the flecainide-treated group of the study but not in the moricizine-treated group. A retrospective analysis of the data collected from a similar cohort of patients in the Bristol-Myers data base showed a 1-year cumulative incidence of 10.2% in patients with a history of myocardial infarction. A retrospective analysis of mortality data in patients with supraventricular arrhythmias (301 patients) showed this to be slightly lower than in a matched sample of the general U.S. population. The sudden death mortality in the Ventricular Tachycardia/Heart Disease and Boston studies were similar to those reported with other antiarrhythmic agents. Abnormal laboratory findings caused four patients to be discontinued prematurely, but there have been no reported cases of any blood dyscrasias. Thus, there are currently no data showing that patients with symptomatic reentry supraventricular and life-threatening ventricular arrhythmias are at increased risk with encainide therapy. Encainide should be reserved for those patients who are refractory or intolerant to other antiarrhythmic agents. Encainide is not indicated in patients with symptomatic ventricular arrhythmias and structural heart disease. In patients without structural heart disease and symptomatic ventricular arrhythmias, the benefit and risks of encainide therapy should be carefully considered before it is prescribed.

Synthesis of deuterium- and tritium-labeled 6 beta-bromopenicillanic acid.

The synthesis of 6 beta-bromopenicillanic acid labeled with deuterium and tritium in the beta-methyl group is described. The S-sulfoxide of benzyl- or p-methoxybenzyl 6 alpha-bromopenicillanate is refluxed in benzene containing an excess of tert-BuOD, D2O or HTO. After deoxygenation and deprotection of the ester, the labeled 6 alpha-bromopenicillanic acid is epimerized (N,O-bis(trimethylsilyl)acetamide/1,5-diazabicyclo[4.3.0]non-5-ene in CH2Cl2). The two epimers are separated by column chromatography.

Once daily administration of low-dose xipamide: a long-term study in mild to moderate hypertension.

The anti-hypertensive effects of xipamide in doses of 5-20 mg once daily were studied in a multicenter study. Three general practitioners recruited 74 patients with uncomplicated hypertension. After a run-in period, patients entered a dose-ranging study and were followed for an average period of 10.4 months. Supine and standing blood pressures were significantly decreased (22.2/14 and 21/14 mmHg) during xipamide therapy with average daily dose of 12.2 mg. Serum potassium values dropped from 4.43 +/- 0.06 to 3.96 +/- 0.5 mEq/l, and serum uric acid increased from 5.47 +/- 0.06 to 6.04 +/- 0.18 mg%. In a second part 47 patients entered a double-blind, crossover study of placebo. Their optimum xipamide doses confirmed that in the majority of patients with mild to moderate hypertension xipamide in doses lower than 20 mg is effective in lowering blood pressure. The study further confirmed that xipamide exerted its anti-hypertensive effects for at least 24 h.

Diverging effects of cholestyramine on apolipoprotein B and lipoprotein Lp(a). A dose-response study of the effects of cholestyramine in hypercholesterolaemia.

Nineteen hypercholesterolaemic patients were randomly treated with either 16 or 8 g cholestyramine with a changeover after 6 weeks for a second 6-week period. During a third consecutive 6-week period all patients received 4 g cholestyramine daily. The low density lipoprotein (LDL) cholesterol and triglyceride concentrations decreased significantly (- 11%, - 21% and - 26% for LDL cholesterol on 4, 8 and 16 g, respectively) with a dose-response effect. However, the increase from 8 g to 16 g only caused a modest additional reduction of the lipid levels. The serum concentration of apolipoprotein (apo) B was correlated to the LDL cholesterol and decreased similarly in a dose-response fashion. However, the average reduction of apo B was less pronounced (- 4%, - 13% and - 17% on 4, 8 and 16 g of cholestyramine, respectively) resulting in a significant change of the apo B/LDL cholesterol ratio during treatment. There was a significant increase of the high density lipoprotein (HDL) cholesterol concentration, which was similar at all dose levels. Also, the apo A-I concentration in serum increased significantly but the relative decrease was less pronounced than that of HDL cholesterol, causing a significant decrease of the apo A-I/HDL cholesterol ratio. The apo A-II concentration in serum was unchanged or slightly decreased and the apo A-I/apo A-II ratio increased significantly.

Electrocardiographic changes after long-term treatment with sotalol in hypertensive patients.

The long-term electrocardiographic effects of sotalol, a beta blocker tha prolongs the cardiac repolarization time in animals, were investigated in ten hypertensive patients and compared to ten matched hypertensive patients treated with diuretics. An electrocardiogram was recorded before and during an exercise test on a bicycle. Heart rate was lower at rest and throughout exercise in the sotalol-treated patients. The PR and QT intervals of the ECG were significantly longer at rest and after exercise in the sotalol group, whereas QRS widths were similar in both groups. The QTC interval in the sotalol group was 0.41 +/- 0.02 s and 0.47 +/- 0.01 s, at rest and after exercise, respectively, which was not significantly different from 0.42 +/- 0.01 s and 0.43 +/- 0.02 s, respectively, in the diuretic group. These findings were discussed in relation to observations made with other beta blockers.

