Biomedical subjects

Remigijus Didziapetris

Publications and source records attributed to Remigijus Didziapetris.

6 recordsLinked to original sources

PubMed2004

Cancer incidence in the workers cohort of textile manufacturing factory in Alytus, Lithuania.

Altogether 14,650 workers employed at least for 1 year a the textile factory in Alytus, Lithuania, were included in the cohort and followed during the period from 1978 to 1997. The standardized incidence ratio (SIR) for men was 1.28. The incidence of esophagus cancer was significant higher (SIR 3.42). It increased only slightly for lung (SIR 1.35). In the women cohort, SIR was 1.05. However, there was a significant increase of the incidence of gallbladder cancer (SIR 3.19). Among textile-processing (spinning and weaving departments) women workers, we found elevated total cancer incidence (SIR 1.35), incidence of breast cancer (SIR 1.49), and cervical cancer (SIR 1.82). In this cohort increased SIR values were observed for more than 10 years since first exposure for all cancer (SIR 1.70) and cervical cancer (SIR 2.44).

Adult↗

PubMed2003

Classification structure-activity relations (C-SAR) in prediction of human intestinal absorption.

AB/HIA is a "soft" filter for identifying compounds with poor intestinal membrane permeability. The analyzed data set included over 1000 drug-like compounds with experimental human intestinal absorption (HIA) values. A sequence of recursive partitioning analyses based on multiple physicochemical and structural descriptors led to the derivation of the rule-based algorithm (filter). The obtained rules reveal a simple physicochemical model of intestinal permeability; they also account for the specific effects caused by quarternary nitrogens and biphosphonate groups. Comparison of the observed and predicted values revealed very low percent of disagreement (15% false-positives and 3% false-negatives). The unusual absorption of compounds that deviated from the predicted values was explained in terms of active transport, efflux, chemical stability, chelating ability, and solubility. Most of these effects can be accounted for by new, substructure-specific rules that can be added into the existing filter. This can lead to the development of a reliable theoretical model for predicting human intestinal absorption. If combined with other models for predicting first pass metabolism, the updated AB/HIA filter can be very useful in predicting oral bioavailability.

Humans↗

PubMed2003

Classification analysis of P-glycoprotein substrate specificity.

Prediction of P-glycoprotein substrate specificity (S(PGP)) can be viewed as a constituent part of a compound's "pharmaceutical profiling" in drug design. This task is difficult to achieve due to several factors that raised many contradictory opinions: (i) the disparity between the S(PGP) values obtained in different assays, (ii) the confusion between Pgp substrates and inhibitors, (iii) the confusion between lipophilicity and amphiphilicity of Pgp substrates, and (iv) the dilemma of describing class-specific relationships when Pgp has no binding sites of high ligand specificity. In this work, we compiled S(PGP) data for 1000 compounds. All data were represented in a binary format, assigning S(PGP) = 1 for substrates and S(PGP) = 0 for non-substrates. Each value was ranked according to the reliability of experimental assay. Two data sets were considered. Set 1 included 220 compounds with S(PGP) from polarized transport across MDR1 transfected cell monolayers. Set 2 included the entire list of 1000 compounds, with S(PGP) values of generally lower reliability. Both sets were analysed using a stepwise classification structure-activity relationship (C-SAR) method, leading to derivation of simple rules for crude estimation of S(PGP) values. The obtained rules are based on the following factors: (i) compound's size expressed through molar weight or volume, (ii) H-accepting given by the Abraham's beta (that can be crudely approximated by the sum of O and N atoms), and (iii) ionization given by the acid and base pKa values. Very roughly, S(PGP) can be estimated by the "rule of fours". Compounds with (N + O) > or = 8, MW > 400 and acid pKa > 4 are likely to be Pgp substrates, whereas compounds with (N + O) < or = 4, MW < 400 and base pKa < 8 are likely to be non-substrates. The obtained results support the view that Pgp functioning can be compared to a complex "mini-pharmacokinetic" system with fuzzy specificity. This system can be described by a probabilistic version of Abraham's solvation equation, suggesting a certain similarity between Pgp transport and chromatographic retention. The chromatographic model does not work in the case of "marginal" compounds with properties close to the "global" physicochemical cut-offs. In the latter case various class-specific rules must be considered. These can be associated with the "amphiphilicity" and "biological similarity" of compounds. The definition of class-specific effects entails construction of the knowledge base that can be very useful in ADME profiling of new drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Progress in toxinformatics: the challenge of predicting acute toxicity.

