Using bivariate and multivariate methods, we retrospectively analyzed the influence of patient age and the use of concomitant antiepileptic drugs (AEDs) on the lamotrigine (LTG) concentration-to-dose (C/D) ratio in samples from 164 patients (68 children, 96 adults) with epilepsy receiving LTG alone (n = 28) or in combination with various antiepileptic drugs (n = 136). The LTG C/D ratio increased with age in children receiving LTG alone (r = 0.60, p < 0.01), but decreased with age in adults receiving LTG and inducers (r = -0.42, p < 0.001). In patients receiving LTG and inducers, the ratio was statistically lower in those younger than 9 years of age (0.23 +/- 0.08) and older than 30 years of age (0.32 +/- 0.15) than it was in those between 9 and 30 years of age (0.44 +/- 0.15). The mean LTG C/D ratio was 0.37 +/- 0.15 in patients receiving LTG and inducers (n = 92), 0.84 +/- 0.41 in patients receiving LTG alone (n = 28), 1.09 +/- 0.44 in those receiving LTG with VPA plus inducers (n = 17), and 3.41 +/- 1.18 in those receiving LTG and VPA (n = 27). Differences in the LTG C/D ratio between treatment groups were similar in children and in adults. We reached the following conclusions: The LTG C/D ratio increased with age in children but may decrease with age in adults receiving concomitant enzyme-inducing AEDs; the LTG C/D ratio was 10 times lower in patients receiving LTG and inducers than in those receiving LTG and VPA (in both children and adults), and this difference was higher than the four-fold difference described for LTG half-life and the two-fold differences currently used in LTG dosage.
Out-of-hospital administration of intravenous metoprolol by EMS within 4.5 hours of symptom onset in our subjects reduced infarct size and improved left ventricular ejection fraction with no excess of adverse events during the first 24 hours.
Patients and Methods
This parallel‐group, double‐blind trial compared the efficacy and tolerability of topical prednicarbate, 0.25% ointment, with that of fluocortin butyl ester, 0.75% ointment.
The trial included 79 outpatients at three participating centers. All patients had a diagnosis of atopic dermatitis on the basis of Hanifin and Rajka's criteria.1 Other inclusion criteria were: age ≥ 18 years and stability or worsening of the condition for at least 1 week in the current episode. Patients were required to have been treatment‐free for minimum periods of: 7 days if previously treated with other topical corticosteroids; 1 month if previously treated with systemic corticosteroids; 3 days if previously treated with shortacting antihistamines; 2 months if previously treated with astemizole.
Exclusion criteria were: severe incapacitating dermatitis; infectious processes or association with other skin changes; need for the concomitant administration of antihistamines or antimicrobials; serious concurrent illness. Women not using adequate contraception were also excluded.
A thin layer of topical prednicarbate (N = 42) or fluocortin butyl ester (N = 37) was applied to the affected area of skin twice daily, without occlusion. The duration of treatment was set at 21 days, but it could be interrupted earlier, at the discretion of the investigator, on the grounds of total disappearance of the condition, inefficacy, or the appearance of any adverse reaction. A daily application of an emollient oil and/or a cleaning or emollient aqueous cream could be used at the investigator's discretion.
At the start of treatment and at 4, 7, 14, and 21 days, each of the following features was rated on a scale of 0 to 3 (0; absent, 1: mild, 2: moderate, 3: severe): pruritus; excoriations; erythema; scaling; lichenification; vesiculation; hyper‐keratosis. On the basis of these scores, the overall efficacy of treatment was rated as: improvement > improvement of > 50 to 75%; improvement of > 25 to 50%; improvement < 25%; no improvement; worsening.
If the treatment ended before 21 days, owing to either cure or inefficacy, the score for the last evaluation was used for all subsequent followup points. At the end of treatment the investigator and the patient rated treatment as excellent, good, fair, or poor. Cosmetic acceptance by the patient was evaluated in the same terms.
The relationship between the ratio of vigabatrin concentration to dosage (VGB C/D) and both patient age and the presence of other antiepileptic drugs (AEDs) was analyzed retrospectively by bivariate and multivariate methods in 179 patients with epilepsy (114 children and 65 adults). Of the 179 patients, 33 received VGB alone (30 children and 3 adults) and 146 received VGB with other AEDs (84 children and 62 adults). Vigabatrin trough steady-state serum concentration correlated better with VGB dosage in milligrams per kilogram than the dosage in milligrams in children (r = 0.62 vs. r = 0.17, P < 0.001) but not in adults (r = 0.51 vs. r = 0.49, NS). The correlation between milligrams per kilogram and serum concentration of VGB was greater in children on monotherapy (r = 0.83) than in those on polytherapy (r = 0.46). Vigabatrin C/D ratio increased significantly with age (r = 0.51, P < 0.001), being lower in children than in adults both by Student's t-test (0.087 +/- 0.039 vs. 0.128 +/- 0.057, mean +/- SD, P < 0.001) and by two-way analysis of variance when controlling for other AEDs (P < 0.001). Inducing AEDs seemed to increase VGB C/D ratio in the bivariate tests, but this influence decreased and even disappeared if patient age was considered in the multivariate analysis. However, the increase in VGB C/D ratio with VPA serum concentration (r = 0.46, P < 0.001) was confirmed by multiple regression including age (P < 0.001). Intrapatient variability of VGB C/D ratio was 29 +/- 18%. It was concluded that trough steady state VGB serum concentration may be more predictable in children based on the milligrams per kilogram dosage than on the milligram dosage, and that the influence of patient age should be considered if the VGB C/D ratio is used to estimate patient compliance.
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