Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients

Background: Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug's distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds' molecular descriptors and the compounds' tissue:plasma partition coefficients (Kt:p) - often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds' molecular descriptors but also (a subset of) their predicted Kt:p values. Results: Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied. Conclusions: Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models. Figure not available: see fulltext. © 2015 Freitas et al.; licensee Springer

Effects of disulfiram, metal complexes of meloxicam and their combinations on viability and proliferation of human non-small cell lung cancer cells

The selective non-steroidal anti-inflammatory drug meloxicam and its metal [Zn(II), Cu(II), Co(II), Ni(II)] complexes were found in our previous investigations to inhibit the in vitro growth of cultured cell lines established from various cancers (virus-induced transplantable chicken hepatoma and rat sarcoma, human cervical carcinoma and glioblastoma multiforme).Disulfiram, used for decades in the treatment of chronic alcoholism, was proved to express also promising antineoplastic properties.The aim of the present study was to evaluate the influence of disulfiram, metal complexes of meloxicam and their combinations on viability and proliferation of human non-small cell lung cancer cells. The permanent cell line A549 reported to express the cyclooxigenase 2, was used as a model system. Disulfiram was applied at concentrations of 03-100 µg/ml; meloxicam and its Zn(II), Cu(II) and Co(II) complexes were administered at a concentration range of 10-500µg/ml. The investigations were performed using MTT test - the golden standard for cytotoxicity assays, neutral red uptake cytotoxicity assay and double staining with acridine orange and propidium iodide. The results obtained revealed that:  i) Disulfiram decreased viability and proliferation of the treated cells in a time- and concentration-dependent manner; ii) The percent of viable A549 cells cultured in the presence of meloxicam  and its metal complexes was relatively high as compared to the control (CC50 were not determined); iii)   The cytotoxic/cytostatic effect of Cu(II) comlex of Meloxicam was significantly increased when combined with Disulfiram (applied at relatively low toxic concentrations of 6.25 and 12.5µg/ml).Acknowledgements: This study was funded by the Program `Support of Young Scientists at the Bulgarian Academy of Sciences` and a bilateral project between Bulgarian Academy of Sciences and Romanian Academy

Hepatitis E Virus (HEV) Infection Among Immunocompromised Individuals: A Brief Narrative Review

Radostina Alexandrova,1 Ilia Tsachev,2 Plamen Kirov,1 Abedulkadir Abudalleh,1 Hristo Hristov,1 Tanya Zhivkova,1 Lora Dyakova,3 Magdalena Baymakova4 1Department of Pathology, Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; 2Department of Microbiology, Infectious and Parasitic Diseases, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria; 3Department of Synaptic Signaling and Communication, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria; 4Department of Infectious Diseases, Military Medical Academy, Sofia, BulgariaCorrespondence: Magdalena Baymakova, Department of Infectious Diseases, Military Medical Academy, Sofia, Bulgaria, Tel +359-882-28-50-87, Email [email protected]: Hepatitis E virus (HEV) is a single-stranded positive-sense RNA virus that belongs to Hepeviridae family. HEV is the most common cause of acute viral hepatitis worldwide. According to the World Health Organization (WHO), there are estimated 20 million HEV infections worldwide every year, leading to estimated 3.3 million symptomatic cases of HEV infection. The WHO estimates that HEV infection caused approximately 44,000 deaths in 2015, which represents 3.3% of mortality rates due to viral hepatitis. In low-income (LI) countries and lower-middle-income (LMI) countries, HEV is a waterborne infection induced by HEV genotype (gt) 1 and HEV gt 2 that cause large outbreaks and affect young individuals with a high mortality rate in pregnant women from South Asian countries and patients with liver diseases. HEV gt 3, HEV gt 4, and HEV gt 7 are responsible for sporadic infections with zoonotic transmission mainly through the consumption of raw or undercooked meat from different animals. Acute HEV infection is relatively asymptomatic or mild clinical form, in rare cases the disease can be moderate/severe clinical forms and result in fulminant hepatitis or acute liver failure (ALF). Furthermore, HEV infection is associated with extrahepatic manifestations, including renal and neurological clinical signs and symptoms. Pregnant women, infants, older people, immunocompromised individuals, patients with comorbidities, and workers who come into close contact with HEV-infected animals are recognized as major risk groups for severe clinical form of HEV infection and fatal outcome. Chronic HEV infection can occur in immunocompromised individuals with the possibility of progression to cirrhosis.Keywords: acute and chronic infection, cancer, cirrhosis, hepatitis E virus, HEV, HIV, solid organ transplant

Establishment and application of cell cultures from mouse bone explants

The aim of our study was to establish primary cell cultures from mouse bone explants and to introduce them in our laboratory as routine model system in biocompatibility assessment of new materials for bone implants. The cultures were obtained from ICR mice both sexes. Some of their characteristics were studied such as optimal growth conditions (cell culture media and supplements), morphology, in vitro growth properties (doubling time, plating efficiency, ability to form 3D colonies in soft agar), tumorigenic potential in vivo. The cells were maintained as adherent cultures in a Dulbecco`s modified Eagle`s medium (D-MEM) supplemented with 10% fetal bovine serum and antibiotics penicillin (100 U/mL) and streptomycin (100 mg/mL) at standard concentrations. For routine passages the cells were detached using a mixture of 0.05% trypsin and 0.02% EDTA. Some of the cultures survived for more than 50 passages and are still under cultivation. The cells did not form 3D colonies in semi-solid medium and did not induce tumor growths when implanted s.c. into the back of new born ICR mice (7 x 106 cells/mouse). The cultures were successfully applied in biocompatibility assessment of new materials (obtained from bacterial cellulose) for bone implants

