Wojciech Jawień

Acute CO Poisoning is Associated with Impaired Fibrinolysis and Increased Thrombin Generation

Carbon monoxide (CO) poisoning is a leading cause of unintentional poisoning deaths in many countries. In ex vivo studies, CO released from carbon monoxide‐releasing molecules has been shown to attenuate fibrinolysis via increased alpha‐2‐antiplasmin activity. Hypofibrinolysis is associated with coronary ischaemia, which is also commonly observed in CO poisoning. We examined fibrin clot properties in acutely poisoned CO patients. Ex vivo plasma fibrin clot permeability, turbidimetry and efficiency of fibrinolysis were investigated in 48 patients and controls matched for age and sex. CO‐poisoned patients had 11.6% longer clot lysis time than the controls (p < 0.0001). No intergroup differences in clot permeability or turbidimetric variables were observed. Plasma tissue‐type plasminogen antigen (tPA), plasminogen activator inhibitor‐1 (PAI‐1) antigen and activity and F1.2 prothrombin fragments were higher in the patients than in the controls (all p < 0.0001). Plasma tPA activity was lower in the CO‐poisoned group. Multiple linear regression showed that a thrombin generation marker, F1.2, is the strongest predictor of clot lysis time, followed by PAI‐1 activity and carboxyhaemoglobin levels. In conclusion, this report is the first to demonstrate that acute CO poisoning in human beings is linked to increased thrombin generation and impaired fibrinolysis, which might contribute to ischaemic complications.

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.

Population pharmacokinetic modelling of valproic acid and its selected metabolites in acute VPA poisoning

BACKGROUND Valproic acid (VPA) is a first-line antiepileptic drug. It is used in the treatment of many different types of partial and generalized epileptic seizures. Though the clinical pharmacokinetics of VPA has been well defined, information about pharmacokinetics after overdoses is rare. The aim of this study was to try to build a population pharmacokinetic model that would describe the time course of VPA and its selected metabolites when the drug is ingested in an overdose situation. METHODS Blood samples were collected during admission to the hospital and several times during treatment for poisoning (10 men and 10 women). The concentration of VPA and its metabolites were determined by liquid chromatography coupled with mass spectrometry. For population pharmacokinetic evaluation of VPA and its metabolites, the two-compartment-model was applied. RESULTS The estimated doses of VPA taken ranged from 6 to 65g, while the time after ingestion ranged from 1 to 30h. Results showed that the β-oxidation process exhibited Michaelis-Menten kinetics becoming saturated during acute intoxication. The same could not be said for the desaturation route. VPA therapy increased the Vmax for β-oxidation by 59% while decontamination appeared to be of moderate efficacy lowering the F value by 34% on the average. CONCLUSIONS None of the models perfectly described the experimental data. Important factors like the variable degree of protein binding by VPA could not be included in the models. The small number of subjects used in the study made the analysis of more covariates impossible.

Abnormal olanzapine toxicokinetic profiles--population pharmacokinetic analysis.

Abstract Context: Olanzapine is widely used in the treatment of schizophrenia and it is becoming more frequently responsible for overdoses. Standard pharmacokinetic models do not fit to the toxic concentration data. Objective: The aim of present study is to investigate the reasons for an abnormal olanzapine plasma concentration time curve in the range of toxic concentrations. Two hypotheses were verified: entering the enterohepatic cycle, and drug deposition and its desorption from activated charcoal used for gastrointestinal decontamination. Materials and methods: One-hundred thirty-five plasma concentration data from 21 patients hospitalized for acute olanzapine poisoning were analyzed with the use of the population pharmacokinetic approach. A non-linear mixed-effects modeling approach with Monolix 4.3.1 was employed. Results: A model assuming gallbladder emptying at irregular intervals was developed. Also, a model that describes desorption of olanzapine from the charcoal surface, in which the dose is divided into two absorbed fractions, was constructed. The analysis has found gastrointestinal decontamination and previous olanzapine treatment, as the significant covariates for toxicokinetic parameters of olanzapine. Conclusion: Our study provides interesting models for investigation of toxic concentration of olanzapine, which may also be used as the basis for further model development for other drugs as well. The investigated population was not large enough to reliably confirm any of the proposed models. It would be well worth continuing this study with more substantial data. Also, any additional information about olanzapine metabolite concentration could be vital.

Molecular interaction in mixed spread films at the water/air interface

Abstract The treatment of a two-dimensional system of three components of isomegetic molecules, adapted from statistical thermodynamics, is used to derive parameters which can be related to the interaction between molecules at the collapse pressure in mixed spread films at the water/air interface. The theory is illustrated by the mixed system of stearic acid and 1-octadecanol.

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 α-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.

Study of the interaction in the three-component system of p-cresol/p-halophenols/water

Abstract A regular solution theory, extended to a system of three components of different molecular sizes, is used to interpret the behaviour of two surface-active compounds dissolved in water. Mixtures of p -cresol with p -chloro-, p -bromo- and p -iodophenol have been studied at 20°C, using surface tension measurements. The parameters related to molecular interactions in the bulk phase and at the interface have been obtained for all the systems studied.

Surface behaviour of some phenol para-derivatives adsorbed at the free surface of water

Abstract Comparison is made between two methods for the determination of the average orientation angle of molecules adsorbed at the free surface of water; one based on electric surface potential measurements, the other on second harmonic generation. Assuming that the model of energetics of adsorbed molecules is similar to that of a system of non-interacting permanent dipoles in an external homogeneous field, the parameters of the probability density function in the form exp[ —a cos(0-0o)], a =w/kT, w, being the absolute orientational energy, have been calculated for phenol, p-methyl-, p-nitro-, and p-bromophenol.

How to combine non-compartmental analysis with the population pharmacokinetics? A study of tobacco smoke's influence on the bioavailability of racemic citalopram in rats.

BACKGROUND Citalopram (CIT) is an antidepressant drug from the group of selective serotonin reuptake inhibitors in which it is the most potent selective inhibitor of serotonin uptake currently available. Patients treated with CIT are often heavy cigarette smokers. Individual pharmacokinetic parameters cannot be directly estimated if full pharmacokinetic profiles are not available for each subject. Sparse sampling is common to experiments using small animals, such as the case that our study is concerned with. METHODS The aim of the study was to demonstrate how the two (non-compartmental analysis (NCA) and nonlinear mixed-effect (NLME)) approaches, used simultaneously, can help overcome specific limitations of these separate methods whilst at the same time preserve their respective benefits. RESULTS Despite the ultra-sparse design, the NLME approach enabled us to develop a pharmacostatistic model with the required covariate--exposition to the tobacco smoke. CONCLUSIONS A tobacco smoke slows down the absorption of the CIT and at the same time makes it more effective. The consistency of results obtained both with NCA and NLME decreased the risk of model misspecification and increased confidence in the final conclusions. Combining NLME with NCA may therefore be recommended for investigating pharmacokinetic properties of the drug in the sparse designs.

Searching for an optimal AUC estimation method: a never-ending task?

AbstractAn effective method of construction of a linear estimator of AUC in the finite interval, optimal in the minimax sense, is developed and demonstrated for five PK models. The models may be given as an explicit C(t) relationship or defined by differential equations. For high variability and rich sampling the optimal method is only moderately advantageous over optimal trapezoid or standard numerical approaches (Gauss-Legendre or Clenshaw-Curtis quadratures). The difference between the optimal estimator and other methods becomes more pronounced with a decrease in sample size or decrease in the variability. The described estimation method may appear useful in development of limited-sampling strategies for AUC determination, as an alternative to the widely used regression-based approach. It is indicated that many alternative approaches are also possible.