Natasa Milosevic

Reversed-phase TLC and HPLC retention data in correlation studies with in silico molecular descriptors and druglikeness properties of newly synthesized anticonvulsant succinimide derivatives.

The properties relevant to pharmacokinetics of two series of newly synthesized succinimide derivatives have been studied. The properties under consideration have been either determined empirically, by reversed-phase liquid chromatography (TLC and HPLC technique), or calculated with the use of established theoretical medicinal chemistry/drug design software. Chromatographic techniques allowed determination of the retention constants R(M)⁰ and log k(w), which characterize lipophilicity of compounds. Considering potential pharmaceutical importance of succinimide derivatives, we (i) examined the retention behavior in the reversed-phase liquid chromatographic (RP LC) systems, in both planar and column LC, and (ii) determined the relationships between chromatographic data and selected structural features of analytes that are believed to markedly affect their processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox). Significant relationships were found between the retention constants, R(M)⁰ and log k(w), and the in silico calculated bioactivity descriptors, in particular HIA (human intestinal absorption) and PPB (plasma protein binding) parameters. The R(M)⁰ and log k(w) values of the investigated compounds have been recommended for description of their lipophilicity and evaluating pharmacokinetic properties. In view of results of this study the newly synthesized succinimide agents meet pharmacokinetic criteria of preselection of drug candidates and hence qualify for pharmacodynamic phase of antiepileptic drug development. Best compromising human intestinal absorption and plasma protein binding features appear to be compounds A4, A5, A10 and A11.

The influence of phthalates and bisphenol A on the obesity development and glucose metabolism disorders

The prevalence of obesity and type 2 diabetes mellitus epidemics presents a great health problem worldwide. Beside the changes in diet and decreased physical activity, there is growing interest in endocrine disrupting chemicals that may have effects on these conditions. Among them, the role of certain phthalates and bisphenol A is confirmed. We have summarized the existing literature on this issue including cross-sectional, follow up epidemiological studies and in vivo and in vitro studies. Most data support the effects of bisphenol A and some phthalates, such as di-2-ethyl-hexyl phthalate, diethyl phthalate, dibuthyl phthalate, dimethyl phthalate, dibenzyl phthalate, diisononyl phthalate and others on the development obesity and type 2 diabetes mellitus. These endocrine disrupting chemicals interfere with different cell signaling pathways involved in weight and glucose homeostasis. Since the data are rather inconsistent, there is a need for new, well-designed prospective studies.

Chromatographic retention parameters in correlation analysis with in silico biological descriptors of a novel series of N-phenyl-3-methyl succinimide derivatives.

Reversed-phase thin-layer chromatographic (RP TLC) retention coefficients for a newly designed series of N-phenyl-3-methyl succinimide derivatives, of a rationally expected anticonvusant activity, were determined as parameters of their lipophilicity. Basic pharmacokinetic descriptors of the agents were calculated in silico with the use of the established medicinal chemistry/drug design software. Highly significant, predictive relationships were found between the chromatographic retention constants and the bioactivity descriptors, which are assumed to account for drug absorption, distribution, elimination and toxicity (ADMETox) in humans. Among the agents investigated, the compounds with halogen substituent (Compounds nos. 9-13 in Fig. 1), were identified as the best drug candidates, because of their predicted proper pharmacokinetics, and have been selected for further research and development studies on new antiepileptic drugs. At the same time, among the congeners studied these can be indicated, which should not be rationally subjected to bioactivity tests.