Cytotoxic activity of new Zn(II), Co(II) and Ni(II) complexes with kojic acid

Metals have been used in the treatment of various diseases since ancient times. The discovery of cisplatin in 1960 - one of the most effective and widely used drugs in current clinical oncology, opened a new page in medical chemistry and stimulated scientists to search for new metal compounds with promising antitumor activity and acceptable tolerance.The aim of our study was to evaluate the influence of Zn(II), Co(II) and Ni(II) complexes with kojic acid on via­bility and proliferation of human cancer (HeLa uterine cervical carcinoma) and non-cancer (Lep-3 embryonic fi­broblasts) cells. The investigations were based on short-term (up to 72 h, with monolayer cultures) and long-term (up to 40 days, with 3D cancer cell colonies) experiments using methods with different cellular/molecular targets and mechanisms of action: MTT test, neutral red uptake cytotoxicity assay, crystal-violet staining, double stain­ing with acridine orange and propidium iodide, Annexin V/FITC assay and colony-forming method. The results obtained revealed that: i) applied at a concentration range of 5 - 200 μg/mL the compounds tested decrease the percent of the viable treated cells (as compared to the control) in a time- and concentration-dependent manner; ii) administered at a concentration of 200 μg/ml the complexes completely inhibit the ability of HeLa uterine cer­vical carcinoma cells to form 3D cell colonies in a semi-solid medium; iii) cancer HeLa cells have been found to be more sensitive to the cytotoxic effect of the compounds examined as compared to the non-cancer Lep-3 fibro­blasts; iv) Co(II) complex with kojic acid shows the highest cytotoxic activity among the compounds investigated and has demonstrated to be more effective than cisplatin.This study was funded by Grant DFNP-17-73/28.07.2017 from the Program `Support of Young Scientists at the Bulgarian Academy of Sciences` and by a mutual project between the Bulgarian Academy of Sciences and the Ro­manian Academy

Metal complexes of ursodeoxycholic acid and its metal complexes as potential antitumor agents against colon cancer

Colorectal cancer (CRC) takes the third place among the most commonly diagnosed cancer in males and the sec­ond in females. It is the second leading cause of death among neoplastic diseases worldwide.The physiological role of bile acids (BAs) is well known. The prevalence and clinical application of ursodeoxycho­lic acid (UDCA) as well as the data on participation of BAs in the pathogenesis of several liver diseases and gas­trointestinal (colon) tumorigenesis provoke interest in the relationship between UDCA and cancer. Experimen­tal evidence (in vitro and animal studies) suggests that ursodeoxycholic acid may have chemopreventive actions in colorectal cancer.The aim of our study was to evaluate the influence of Cu(II), Zn(II) and Ni(II) complexes of ursodeoxycholic ac­ids on viability and proliferation of cultured human colon cancer cells.In our investigations, we used the permanent cell line HT29 (human colorectal carcinoma) as a model system. The compounds tested were applied at concentrations of 10-200 μg/mL for 24-96 h (for short-term experiments with monolayer cell cultures) and 30 days (for long-term experiments with 3D cell colonies) and their effect on cell viability and proliferation was evaluated by the MTT test, neutral red uptake cytotoxicity assay, crystal violet staining, trypan blue dye exclusion technique, double staining with acridine orange and propidium iodide and colony-forming method.Our results showed that the compounds investigated decreased viability and proliferation of the treated cells in a time- and concentration-dependent manner. Metal complexes expressed more pronounced cytotoxic/cytostatic activity compared to the corresponding ligand ursodeoxycholic acid.The metal complexes examined exhibited promising cytotoxic/antiproliferative properties against HT29 colon cancer cells and deserve further studies to clarify better their anti-tumor potential.Acknowledgements: This study was funded by Grant DFNP-17-89/28.07.2017 from the Program `Support of Young Scientists at the Bulgarian Academy of Sciences` and by a mutual project between the Bulgarian Academy of Sciences and the Romanian Academy

Application and optimization of a complex approach for identification of multi-target anticancer agents

Drug resistance and toxic side effects are among the main obstacles preventing successful treatment of neoplastic diseases. Development and application of agents that have the capability to interact selectively with two or more macromolecular targets is a promising strategy to overcome these challenges. The identification of compounds with anticancer potential requires a complex approach based on a wide spectrum of model systems and methods with different molecular/cellular targets and mechanisms of action. The optimization and introduction of such an approach in our laboratory was the aim of the study presented.The cytotoxic activity of various synthetic compounds with different structure and physico-chemical character­istics (cisplatin, disulfiram, Cu(II) complexes with Schiff bases, etc.) was evaluated in short-term (24-72h, with monolayer cultures) and long-term (30-45 days, with 3D cancer cell colonies) experiments by the MTT test, neu­tral red uptake cytotoxicity assay, crystal violet staining, trypan blue dye exclusion technique, lactate dehydro­genase activity assay, double staining with acridine orange and propidium iodide, Annexin V/FITC assay, Com­et assay and colony-forming method. The investigations were performed using permanent cell lines established from chicken (hepatoma), rat (sarcoma) and human (breast cancer, cervical carcinoma, liver cancer, non-small cell lung cancer, glioblastoma multiforme) cancers of different etiology, histological type and expression of hor­monal receptors (in the case of breast cancer).The conditions for carrying out these methods were optimized and their advantages and disadvantages were specified. Information regarding the influence of the compounds investigated on cell survival and proliferation was obtained. Our results indicate that in order to obtain adequate experimental data, the approach described above has to be adapted to each individual `cell line - compound` system.Acknowledgements: This study was supported by Grant -DCOST 01/16 from 17.08.2017, COST Action CA15135 and a bilateral project between the Bulgarian Academy of Sciences and the Romanian Academy