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Ivermectin is a commonly used broad-spectrum antiparasitic drug, yet doses that produce consistent exposure coverage across age have not been characterized, and no data are available in children weighing

Background Current labeling recommends that therapy with sotalol be initiated in a monitored setting at 80 mg every 12 hours for 2 to 3 days, followed by 120 to 160 mg every 12 hours for at least 2 days before safety and efficacy can be ascertained and patients discharged. An accelerated titration regimen that shortens hospital stay without compromising patient safety would improve the usefulness of the drug. Although such regimens have been used by clinicians, they have not been formally evaluated. Methods Healthy, middle-aged sedentary men and women received sotalol in a double-blind, two-way crossover study with a 2-week washout phase to evaluate an accelerated titration regimen—placebo every 6 hours for four doses, followed by 80 mg sotalol every 6 hours for four doses, then 160 mg sotalol every 12 hours for nine doses—and compare it with the standard titration—placebo alternating with 80 mg sotalol every 6 hours for eight doses, followed by 160 mg sotalol every 12 hours for nine doses. QT intervals, RR intervals, and sotalol concentrations in plasma were measured at specific times throughout the study and during washout in a similar fashion for both regimens. Results Thirty-four subjects completed both regimens. The target prolongation of QTc (90% of the value achieved at steady state) was achieved 22 ½ hours sooner with the accelerated titration regimen (P = .0003). There were no cardiovascular adverse events during either loading phase. At no time during the accelerated titration regimen did the sotalol concentrations in plasma or the QTc or RR interval prolongation exceed the values eventually achieved at steady state. The relationship between sotalol concentration and QTc was linear and independent of the regimen. Conclusion The accelerated titration regimen for sotalol can shorten the time to attain the dosage usually required to effectively control arrhythmias, without excessive QT prolongation and the associated increased risk of torsades de pointes. The hospital stay of patients in whom antiarrhythmic therapy with sotalol is initiated can be shortened by 1 day if this accelerated titration regimen is used. Clinical Pharmacology & Therapeutics (1999) 66, 91–99

Objective To evaluate the relationship between dose of N-0861 ([±]N6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A1-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A1-selectivity of these effects. Methods The study was conducted in patients undergoing a clinically indicated electrophysiology study to evaluate atrioventricular nodal conduction. Nineteen subjects were enrolled in the study and received adenosine (60 to 140 μg/kg) before or during a bolus dose and maintenance infusion of specific doses of N-0861. Adenosine-induced slowing of atrioventricular nodal conduction was determined by measuring A-H intervals on the intracardiac electrocardiograms. Plasma concentrations of N-0861 were determined with an HPLC method. A1-Receptor occupancy by antagonist present in plasma from identical time points was determined with use of a radioreceptor assay. Results A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 μg/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A1 occupancy and N-0861 concentration and between occupancy and antagonism of adenosine-induced A-H prolongation. Conclusion The results suggest that the effect of N-0861 on antagonism of adenosine-induced prolongation of A-H interval, at the doses used in this study, were the result of effects at the A1 receptor. Clinical Pharmacology & Therapeutics (1998) 64, 536–541; doi

Objective To establish whether the antihistamine cetirizine has the potential to prolong the QTC interval in normal volunteers at up to six times the usual recommended dose. Methods Twenty-five healthy volunteers were studied in a prospective, double-blind crossover design conducted on inpatients in a Clinical Research Center. The primary end point of the study was QTC prolongation on the surface electrocardiogram (ECG). Plasma concentrations of cetirizine were also measured for pharmacokinetic analysis. The end point for the pharmacokinetic analysis was the dose/area under the concentration-time curve (apparent clearance of an oral dose). The subjects received the following three treatments in random sequence: placebo, 20 mg/day cetirizine, and 60 mg/day cetirizine for 7 consecutive days. A series of baseline ECGs was recorded over 2 days before each treatment, while the subject receiving placebo. ECG effects of the treatments were then compared with the baseline ECGs. Results Analysis of variance showed no difference between the treatment groups (placebo, 20 mg cetirizine, and 60 mg cetirizine every day) in effect on QTC compared with baseline. A paired Student t test showed no difference in dose/area under the concentration-time curve between the 20 mg/day and 60 mg/day dosing groups at steady state. Conclusion In healthy volunteers, cetirizine does not prolong the QTC interval at doses of up to six times the usual recommended dose. Clinical Pharmacology and Therapeutics (1994) 56, 295–301; doi:10.1038/clpt.1994.140