Search

The anticancer effects of metformin (an antihyperglycaemic agent) and itraconazole (an antifungal agent), which are established non-oncologic drugs, were investigated in the present study. The weight, diameter, volume, density, surface, surface to volume ratio and immunohistochemistry of experimental fibrosarcoma tumors were investigated in hamsters treated with metformin and itraconazole. Briefly, the hamsters were injected with BHK-21/C13 cells in order to induce fibrosarcoma, and the animals were treated daily with metformin, itraconazole or a combination of the two drugs. Subsequently, blood samples were obtained for biochemical analyses and the tumors were excised, weighed and measured. The tumor samples were pathohistologically and immunohistochemically assessed for proliferation marker protein Ki-67, hematopoietic progenitor cell antigen CD34, cytochrome c oxidase subunit 4 (COX4), glucose transporter 1 (GLUT1) and inducible nitric oxide synthase (iNOS), and vital organs were toxicologically tested. Ki-67-positivity and cytoplasmic marker (CD34, COX4, GLUT1, iNOS) immunoexpression in the tumor samples were quantified. The results revealed that the combination of metformin and itraconazole significantly altered the physicochemical and pathohistological characteristics of the hamster fibrosarcoma tumors, including absolute and relative weight, volume, density, length, surface area, surface to volume ratio, Ki-67-positivity and the immunoexpression of cytoplasmic markers, without indications of toxicity. Furthermore, metformin with itraconazole demonstrated antiproliferative functions in cervical carcinoma HeLa, colon carcinoma HT-29, lung carcinoma A549 and fibrosarcoma BHK-21/C13 cells, with markedly lower cytotoxicity in the normal fetal lung MRC-5 cells. In conclusion, the administration of metformin in combination with itraconazole may inhibit the growth of fibrosarcoma tumors in vivo and the proliferation of various malignant cell lines in vitro, suggesting that this may be an effective and safe approach as a nontoxic anticancer adjuvant and relapse prevention therapy.

We investigated the anticancer effect of disulfiram and metformin combination on fibrosarcoma in hamsters. Hamsters of both sexes (~ 70 g) were randomly allocated to control and experimental groups (8 animals per group). In all 10 groups, 2 × 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals’ backs. Peroral treatments were carried out with disulfiram 50 mg/kg daily, or with metformin 500 mg/kg daily, or with their combination. Validation and rescue grups were treated by double doses of the single therapy and by the combination with addition of rescue daily doses of ROS inhibitor nitroglycerin 25 mg/kg or NF-κB stimulator mebendazole 460 mg/kg, via a gastric probe after tumor inoculation. After 19 days all animals were sacrificed. Blood samples were collected for hematological and biochemical analyses, the tumors were excised and weighed, and their diameters and volumes were measured. The tumor samples were pathohistologically and immunohistochemically assessed (Ki-67, PCNA, CD34, CD31, COX4, Cytochrome C, GLUT1, iNOS), and the main organs were toxicologically tested. The combination of disulfiram and metformin significantly inhibited fibrosarcoma growth in hamsters without toxicity, compared to monotherapy or control. The single treatments did not show significant antisarcoma effect. Co-treatment with nitroglycerin partly rescued tumor progression, probably by ROS inhibition, while mebendazole completely blocked anticancer activity of the disulfiram and metformin combination, most likely by NF-κB stimulation. Combination of disulfiram with metformin may be used as an effective and safe candidate for novel nontoxic adjuvant and relapse prevention anticancer therapy.

Purpose: To investigate the effect of mebendazole on an in vivo solid tumor model of fibrosarcoma in hamsters.Methods: 24 Syrian golden hamsters of both sexes with the approximate body weight of 100g were randomly distributed in 2 experimental and 2 control groups, with 6 animals in each group. BHK-21/C13 cells (2 x 106) in 1 mL Glasgow Minimum Essential Medium (GMEM) were injected subcutaneously into the back of each animal in 3 groups. The experimental groups were treated with mebendazole (460 mg/kg) via a gastric tube on a daily basis, immediately after tumor inoculation. In addition, one experimental group received deoxycholic acid 20 mg/kg once a day. After 2 weeks, when the tumors were approximately 1 - 2 cm in the control group, all the animals were sacrificed, and their blood collected for laboratory analysis. The tumors were excised, their weight and diameters measured, and the volumes calculated. The tumor samples were histopathologically assessed and the main organs toxicologically analyzed. Images were taken and processed by an imaging software, and Ki-67-positive cells in the tumor samples were quantified.Results: Mebendazole diminished tumor mitosis from 18.5 ± 3.02 to 13.5 ± 3.45 (p < 0.05), vasculature and tissue penetration, and increased necroses in tumor slices. Tumor volume and weight were insignificantly attenuated. Toxicity was not observed.Conclusion: Mebendazole might be an effective non-toxic agent in sarcoma therapy.Keywords: Mebendazole, Hamsters, BHK-21/C13 cells, Fibrosarcoma therapy, Tumor mitosis