Phytotherapy and NAFLD - from Goals and Challenges to Clinical Practice

Non-alcoholic fatty liver disease (NAFLD) is a global problem and one of the most common liver diseases in the world. Various pharmacological and non-pharmacological therapies seem to be non-effective and the patients are often advised not to expect a positive outcome. Hence, even in the modern Western society many patients reach for traditional herbal products. Silymarin, a lipophilic extract derived from milk thistle (Silybum marianum) has been used in liver and bile disorders for centuries. Strong antifibrotic, antioxidant, antiviral and anti-inflammatory activities of silymarin joined with its metabolic effect proven in vitro make it ideal as a drug candidate in the therapy of NAFLD. Several recent randomized clinical studies have demonstrated that silymarin versus placebo significantly contributes to amelioration of the liver condition affected by NAFLD since it reduces steatosis severity, liver ballooning and fibrosis, followed by lowered aminotransferase levels in both short and long lasting therapies. Silymarin is also as efficient as an insulin sensitizer in the NAFLD therapy, but with less adverse effects. Phase III clinical trials have confirmed silymarin to be currently the best medication for the NAFLD patients, but the problems associated with its standardization, formulation and dosage are yet to be solved. However, green tea (Camellia sinensis) and licorice (Glycyrrhiza glabra) root extracts have also been studied in the clinical trials in the therapy of NAFLD patients. Some other herbal products, which have been tested on animals and have the potential to be used in clinical trials, are briefly summarized in this paper.

Reversed- and normal-phase liquid chromatography in quantitative structure retention–property relationships of newly synthesized seco-androstene derivatives

The rational preselection of drug candidates includes also correlation between physico-chemical properties (lipophilicity, as the key one) and pharmacokinetic properties, as well as pharmacodynamic activity. Lipophilicity can be determined alternatively by chromatographic methods. Chromatographic behavior of nineteen newly synthesized derivatives of 16-cyano-16,17-seco-5-androstene has been studied by reversed-phase and normal-phase thin-layer chromatography (RP- and NP-TLC). Commercial plates RP-C18-HPTLC and water-dioxane and water-acetonitrile, as well as Lux(®) silica gel plates and toluene-dioxane and toluene-acetonitrile mixtures with different volume fractions of the solvents were used. Retention constants RM(0) and C0 for each compound were determined and correlated with (i) theoretical log P values and (ii) pharmacokinetic predictors determined in silico. Significant linear relationship was found between RP TLC retention constants, RM(0), and computational logP values as well as between NP TLC retention constants, C0, and logP. Lipophilicity values for the analytes, determined by RP TLC and NP TLC, were also correlated with computer calculated absorption constants, affinity for plasma proteins, volume of distribution and logarithm of blood-brain permeation. Significant linear relationships were obtained. These relations were further improved by introducing other regressors, as molecular size descriptors (molecular mass and/or volume) and a molecular polarity descriptor (total polar surface area). Retention parameters, RM(0) and C0, are recommended for lipophilicity expression of analyzed compounds. In silico pharmacokinetic descriptors for the analytes can be expressed as function of the lipophilicity determined by chromatographic methods, the size and the polarity of the molecules expressed as molecular mass/volume and total polar surface area. The analyzed seco-androstene derivatives have adequate lipophilicity which should provide druglikeness and good pharmacokinetic profiles and they can be recommended for further studies in which their biological activity would be examined.

RP TLC data in correlation studies with in silico pharmacokinetic properties of benzimidazole and benztriazole derivatives.

Reversed-phase thin-layer chromatographic (RP TLC) retention constants for a newly designed series benzimidazole/benztriazole with expected biological activity were determined as parameters of their lipophilicity and this series was recognized as congeneric. Pharmacokinetic descriptors of the compounds investigated were calculated in silico with the use of the established drug design software. The bioactivity descriptors, which are assumed to predicted drug absorption, distribution, metabolism, elimination and toxicity (ADMETox) in humans, were correlated with retention constants and good statistical parameters were obtained. Multiple regression analysis which was introduced suggested that the absorption through different epithelial membranes (intestinal, blood-brain or erythrocyte membrane) and distribution process depend on retention constants (as measure of lipophilicty) and total polar surface area and molar weight/volume of the analyte. Finally, the compounds with halogen substituent (compounds A4/A7 and A5/A8 in Table 1), were suggested as the best drug candidates, because of their predicted proper pharmacokinetics and have been proposed for further biological tests.