Comparison of once and twice daily sotalol in exercise-induced angina pectoris.

The efficacy of chronic oral treatment with a total daily dose of 320 mg sotalol, given as a single or as two divided doses, was compared with placebo in a double-blind cross-over study of 12 patients with angina pectoris. Sotalol given once or twice daily significantly reduced heart rate and systolic and diastolic blood pressures at rest. The exercise heart rates were significantly decreased in both treatment groups. After sotalol 320 mg once daily, there was a greater reduction in the maximum exercise heart rate 2 h after taking the last tablet than after sotalol 160 mg b.i.d. The systolic blood pressure at the highest comparable work-load was significantly and equally reduced by sotalol both once and twice daily. Total work (watts X minutes in both sotalol treatment groups was significantly increased compared to placebo. There was no difference between the two sotalol dosage regimens. The peak plasma levels were higher after the once daily treatment, but the trough levels were similar for both regimens. No serious side effects were observed.

Prediction of creatinine clearance from serum creatinine concentration based on lean body mass.

An equation for predicting endogenous creatinine clearance (CrCl) in adults and children (with both stable and unstable renal function) from serum creatinine concentration is presented. The predictions are compared with four other available estimating methods, bases on values in 110 subjects with renal impairment of widely differing degrees. In patients with stable and with unstable renal function the corelaion between measured and predicted CrCl was better with the new equation. In patients with rapid changing renal function the new equation resulted in accurate predictions CrCl within a few hours after the change, as opposed to several with the other methods. The elimination rate constant of the aminoglycoside antibiotic amikacin correlated more precisely with CrCl values estimated from the new equation that with those measured doing 24 hr or with the other prediction methods.

Sotalol and metoprolol comparison of their anti-hypertensive effect.

28 patients, aged 35-62 years, with uncomplicated hypertension, entered a double-blind, crossover study, in which the effects of single daily doses of sotalol and metoprolol were compared. Both drugs exerted a clinically useful anti-hypertensive effect as monotherapy, or in combination with a thiazide diuretic. No significant difference in hypotensive effects was noted between the two beta-blocking agents, when the dose was titrated to an optimal clinical effect. Treatment with sotalol and metoprolol was associated with a clinically insignificant increase in serum uric acid concentration. The side-effects observed were few, and in only two cases was therapy discontinued. We regard both sotalol and metoprolol as useful anti-hypertensive drugs.

Pharmacokinetics of sotalol after chronic administration to patients with renal insufficiency.

Ten hypertensive patients with modern to severe impairment of renal function were treated with sotalol for 5 to 10 weeks (average 6.4 weeks). Dosage was individually titrated (range 80 to 480 mg daily). The drug was given once daily in the morning. In eight patients blood pressure was satisfactorily controlled. Higher steady-state levels were observed than have been reported after similar doses in patients with normal renal function. The apparent first-order elimination rate constant and plasma clearance were significantly correlated with glomerular filtration rate. For an anuric patient, serum half-life was calculated to be 69 h. In relation to the raised plasma levels, side effects were uncommon. Since sotalol is excreted predominantly via the kidney, therapy in patients with impaired renal function should start with a low dose and any increase in dosage should be made carefully. As the anti-hypertensive effect does not appear to be correlated with the plasma level or with tolerance, adjustment of dose should be based on clinical response.

Preparation and properties of 5-phenylphenoxymethylpenicillin.

Cycloaddition of azidoacetyl chloride to benzyl D-5,5-dimethyl-5-phenyl-2-thiazoline-4-carboxylate (1a) gave 5-phenyl-6alpha-azidopenicillanate (2a). By catalytic reduction of 2a and reaction with phenoxyacetyl chloride, 5-phenyl-6-epiphenoxymethylpenicillin benzyl ester (4a) was obtained. Oxidation of 4a gave the sulfoxide 6, which was isomerized in the presence of DBN. The sulfoxide 7 with the normal configuration could be isolated but deoxygenation of the sulfoxide was not successful. Isomerization of 4a with DBN, either with or without silylation of the side chain, gave a mixture from which 5-phenylphenoxymethylpenicillin benzyl ester (5) was isolated. Compound 5 was debenzylated to 5-phenylphenoxymethylpenicillin potassium salt (8). The antibacterial activity of 8 was low, whereas the 6-epimer 9 was inactive. Contary to published information, the 5-phenylpenam derivative 4c could be prepared by the same method.