Elevated free fractions of valproic acid in a heart transplant patient with hypoalbuminemia.

OBJECTIVE: To report a case demonstrating the importance of monitoring unbound valproic acid (VPA) serum concentrations in a patient with hypoalbuminemia. CASE SUMMARY: A 53-year-old white woman status-post heart transplantation was admitted to the hospital for declining cardiac function, possible rejection, and increased lethargy requiring intubation. An extensive workup of the patient's profound lethargy was initiated, including an evaluation of her VPA regimen. Initially, VPA dosages were adjusted based on the total serum concentration of VPA. Hypoalbuminemia compounded with increased lethargy prompted the measurement of unbound serum concentrations of VPA. The VPA dosage was then adjusted based on the unbound rather than the total VPA serum concentration; the patient eventually improved and was discharged from the hospital. DISCUSSION: Lethargy is a concentration-related adverse effect of VPA. The nonlinear pharmacokinetic and protein saturation characteristics of VPA may result in nonproportional elevations in unbound drug, and subsequent increases in adverse effects, when dosage adjustments are based solely on measurement of total VPA serum concentrations in patients with hypoalbuminemia. CONCLUSIONS: This case report suggests that appropriate monitoring of unbound drug concentrations of VPA may prevent unrecognized concentration-related adverse effects. Awareness of the pharmacokinetic relationship and adverse effects of VPA will aid clinicians in identifying the etiology of symptoms.

Predicting unbound phenytoin concentrations in patients receiving valproic acid: a comparison of two prediction methods.

OBJECTIVE: To compare the predictive performance of 2 equations that estimate unbound (free) phenytoin plasma concentrations when valproic acid (VPA) and phenytoin are administered concurrently. DESIGN: Eighty-eight adults receiving VPA and phenytoin concurrently were included in the study. Steady-state plasma concentration measurements of total phenytoin, total VPA, and unbound phenytoin were collected prospectively in the inpatient group (group 1) and retrospectively in the outpatient group (group 2). Using the equations developed by Haidukewych and May, unbound phenytoin concentrations were calculated. The mean predicted unbound phenytoin concentrations then were compared with mean actual unbound phenytoin concentrations measured in the laboratory. Identical assays were performed to measure unbound phenytoin, total phenytoin, and VPA from each patient group. SETTING/PARTICIPANTS: Antiepileptic drug concentration measurements were collected from 43 inpatients (mean age 34.8 y) from the epilepsy unit at Abbott Northwestern Hospital and 45 outpatients (mean age 37.3 y) at the MINCEP Epilepsy Care clinic, Minneapolis, MN. MAIN OUTCOME MEASURES: Mean prediction error (MPE) and mean squared error (MSE) were calculated to determine which equation was the least biased and most precise in predicting unbound phenytoin when total VPA and phenytoin concentrations are known. Linear regression of predicted unbound phenytoin on measured unbound phenytoin values determined the correlation coefficients (r). A paired Student's t-test also was performed comparing mean predicted unbound phenytoin concentration with mean actual unbound phenytoin concentrations in both groups. RESULTS: The MPE from May's equation was -0.49 and -0.45 for groups 1 and 2, respectively; using the Haidukewych equation, MPE was -0.02 and 0.08 for groups 1 and 2, respectively. The MSE using May's equation was 0.34 for both groups. Using the Haidukewych equation, group 1 MSE was 0.07, and for group 2, 0.12. Correlation coefficients were more than 0.91 (p < 0.001) from each equation in both patient groups. In group 1, mean actual unbound phenytoin concentration was 2.02 micrograms/mL; May's equation predicted 1.52 micrograms/mL (p < 0.001) and the Haidukewych equation predicted 2.00 micrograms/mL (p = 0.64). In group 2, mean actual unbound phenytoin concentration was 2.10 micrograms/mL; May's equation predicted 1.65 micrograms/mL (p < 0.001) and the Haidukewych equation predicted 2.18 micrograms/mL (p = 0.11). CONCLUSIONS: Haidukewych's equation predicts unbound phenytoin concentrations with the least bias and most precision with statistical significance. May's equation consistently underpredicted unbound phenytoin concentrations. Because unbound phenytoin fraction is not constant (and usually more than the expected 10%) in patients comedicated with VPA, unbound phenytoin concentrations cannot be predicted even though total VPA and phenytoin concentrations are known. If unbound phenytoin concentrations cannot be readily measured, Haidukewych's equation is a reliable predictor of unbound phenytoin concentrations.

Antiepileptic medication interactions.

This overview of AEM interactions underscores the importance of understanding the pharmacokinetic properties of AEMs and demonstrates the need for careful analysis of AEM concentrations in situations in which combinations of AEMs are used. Although generalizations concerning the clinical significance of drug interactions can be made, major interpatient variations occur. Thus, whenever an AEM is added or deleted, concentrations of drugs should be measured. Refractory individuals or those with multiple seizure types may need polypharmacy, and, under these circumstances, both total and unbound concentrations may need to be measured. New AEMs may have the potential for clinically significant interactions. If these are not identified and understood early, the development and ultimate clinical usefulness of these new agents may be inhibited.

[Blood alcohol concentration is dependent on the sequence of the combined administration of trichlorethylene and ethanol]. / Blutalkoholwerte in Abhängigkeit von der Sequenz kombinierter Gaben von Trichlorethylen und Ethanol.

In equimolar amounts ethanol and trichloroethylene were administered intraperitoneally to male ICR mice in varying sequences. The sequence of administration proved to be decisive for the blood alcohol levels. In relation to ethanol alone following the simultaneous administration of trichloroethylene and ethanol the blood alcohol levels were elevated. This effect is furthermore enhanced if trichloroethylene was administered 1 h prior to ethanol administration. The reversed sequence had no effect on blood alcohol levels.

[Circadian rhythm of mortality, spontaneous locomotor activity, and LD50 following application of 1,1,2,2,-tetrabromoethane alone and in combination with ethanol]. / Zirkadiane Mortalitätsrhythmik, spontane lokomotorische Aktivität und LD50 nach Applikation von 1,1,2,2-Tetrabromäthan allein und in Kombination mit Athanol.

The LD50, the spontaneous locomotor activity, and the circadian rhythm of mortality were determined in male ICR-mice following intraperitoneal injection of 1,1,2,2-tetrabromoethane. By solving the substance in ethanol its toxicity increased significantly, in case of the LD50 by the factor 3.4 and threefold concerning the general mortality. The regression lines calculated for the spontaneous locomotor activity differed significantly with regard to the distance. Significant circadian rhythms of mortality were demonstrated after injections of 1,1,2,2-tetrabromoethane, of tetrabromoethane in ethanol, and of ethanol.

[Passive avoidance learning in the rat as an industrial toxicology test]. / Passives Vermeidungslernen der Ratte als industrietoxikologischer Test.

The techniqual design of a test procedure for determining the passive avoidance learning of rats is described. Experimental results with 1.1.2.2-tetrachloroethylene and benzene demonstrated the principal usefullness of this method in industrial toxicology.