Although clinical trials have not been completed, it has already been confirmed that mebendazole, a well-known anti-parasitic drug widely used in the tropical areas, inhibits cancer cell growth. Preclinical studies show that mebendazole notably impedes the growth of malignant and metastatic tumors such as osteosarcoma and soft tissue sarcoma, melanoma, carcinoma (lung, colorectal, breast, ovarian, hepatocellular and adrenocortical), acute myeloid leukaemia, glioblastoma multiforme and meduloblastoma. Mebendazole can induce the depolymerization of microtubules in neoplasms and newly formed vasculature, stopping tumor growth and neoangiogenesis, along with other proposed mechanisms of action.Keywords: Anthelmintic, Mebendazole, Cancer treatment, Antimicrotubullar effect, Antineoangiogenesis

We investigated the effect of nitroglycerin with metformin on fibrosarcoma in hamsters. Syrian golden hamsters of both sexes, weighing approximately 60 g, were randomly allocated to control and experimental groups, with 8 animals per group. In all groups, 2 × 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals’ backs. Peroral treatment carried out with nitroglycerin 25 mg/kg daily, or with metformin 500 mg/kg daily, or with a combination of nitroglycerin 25 mg/kg and metformin 500 mg/kg daily. Later validation experiments were conducted with double doses of the single therapy and additional rescue doses of mebendazole 460 mg/kg daily, via a gastric probe after tumor inoculation. After 2 weeks, when the tumors were approximately 2−3 cm in the control group, all animals were sacrificed. Blood samples were collected for hematological and biochemical analyses, the tumors were excised and weighed, and their diameters and volumes were measured. The tumor samples were pathohistologically and immunohistochemically assessed for proliferation marker protein Ki-67, proliferating cell nuclear antigen PCNA, hematopoietic progenitor cell antigen CD34, cluster of differentiation 31 (CD31), cytochrome c oxidase subunit 4 (COX4), mitochondria marker Cytochrome C, glucose transporter 1 (GLUT1) and inducible nitric oxide synthase (iNOS), and the main organs were toxicologically tested. The Ki-67 and PCNA positivity and the cytoplasmic marker (CD34, CD31, COX4, Cytochrome C, GLUT1, iNOS) immunoexpression in the tumor samples were quantified. The combination of nitroglycerin and metformin significantly inhibited fibrosarcoma growth in hamsters without toxicity, compared to monotherapy or control. The results were validated and confirmed in the subsequently accomplished experiment with doubled doses of the single drug therapy and in the rescue experiment with addition of mebendazole. The single treatments did not show significant antisarcoma effect, regardless of the dose. Co-treatment with mebendazole inhibited anticancer activity of the nitroglycerin and metformin combination. Mebendazole rescued tumor progression suppressed by the combination of nitroglycerin and metformin. Administration of nitroglycerin with metformin might be an effective and safe approach in novel nontoxic adjuvant and relapse prevention anticancer treatment.

Blood loss can be measured directly and indirectly. The latter reflects blood loss through the assessment of hemoglobin level. Thus aim of this study was to determine the applicability of the drop in hemoglobin levels blood loss calculation when transfused blood volume is taken into account on the patients who underwent aneurysmectomy and to estimate whether this model is applicable on geriatric population. In this study, 14 patients were included and their blood loss was calculated based on hemoglobin concentration. Linear correlation (y = 0.18467 + 1.19315·x) with high correlation coefficient (r = 0.90809) was found between calculated and collected blood loss only if transfused blood volume was taken into account. The coefficient of the regression slope for the blood volume measured during surgery and the calculated blood loss in eight patients ≤65 years (y = 0.90866 + 0.86296·x) and six patients >65 years (y = 0.0299 + 1.32707·x) did not show any significant difference. The applicability of the indirect measurement of surgical blood loss, when transfused blood volume was taken into account, was demonstrated in both populations, in the age of 65 and less and in the age over 65 years after aneurysmectomy.

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.

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. Keywords : Phenytoin, Rabbit, Pharmacokinetic model, Multiple dosing, Non-linear, Individualization