Monitoring Protein-Unbound Valproic Acid Serum Concentrations in Clinical Practice.

BACKGROUND: Valproic acid (VPA) is an effective antiepileptic drug and mood stabilizer. A key characteristic of VPA is its high and saturable protein binding at higher concentrations. Although the unbound concentration of VPA is responsible for its pharmacological activity, total drug concentrations are monitored in routine clinical practice. Therapeutic drug monitoring (TDM) of unbound VPA is recommended for specific clinical situations. The goal of this study was to evaluate TDM requests for unbound VPA in clinical practice. METHODS: All TDM requests at our laboratory for unbound VPA in 2014 and 2015 were evaluated retrospectively. In patients with potentially toxic unbound VPA concentrations (ie, >12 mg/L), we evaluated whether toxicity was noted and whether the dose adjustment advice was followed. Total and unbound VPA concentrations were measured by means of a validated immunoassay. RESULTS: A total of 273 unbound VPA serum concentrations in 132 different patients were analyzed. The main reasons for unbound VPA TDM were decreased renal function (34%) and a low serum albumin (27%). The median (range) unbound VPA concentration was 9.8 (2.5-47.6) mg/L. In 49 patients (37%), the initial unbound VPA concentration was above the threshold of 12 mg/L, potentially resulting in toxicity. Only 6 of these 49 patients had elevated total VPA concentrations. Clinical toxicity was noted in 38 of the 49 patients (77.6%) with elevated unbound VPA concentrations. Toxicities included drowsiness (n = 26), decreased consciousness (n = 4), rigidity (n = 2), and confusion (n = 2). In 36 of the 38 patients with elevated unbound VPA concentrations and clinical toxicity, a dose reduction was applied. In 27 of 36 patients who had their dose reduced, dose reduction was associated with improvement or resolution of VPA toxicity. CONCLUSIONS: TDM of unbound VPA is an important tool to manage VPA therapy in selected, vulnerable patients.

A within-subjects comparison of learning and memory performance before and after cardiac catheterization.

OBJECTIVE: To investigate the influence of stress on the recall of neutral information in a clinical setting, a prospective study was performed on patients who were admitted to the hospital for cardiac catheterization. METHODS: During their hospital stay, 39 cardiac patients were tested for verbal recall and face recognition before cardiac catheterization (day 1) and 24 h after (day 2). Plasma cortisol levels were also determined. After catheterization, recognition of faces presented to each patient before catheterization was assessed. RESULTS: Patients' verbal recall scores on both day 1 and day 2 were within normal limits for the age group but were significantly higher on day 1. Face recognition on day 2 was excellent. Blood cortisol levels did not differ significantly on days 1 and 2, and no significant relationship was found between change in cortisol levels and change in verbal recall scores. CONCLUSIONS: In this small group of selected patients, the stress of hospital admission and cardiac catheterization may not have impaired the recall of neutral information. These preliminary results may indicate that whenever it is necessary to provide information to the patient it is advisable to do so before cardiac catheterization.

Clinically relevant anterograde amnesia and its relationship with blood levels of benzodiazepines in suicide attempters who took an overdose.

The relationship between anterograde amnesia, sedation and plasma levels of benzodiazepines was studied prospectively in a group of 24 patients who took an overdose of benzodiazepines. Patients were tested on two sequential days after having taken an overdose. Anterograde amnesia was tested by using a verbal recall test and a photo recognition test. Sedation was scored on a visual analogue scale (VAS) by the patient and the interviewer. The concentration of benzodiazepines in plasma was measured by using a radioreceptor assay that adds benzodiazepines and their active metabolites. The cumulative amount of benzodiazepines was expressed as diazepam equivalents (DZE). Diazepam equivalents determined by this radioreceptor assay were significantly higher on the first day than on the second day. Ratings on the verbal recall test were significantly lower on the first day than on the second day. There was a significant relation between decrease of diazepam equivalents and increase of verbal recall: more than 30% of increase of verbal recall was explained by decrease of diazepam equivalents. There was not a strong relation between decrease of diazepam equivalents and reduction of level of sedation as scored by the patients. There was almost no relation between decrease of diazepam equivalents and reduction of level of sedation as scored by the interviewer. No relation was found between verbal recall, sedation and diazepam equivalents. There was no relation between diazepam equivalents and photo recognition. It was concluded that anterograde amnesia was strongly associated with benzodiazepines in patients who take benzodiazepines in an overdose. Sedation does not predict the degree of anterograde amnesia.

Determination of the benzodiazepine plasma concentrations in suicidal patients using a radioreceptor assay.

Impairments in memory and psychomotor function appear to be induced by benzodiazepines not only after long-term use, but also after administration of a single dose. Because it is known on which neurotransmitter system the benzodiazepines exert their action, the use of a quantitative radioreceptor assay (RRA) can be a useful tool in studying the interrelationship between the neurochemical and memory processes. The RRA measures the sum of the main compound(s) and all active metabolites present, where it relates the biological activity to the pharmacodynamic effect instead of relating it to the plasma levels of the individual compounds. To correlate the loss of memory with the benzodiazepine concentration, plasma concentrations were determined in suicidal patients. From suicidal patients (n = 84), the benzodiazepines in plasma were measured with a direct radioreceptor assay using tritiated flunitrazepam as the labelled ligand. The receptor material was a lyophilized preparation from calf cortex. Furthermore, the samples were subjected to high-performance liquid chromatographic (HPLC) analysis, and the HPLC data were converted to diazepam equivalents using cross-reactivities of the individual compounds. Patients who had ethanol residues in their plasma were excluded from this correlation experiment. The data (n = 40) obtained with the two analytical techniques were compared and correlated to assess the validity of the radioreceptor assay in establishing the relationship between the loss of memory and the total amount of benzodiazepines present. The cumulative amount of diazepam determined with the RRA and the sum of compounds determined with the HPLC method, after correction using the cross-reactivities, were plotted and correlated using regression analysis. Regression analysis showed an x variable of 0.75 and a correlation coefficient of 0.67. The intercept was not significantly different from zero (P = 0.49, t-test), whereas the slope was significantly different from zero (P < 0.01). Benzodiazepines can be directly determined in plasma using this radioreceptor assay. The data obtained from HPLC analysis were easily converted to diazepam equivalents using the cross-reactivities. A discrepancy between the data obtained from the two analytical techniques, however, indicates that certain metabolites are present, which were not quantitated in the HPLC analysis, but were measured in the radioreceptor assay. Therefore, the radioreceptor assay proved to be a valuable tool for the assessment of clinical effects, such as the demonstration of the loss of memory in suicidal patients after a benzodiazepine overdose.