Analysis of variability of concentrations of valproic acid (VPA) and its selected metabolites in the blood serum of patients treated with VPA and patients hospitalized because of VPA poisoning.

AIM OF THE STUDY: To compare the metabolic profile of valproic acid (VPA) in the studied groups of cases through an analysis of variability of concentrations of VPA with its selected metabolites (2-ene-VPA, 4-ene-VPA, 3-keto-VPA). STUDY MATERIAL: Blood serum samples collected from 27 patients treated with VPA drugs in the Psychiatry Unit and in the Neurology and Cerebral Strokes Unit at the Ludwik Rydygier Provincial Specialist Hospital in Krakow, and blood serum samples collected from 26 patients hospitalized because of suspected acute VPA poisoning at the Toxicology Department, Chair of Toxicology and Environmental Diseases, Jagiellonian University Medical College in Krakow. RESULTS AND CONCLUSIONS: The analysis of concentrations of VPA and its selected metabolites has shown that the metabolic profile of VPA determined in cases of acute poisoning is different from cases of VPA therapy. One of VPA's metabolic pathways - the process of desaturation - is unchanged in acute poisoning and prevails over the process of ß-oxidation. The ingestion of toxic VPA doses results in an increased formation of 4-ene-VPA, proportional to an increase in VPA concentration. Acute VPA poisoning involves the saturation of VPA's metabolic transformations at the stage of ß-oxidation. The process of oxidation of 2-ene-VPA to 3-keto-VPA is slowed down after the ingestion of toxic doses.

Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly.

May-Hegglin anomaly (MHA) is an autosomal dominant macrothrombocytopenia of unclear pathogenesis characterized by thrombocytopenia, giant platelets and leukocyte inclusions. Studies have indicated that platelet structure and function are normal, suggesting a defect in megakaryocyte fragmentation. The disorder has been linked to chromosome 22q12-13. Here we screen a candidate gene in this region, encoding non-muscle myosin heavy chain A (MYH9), for mutations in ten families. In each family, we identified one of three sequence variants within either the -helical coiled coil or the tailpiece domain that co-segregated with disease status. The E1841K mutation was found in 5 families and occurs at a conserved site in the rod domain. This mutation was not found in 40 normal individuals. Four families had a nonsense mutation that resulted in truncation of most of the tailpiece. One family had a T1155I mutation present in an affected mother and daughter, but not in the mother's parents, thus representing a new mutation. Among the 30 affected individuals, 21 unaffected individuals and 13 spouses in the 10 families, there was correlation of a variant of MYH9 with the presence of MHA. The identification of MYH9 as the disease gene for MHA establishes the pathogenesis of the disorder, should provide further insight into the processes of normal platelet formation and may facilitate identification of the genetic basis of related disorders.

[Use of different drug form identification systems]. / Zastosowanie systemów identyfikacji róznych postaci leków.

Since the foundation of the Department of Clinical Toxicology one of the unsolved problems is the identification of drugs which are often brought by the emergency service together with the patient. This problem is known to the personnel of Poison Centers and all first-contact physicians who deal with the patient at home or at the place of accident. Many years of observations and experiences allowed for creating Polish system of drugs identification based mainly on the catalogue containing data to be used in identification of an unknown form of a drug. The next step was to create a computer database system allowing for fast and accurate identification of drug forms. Created catalogue contains drug forms categorized by color and shape. The solution is constructed in a way that adding new and extending existing data is possible. The catalogue can be used in drug stores, by emergency services, family doctors and specifically in pediatrics since children are often exposed to the danger of unknown drug intake. The useful option is the color printout which can be obtained from the system. Search procedures enable setting range of criteria and, after initial list is produced, detailed search is possible with the color images on screen. The system was created using MS Access database. Department of Toxicology is the owner of the copyrights.

Influence of tobacco smoke on the pharmacokinetics of citalopram and its enantiomers.

The purpose of this study was to evaluate the influence of tobacco smoke on the pharmacokinetics of citalopram (CIT) and desmethylcitalopram (DCIT) and its enantiomers on an animal model. High performance liquid chromatography (HPLC) with a diode array detector (DAD) was used for the identification and quantification of the studied compounds. The HPLC quantification of racemic mixtures of CIT was performed on a C18 column. The limits of detection (LOD) and quantification (LOQ) were: 7 and 10 ng/ml respectively. HPLC separation of citalopram enantiomers (S- and R-CIT) was performed on a Chirobiotic V column. The limits of detection (LOD) and quantification (LOQ) were: 6 and 15 ng/ml for R- and S-CIT respectively. The experiment was carried out on male Wistar rats. The rats were exposed to tobacco smoke for five days (6 hours per day). After the exposure, citalopram was administered in a dose of 10 mg/kg intragastrically. In the control group (non-exposed animals), citalopram was administered in the same way and at an equal dose. The blood of the animals was collected at nine time points. It was found that tobacco smoke exposure inhibits the biotransformation of citalopram. The half-life of the racemic mixture of citalopram after intragastric administration was increased by about 287%. Changes in the pharmacokinetic parameters of S-citalopram (active isomer) show a similar tendency to those of the racemic mixture. The pharmacokinetics of R-citalopram showed no statistically important differences after tobacco smoke exposure. Alterations in the pharmacological parameters of desmethylcitalopram presented an opposite trend to the parent drug. After exposure to tobacco smoke, the induction of metabolism of this compound was observed.

On continuity of integration methods for AUC. A note.

A lack of monotonicity and discontinuity of some integration methods for AUC, as a function of measured concentration, is demonstrated. Hybrid methods consisting of either parabolas-through-the-origin or the alpha-function method followed by the log-trapezoidal method were found to be discontinuous at the switching point. The stable piecewise third-order polynomial method appeared to be nonmonotonic as well as discontinuous.

Variability of the model-independent AUC: the one sample per individual case.

A theory is developed for estimation of a population value of AUC along with its standard deviation, in the case, when only one concentration-time (C-t) sample is available for each individual. This theory is based on model-independent pharmacokinetics. Integration methods are classified due to their applicability to the presented approach. The main goal of this work is to establish a statistical hypothesis-testing procedure which would make single C-t samples usable for bioequivalence studies. An application of the theory to a number of integration methods currently in use is analyzed in detail. A real data illustration is included.

Autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is linked to chromosome 22q12-13.

Macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is a rare autosomal dominant disorder characterized by thrombocytopenia, giant platelets, and Döhle body-like inclusions in leukocytes. To determine the genetic basis of this disorder, we performed a genome-wide screen for linkage in three families with May-Hegglin anomaly. For the pooled analysis of the three families, three markers on chromosome 22 had two-point logarithm-of-difference (lod) scores greater than 3, with a maximum lod score of 3.91 at a recombination fraction (theta) of 0.076 for marker D22S683. Within the largest family (MHA-1), the maximum lod score was 5.36 at theta=0 at marker D22S445. Fine mapping of recombination events using eight adjacent markers indicated that the minimal disease region of family MHA-1 alone is in the approximately 26 cM region from D22S683 to the telomere. The maximum lod score for the three families combined was 5.84 at theta=0 for marker IL2RB. With the assumption of locus homogeneity, haplotype analysis of family MHA-4 indicated the disease region is centromeric to marker D22S1045. These data best support a minimal disease region from D22S683 to D22S1045, a span of about 1 Mb of DNA that contains 17 known genes and 4 predicted genes. Further analysis of this region will identify the genetic basis of May-Hegglin anomaly, facilitating subsequent characterization of the biochemical role of the disease gene in platelet formation.