Historically, acute toxicity based on LC(50) and LD(50) tests has been analyzed using various quantitative structure-activity relationships (QSARs). The obtained QSAR equations cannot be related to the multiple health effects reflected in the experimental data of analyzed compounds. Therefore little predictive power for novel compounds can be achieved. New methods based on classification SAR (C-SAR) analysis offer new mechanistic knowledge that can be related to new health effects, resulting in better predictive power. To this end, a very careful interpretation of the obtained results is required, implying the use of the existing mechanistic information to the maximum possible extent. The current mini-review aims at determining ways of automated extraction of new mechanistic knowledge from existing data, as well as ways of relating this knowledge to various health effects. A comparison of "statistical induction" and "knowledge-based" approaches is provided. The existing and future developments in predictive acute toxicity are discussed.

Algorithms↗

PubMed2002

[Malignant tumor incidence in employees of the Alytus textile factory (1978-1997)].

UNLABELLED: The purpose of this study was to evaluate cancer incidence in the large cotton-manufacturing factory in Lithuania. Altogether 10,198 workers employed at least 1 year in 1969-1997 were included in the cohort and followed during the period 1978/01/01-1997/12/31. National cancer rates were used to calculate the expected number of cancer cases. The overall cancer risk for men was slightly higher than that in the general population (standardized incidence rate (SIR) 1.15, 95% confidence interval (95% CI) 0.98-1.34). A significant increase in the incidence of esophagus (11 observed cases, SIR 3.76, 95% CI 1.88-6.67) and slightly increased of lung (42 observed cases, SIR 1.26, 95% CI 0.91-1.70) cancer became evident. None of the cancer risk showed statistically significant excess cancer incidence in the textile-processing (spinning and weaving) departments (SIR 0.98). In the women cohort the level of the general incidence was very close to expected, standardized incidence rates (SIR) being 0.99 (95% CI 0.88-1.13). However, there was a significant increase in the number of cases of gall bladder (6 observed, SIR 3.19, 95% CI 1.17-6.95). The analysis of the results among textile-processing (spinning and weaving departments) workers indicated the elevated risk of breast cancer (44 observed cases, SIR 1.49, 95% CI 1.08-2.0) and cervical cancer (24 observed cases, SIR 1.68, 95% CI 1.08-2.50). The number of lung cancer cases in this group was a higher, but statistically not significant (5 observed cases, SIR 1.53, 95% CI 0.5-3.58). Increased SIR values were observed for > or = 10 years since the first exposure for all cancers, cervix uteri, ovary and kidney. CONCLUSIONS: The overall cancer risk for men cohort was slightly higher than that in the general population. There was a significant increase in the number of cancer of the esophagus. The overall excess risk in women cohort was only for gall bladder, but for spinners and weavers the elevated risk was for cervix uteri and breast cancer. After 10 years of employment the excess risk was already for all cancers, cervix uteri, ovary and kidney malignant tumors.

Adult↗

PubMedDate not supplied

The effects of jatrophane derivatives on the reversion of MDR1- and MRP-mediated multidrug resistance in the MDA-MB-231 (HTB-26) cell line.

Multidrug resistance (MDR) of cancer cells can be the result of a variety of mechanisms that are not completely understood. One of the most significant among them concerns altered membrane transport in tumor cells, often referred to as typical or classic MDR. This mechanism is related to the overexpression of a variety of proteins, that belong to the super family of ABC transporters. The aim or this study was to look for new effective modulators of MDR1 and multidrug resistance-associated protein (MRP) transporters. Ten diterpenes based on the jatrophane skeleton, including rearranged polycyclic derivatives, were studied on the MDA-MB-231 (HTB-26) human breast cancer cell line. The majority of those compounds were able to strongly enhance the rhodamine 123 accumulation of the human MDR1 gene transfected mouse lymphoma cell line, as previously described. In the present study, the MDR reversal of the same jatrophanes on MDR1- and MRP- mediated resistance of human breast cancer cells is reported. These cells simultaneously express MDR1 and MRP proteins when identified by monoclonal antibodies. However, in a functional assay, where rhodamine 123 accumulation was measured and verapamil was the traditional positive control, only MRP was active, while MDR1 was inactive. Carboxyfluorescein served as a substrate for MRP-mediated drug efflux, and indomethacine was the positive control used as an inhibitor of MRP in the flow cytometric experiments. The effectivity of various jatrophanes was different on the carboxyfluorescein efflux inhibition of the human breast cancer cells. These results may have importance in the planning of a new type of combination chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