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The aim was to detect and correlate anticancer effects of metformin in combinations with other repurposed drugs, already registered for other indications, which may be immediately applied and clinically investigated in oncology, reducing the time and cost of research for new cancer treatments. Immunohistochemistry was performed for tumors treated by dual drug combinations containing metformin with deoxycholic acid, caffeine, itraconazole, nitroglycerin, disulfiram or diclofenac. The drugs were applied in Syrian golden hamsters (6 animals per group) with the inoculated BHK21/C13 fibrosarcoma in doses equivalent to usual human doses,

Introduction/Objective. Many drugs registered for various other indications can act selectively on tumor receptors, signaling pathways, metabolic processes, bioenergetic factors, enzymes, proteins and genes that regulate tumor proliferation, apoptosis, and neoangiogenesis without affecting these activities in healthy cells. Introduction of new drugs is a very long, complex, and expensive process of research. Detecting an anticancer effect in drugs already registered for other indications and forming their combinations may directly reduce the time and cost of such research. Methods. Anticancer efficacy of metformin and its combinations with caffeine, itraconazole and nitroglycerin was tested on fibrosarcoma experimentally induced by BHK21/C13 cells in Syrian golden hamsters (six animals per group, randomly allocated to control and experimental groups, doses equivalent to usual human doses). After animal sacrifice, tumors were excised and their size, biophysical characteristics, histology, and immunohistochemistry were assessed. Blood samples were collected for hematological and biochemical analyses and the main organs were toxicologically analyzed. Statistical significance was determined by one-way ANOVA followed by the Student–Newman–Keuls post hoc test. Results. Two-drug combinations of metformin with caffeine or itraconazole or nitroglycerin showed significant antitumor effects on hamster fibrosarcoma compared to control, regarding all tested tumor parameters (p < 0.05) without toxicity. Conclusion. Administration of metformin in combination with caffeine or itraconazole or nitroglycerin might be an effective and safe approach in novel nontoxic adjuvant anticancer treatment.

Introduction/Objective. Large diversity in molecular mechanisms of cancer regulation allows some marketed pleiotropic non-oncological non-toxic pharmaceuticals to be used in oncology, which reduces duration and cost of novel anticancer treatment research. To date, there are no published in vivo results on anticancer effects of certain combinations of non-oncological pleiotropic drugs (disulfiram, metformin, deoxycholic acid, mebendazole) that influence MAPK/PI3K/AKT/mTOR/NF-κB signaling. Methods. The anticancer effects of certain aforementioned repurposed drugs combinations, < 50 % LD50 (equivalent to the usual human dose) were assessed by fibrosarcoma growth kinetics (measured daily in vivo by calipers) and tumor proliferation (Ki-67, PCNA), neoangiogenesis (CD34, CD31), glucose metabolism (GLUT1), NO metabolism (iNOS) and apoptosis (COX4, cytochrome C) in hamsters, randomly allocated to control and experimental groups (six animals per group). The animals were sacrificed 19 days after BHK-21/C13 tumor inoculation. The tumors were excised, measured, and blood was collected. Biophysical, pathohistological, toxicological, hematological, and biochemical analyses were performed. Results. Disulfiram with metformin, disulfiram with deoxycholic acid and deoxycholic acid with metformin are the combinations that have shown significant antitumor effects on the fibrosarcoma growth kinetics and tumor immunohistochemical markers in hamsters (p < 0.05). All used drugs in efficacious combinations can inhibit MAPK/PI3K/AKT/mTOR/NF-κB signaling. The addition of NF-κB stimulator mebendazole to effective two-drug combinations rescued cancer growth, indicating that these pathways may be responsible for antitumor action. Conclusion. Combinations of non-oncological drugs: disulfiram with metformin, disulfiram with deoxycholic acid and deoxycholic acid with metformin have the potential to be used as effective non-toxic adjuvant anticancer therapy in oncology.

Bile acids are well known natural surfactants able to modify the per­meability of biological membranes. The logarithm of partition coefficient between, tradi­tionally used, n-octanol and water is a measure of lipophilicity as a predictor of solute membrane partitioning. The aim of this work was to determine partition coefficients of bile acids in a mixture of water and chloroform and dibutyl ether at different pH values and with addition of different concentrations of sodium ions, and to examine the influence of the structure of bile acid nucleus on measured partition coefficients. Partition coefficients of three bile acid salts were determined using shake-flask method and the concentration of bile acids was determined after twelve hours of shaking at the room temperature in aqueous and organic layer using reversed phase HPLC with DAD detector on 210 nm. For all three analysed bile acid salts values of logP are lower in dibutyl ether than in chloroform. At certain pH values, curves representing the dependence of partition coeffi­cient on pH value intersect, and these are the pH values for which partition coefficients are the same for both solvents. Increasing the solution ionic strength, this intersection is shifted toward lower pH values. It is found that, for both organic solvents, after the addition of hy­droxyl group in the steroid nucleus (i.e. if the bile acid is less hydrophobic) the value of logP falls, especially if more hydroxyl groups are present. With chloroform as a solvent, system quickly comes to excess with electrolyte ions than with dibutyl ether. [Projekat Ministarstva nauke Republike Srbije, br. 172021]

Purpose: To evaluate the predictive performance of phenytoin multiple dosing non-linear pharmacokinetic model in rabbits for possible application in therapy individualization in humans. Methods: Phenytoin was intravenously administered to 10 rabbits (2 - 3 kg). Plasma concentrations were measured by high pressure liquid chromatography (HPLC). Rabbits received 3 single phenytoin doses (11, 22 and 44 mg/kg) and plasma concentrations were fitted according to linear twocompartmental model. In all the rabbits, based on 3 different multiple doses (D1, D2, D3, range 9 - 15 mg/kg), 3 steady state plasma concentrations (Css1, Css2 Css3, range 20 - 56mg/l) were achieved. For multiple dosage, the non-linear parameters, Km and Vm, were calculated according to the equations: Km = (D1-D2)/[(D2/Css2)-(D1/Css1)] and Vm = D2+KmD2/Css2, and individually used to calculate Css3 = D3Km/(Vm-D3). Predicted and measured Css3 values were compared. Results: The values for pharmacokinetic parameters after single doses were dose-dependent. The pronounced inter-individual variations in Km (extreme values 18 - 91 mg/l differed 5.5 times) and Vm (11 - 28 mg/kg/h) values were recorded. Significant correlation of predicted Css3 with the measured value for the same dose (D3) was found (r = 0.854, N = 10, p < 0.01). There was no statistical difference between predicted and measured concentrations (t-dependent test = 1.074, p < 0.05). Conclusion: Non-linear parameters, Km and Vm, obtained from only two steady-state concentration measurements can be successfully used to compute and achieve a particular steady-state plasma concentration and optimal dosage regimen. [ABSTRACT FROM AUTHOR]