Biljana Govedarica

Protective effects of fullerenol C60(OH)24 against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats with colorectal cancer

The effects of fullerenol C60(OH)24 (Frl) at doses of 25, 50, and 100mg/kg/week (for a time-span of 3 weeks) on heart and liver tissue after doxorubicin (Dox)-induced toxicity in rats with colorectal cancer were investigated. In the present study, we used an in vivo Wistar male rat model to explore whether Frl could protect against Dox-induced (1.5mg/kg/week for 3 weeks) chronic cardio- and hepato- toxicity and compared the effect with a well-known antioxidant, vitamin C (100mg/kg/week for 3 weeks). According to macroscopic, microscopic, hematological, biochemical, physiological, pharmacological, and pharmacokinetic results, we confirmed that, at all examined doses, Frl exhibits a protective influence on the heart and liver tissue against chronic toxicity induced by Dox.

Acute doxorubicin pulmotoxicity in rats with malignant neoplasm is effectively treated with fullerenol C60(OH)24 through inhibition of oxidative stress

The aim of this study was to investigate the possible protective role of fullerenol (FLR, C(60)(OH)(24) on doxorubicin (DOX)-induced lung toxicity using biochemical and histopathological approaches. Rats (Sprague-Dawley outbred) were randomly divided into five groups. The healthy control group received no medication (saline only). The other four groups had chemically induced breast cancer (1-methyl-1-nitrosourea; 50 mg/kg, ip). The second group was the cancer control group (saline only). The other three groups were DOX (8 mg/kg, ip), FLR/DOX (100 mg/kg, ip, 30 min before DOX; 8 mg/kg, ip), and FLR (100 mg/kg, ip), respectively. The levels of malondialdehyde (MDA) and oxidized glutathione (GSSG) in the lung tissue were higher in the group treated with DOX alone than in the control groups. The activities of catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), and lactate dehydrogenase (LDH) were found to be increased in the lung tissue of the animals in the DOX group over all the other groups, while GSH-Px significantly decreased in activity compared with the control and FLR groups. There was no significant difference in MDA and GSSG levels and enzyme activities in either control (healthy; cancer) or FLR (FLR/DOX; FLR) groups. The acute change found in the DOX group was subpleural edema. In contrast, the groups treated with FLR appeared to be virtually histopathologically normal. In conclusion, this study clearly indicates that DOX treatment markedly impairs pulmonary function and that pre-treatment with FLR might prevent this toxicity in rats through inhibition of oxidative stress.

Deformation properties of pharmaceutical excipients determined using an in-die and out-die method

This study investigated deformation mechanisms of some commonly used pharmaceutical fillers, such as microcrystalline cellulose, lactose, dicalcium phosphate, isomalt and cornstarch, using a combination of the in-die and out-die method with the Heckel and Walker models. The tableting mixtures contained of 98.5% (w/w) filler, the rest consisted of dry binder and an antiadhesive agent. Our results showed that plasticity and elasticity may be considered independent deformation properties as highly plastic materials (microcrystalline cellulose, cornstarch) also exhibited high elasticity. Particular emphasis was placed on explaining the differences observed between the in-die and out-die method-comparison revealed that the differences are a consequence of the materials elastic properties. Larger error of in-die results can be expected for more elastic materials, and thus in-die Heckel should be used with some considerations. In contrast, the Walker model was found to be more robust and smaller differences were observed between the two methods. We consider the most correct results to have been obtained by the out-die approach, which excludes the elastic properties of the material evaluated. An excellent correlation between elastic determination at the single-particle level and multiple-particle scale was demonstrated, suggesting a great potential of nanoscale determination of a materials mechanical properties for better elucidation of deformation mechanisms.

Nanosized particles of orlistat with enhanced in vitro dissolution rate and lipase inhibition

Orlistat is locally acting inhibitor of gastrointestinal lipases which has been developed for the treatment of obesity. The present study was designed with the intent to formulate orlistat in a different way compared to the current practice and investigate its inhibition of gastrointestinal lipases. Orlistat is considered as a technologically problematic and unmanageable substance because of waxy nature, low melting point and low chemical stability. The manuscript presents the critical issues regarding engineering of its nanosuspension with controlled particle size by melt emulsification and high pressure homogenization. In order to formulate dry product, lactose was dissolved in nanosuspension as filler and spray drying has been performed for obtaining the final powder product. Laser diffraction, scanning electron microscopy and atomic force microscopy have been used for orlistat nanosuspension characterization, dissolution studies and lipase inhibition studies were performed to characterize the in vitro efficacy of formulated orlistat. The advantage of selected technological procedures is nanosized orlistat with elevated in vitro dissolution rate in comparison to raw drug, physical mixture and marketed product. Furthermore, nanosuspension demonstrated significantly higher in vitro lipase inhibition in comparison to references. To conclude, the results show new technological solution and remarkable increase of pharmacological effect which could potentially lead to decreasing the dose and consequently dose dependent side effects.

Roxithromycin-loaded lipid nanoparticles for follicular targeting

Particulate drug carriers e.g. nanoparticles (NPs) have been shown to penetrate and accumulate preferentially in skin hair follicles creating high local concentration of a drug. In order to develop such a follicle targeting system we obtained and characterized solid lipid nanoparticles (SLN) loaded with roxithromycin (ROX). The mean particle size (172±2 nm), polydisperisty index (0.237±0.007), zeta potential (-31.68±3.10 mV) and incorporation efficiency (82.1±3.0%) were measured. The long term stability of ROX-loaded SLN suspensions was proved up to 26 weeks. In vitro drug release study was performed using apparatus 4 dialysis adapters. Skin irritation test conducted using the EpiDerm™ tissue model demonstrated no irritation potential for ROX-loaded SLN. Ex vivo human skin penetration studies, employing rhodamine B hexyl ester perchlorate (RBHE) as a fluorescent dye to label the particles, revealed fluorescence deep in the skin, specifically around the hair follicles up to over 1mm depth. The comparison of fluorescence intensities after application of RBHE solution and RBHE-labelled ROX-loaded SLN was done. Then cyanoacrylate follicular biopsies were obtained in vivo and analyzed for ROX content, proving the possibility of penetration to human pilosebaceous units and delivering ROX by using SLN with the size below 200 nm.