Individualization of a pharmacokinetic model by fractional and nonlinear fit improvement

This study presents application of a new linear and nonlinear fractional derivative two compartmental model to the evaluation of individual pharmacokinetics. In the model, the integer order derivatives are replaced by derivatives of real order. A specific nonlinear function is used for the fit improvement of a fractional derivative two compartmental model with the mass balance conservation. The agreement of the values predicted by the proposed model with the values obtained through experiments with bumetanide tablets in human volunteers is shown to be good. Thus, pharmacokinetics of bumetanide can be described well by a linear or a nonlinear two compartmental model with fractional derivatives of the same order proposed here. Parameters in the model are determined by the least squares method and the particle swarm optimization numerical procedure is used. The results show that the linear fractional order two compartmental model for bumetanide is useful improvement of the classical (integer order) two compartmental model and that the nonlinear fractional order model is useful improvement of the linear model in a great number of volunteers.

Estimation of in vivo and in vitro exposure to bisphenol A as food contaminant

The goal of this cross-sectional study was to examine the occurrence of bisphenol A (BPA) in the morning spot urine taken from 145 female volunteers of various ages. Total urine BPA concentration was detected in 38.6% samples in the 0.92-70.96 μg/g Cr range. The majority of BPA + women belonged to the 25 + body mass index (BMI) group (54.5% were overweight and 43.4% were obese women). Occurrence of BPA in the urine samples was higher at 40 + ages. The maximum BPA concentration of 70.96 μg/g Cr was detected in the urine sample of an obese woman. It is known that BPA is highly toxic in vitro. In this study BPA impaired significantly the growth of all investigated cell lines, i.e. the EC50 values were reached at very low concentrations, in the range from 3.24 to 34.85 μg/mL. The obtained in vivo results suggest that a higher exposure to BPA could contribute to weight problems in women and the absence of the BPA in vitro selective toxicity studies indicates to its general toxic mode of action and raises awareness of the health risks associated with its ubiquitous presence in the environment.

Possible influence of the environmental pollutant bisphenol A on the cardiometabolic risk factors.

Abstract Bisphenol A (BPA) is a ubiquitous environmental pollutant which is often associated with various health issues. In this study 103 healthy female volunteers in reproductive age from Serbian north province Vojvodina were enrolled and examined for the BPA exposure in the urine samples after 12 h of fasting. BPA was found in 35.92 % (37/103) of subjects. Statistically significant increment in waist circumference (p = 0.045) and waist-to-height ratio (p = 0.037) was observed among the BPA positive women in comparison with the women who had the same energetic balance and had not been exposed to BPA. Linear correlation was obtained between the BPA concentration in urine samples and body mass index (r2 = 0.35, p = 0.003) waist circumference (r2 = 0.21, p = 0.02) and waist-to-height ratio (r2 = 0.25, p = 0.01) among the obese. High energetic intake and reduced physical activity additionally pronounced BPA positive association with obesity. No statistically significant difference was observed in triglycerides, HDL and LDL cholesterol levels between the BPA exposed and BPA non-exposed female volunteers.

May Patients with Alcohol Liver Disease Benefit from Herbal Medicines

Alcoholism is currently listed as the third leading cause of death. Chronic alcohol consumption brings serious medical complications like gastrointestinal, cardiovascular, musculoskeletal, respiratory system disorders. Liver can be seriously damage by alcohol misuse. Alcoholic Liver Disease (ALD) is the first important warning sign of alcohol abuse. Since effective therapies for ALD are still limited, natural products in the treatment of ALD become very important. In this regard, there have been done very few clinical trials with poor results. Silymarin, glycyrrhizin, garlic show some promising results in ALD patients while the in vivo and in vitro studies with green tee, quercetin and curcumin indicate positive effect on patients with ALD.