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

An 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10928-014-9392-y) contains supplementary material, which is available to authorized users

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 -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 -oxidation. The process of oxidation of 2-ene-VPA to 3-keto-VPA is slowed down after the ingestion of toxic doses

Pharmacokinetics of diclofenac sodium and papaverine hydrochloride after oral administration of tablets to rabbits

Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-μm column (150 mm ◊ 4.6 mm) using methanolwater (55 : 45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose

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

Three-dimensional Collagen Scaffolds in Cultures of Olfactory Ensheathing Cells Used for Severed Spinal Cord Regeneration

BACKGROUND/AIM: The regeneration of a completely damaged spinal cord is still a challenge in modern medicine. A promising treatment method is autologous transplantation of olfactory ensheathing cells (OECs). This study aimed primarily to test methods of culturing OECs with the use of materials and reagents that are certified for pharmaceutical use in the production of an advanced cell therapy product intended for humans. MATERIALS AND METHODS: The culture of OECs was performed using various modifications of the surface of the culture vessels (with fibronectin and poly-D-lysine). The number of cells was assessed after immunofluorescence staining using anti-fibronectin and anti-p75 NGF receptor antibodies. The study compared, in terms of surgical manipulations, scaffolds with OECs prepared based on 3 types of collagen: Acid Solubilized Telo Collagen and Pepsin Solubilized Atelocollagen, and the popular Corning collagen. RESULTS: We have shown that when suspending OECs in collagen gel, it is much better to use acid-solubilized collagen (ASC) than pepsin-solubilized collagen (PSC) because the 3D collagen scaffold from ASC provides much easier handling of the product during a surgical procedure. We also found that the OEC cultures should be grown on the surface modified with fibronectin. Furthermore, we have also shown that the optimal concentration of fetal bovine serum (FBS) for culturing these cells should be around 10%. CONCLUSION: The culture of OECs based on reagents intended for human use can be successfully carried out, obtaining sufficient OECs content in the heterogeneous cell culture to produce a functional advanced therapy medicinal product

Binding of 1-[3-(4-tert-butyl-phenoxy)propyl]piperidine, a new non imidazole histamine H3 receptor antagonist to bovine serum albumin

The degree of binding of a drug to plasma proteins has a significant effect on its distribution, elimination, and pharmacological effect since only the unbound fraction is available for distribution into extra-vascular space. The binding of DL76 (1-[3-(4-tert-butyl-phenoxy)propyl]piperidine) to bovine serum albumin (BSA) was studied in vitro by equilibrium dialysis at 37OC and pH 7.4 over the concentration range of 0.32ñ317.18 μM and at a physiological protein concentration of 602 μM. Drug concentrations were determined by validated LC/MS/MS method. Nonlinear regression analyses of the data pointed to a single class of binding sites (m = 1) with a dissociation constant of DL76 equal 49.20 μM. Scatchard plot concave-down curve might indicate positive cooperativity, which was confirmed by the Hill plot with the slope higher than one

Differences in sex hormone levels in the menstrual cycle due to tobacco smoking — myth or reality?

Introduction: Tobacco smoke contains, among others, polycyclic aromatic hydrocarbons (PAHs), heterocyclic analogues, aromatic amines, N-nitrosamines, volatile hydrocarbons, aldehydes, phenols, miscellaneous organic compounds, metals, and inorganic compounds. Tobacco smoking can harm women’s reproductive system and may reduce fertility. The objective of the study was to explore the effect of tobacco smoke on the menstrual cycle due to smoking and second-hand smoke-exposure. Material and methods: The study was performed on 153 women of reproductive age, who received care at the Gynaecological-Obstetric Clinical Hospital of the Poznan University of Medical Sciences. They were divided into three treatment groups: non-smokers, secondhand smokers, and smokers. Comprehensive assessment of all hormone levels: follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E2), and progesterone (P), in the various phases of the menstrual cycle and with concomitant determinations of serum cotinine concentrations was performed. The menstrual cycle was observed with ultrasonography. Results: Cigarette smoking may be an important factor in disrupting reproduction: 1. The increase in the oestradiol E2 level was accompanied by significantly lowered serum cotinine concentrations in tobacco smokers; 2. In smoking patients, the serum level of LH significantly increased on the first days of the menstrual cycle; 3. The higher levels of P (in the 14th and 21st days) were assumed to be the result of a longer menstrual cycle. Conclusions: Active and passive smoking may be an important contributor to reproductive health issues and deserves greater focus in health education programs directed towards women of reproductive age

The current state of knowledge on the prevention of venous thromboembolism in orthopaedic and trauma surgery — selected topics

Profilaktyka żylnej choroby zakrzepowo-zatorowej w ortopedii i traumatologii narządu ruchu należy do zagadnień najlepiej zbadanych i opracowanych w formie szczegółowych zaleceń i protokołów postępowania oraz do najszybciej rozwijających się w całym zakresie problematyki zakrzepowej. Najnowsze doniesienia naukowe dotyczące tego zagadnienia zmuszają do nieustannej modyfikacji podglądów oraz aktualizacji zasad jej stosowania. Zmiany te mogą być publikowane jako opracowania indywidualne lub prace zespołów badawczych powoływanych w tym celu przez stowarzyszenia naukowe. Takim przedsięwzięciem było wyodrębnienie interdyscyplinarnej grupy specjalistów, której celem było określenie aktualnego stanu wiedzy i opracowanie propozycji zaleceń dotyczących wybranych zagadnień z zakresu profilaktyki żylnej choroby zakrzepowo-zatorowej. Grupa ta działała pod auspicjami Prezesa Polskiego Towarzystwa Ortopedycznego i Traumatologicznego oraz Prezesa Polskiej Fundacji do Walki z Zakrzepicą THROMBOSIS. Wyniki prac zespołu zawarto w poniższym opracowaniu. Acta Angiol 2011; 17, 1: 1–36Prevention of venous thromboembolism in orthopaedic and trauma surgery is one of the best-studied topics, with respect to which the most detailed recommendations and management protocols have been drawn up. It is also the fastest-developing area of the study of thrombotic conditions. The most recent reports make us continually modify our views and update the principles of its use. These changes may be published by individual authors or by research teams appointed for this particular purpose by scientific societies. An example of such efforts was the appointment of a multidisciplinary group of specialists whose aim was to determine the current state of knowledge on the prevention of VTE and to propose recommendations on selected aspects of this topic. The group carried out its activities under the auspices of the Chair of the Polish Society of Orthopaedic and Trauma Surgeons and the Chair of the Polish Foundation Against Thrombosis. This paper presents the results of this team’s efforts. Acta Angiol 2011; 17, 1: 1–3