Thesis (M.Sc.) – Cairo University. Faculty of Pharmacy. Department of Pharmacology & Toxicology.

Includes bibliographical references.

Introduction: Statins are the drug of choice for treatment of hyperlipidemia and prevention of cardiovascular diseases. Treatment with statins dropped off due to adverse effects as hepatotoxicity and myopathy. The purpose of the current study is to make comparison between simvastatin (20 mg/kg) and nano-simvastatin at doses 20mg/kg and 5 mg/kg and to elucidate the synergistic effect of combination of simvastatin (SV), nano-coenzymeQ10 and/or nano-selenium in improving the therapeutic effect and reducing possible side effects.
Methods: this study was divided in to two parts; each group contains (8-10) adult albino rats. First part composed of 5 groups; group 1: rats were received nano-vehicle, group 2: hyperlipidemic rats were introduced to high fat diet (HFD), group 3: hyperlipidemic rats treated by simvastatin (20mg/kg) (HFD & SV), group 4: hyperlipidemic rats treated by nano-simvastatin (20 mg/kg) (HFD & SVNPs20), group 5: hyperlipidemic rats treated by nano-simvastatin (5 mg/kg) (HFD & SVNPs5), Second part composed of 6 groups; group 1: nano-vehicle control group, group 2: hyperlipidemic rats were introduced to high fat diet (HFD), group 3: hyperlipidemic rats treated by simvastatin (20mg/kg) (HFD & SV), group 4: hyperlipidemic rats treated by simvastatin (20 mg/kg) and nano-coQ10 (10 mg/kg) (HFD &SV & coQNPs), group 5: hyperlipidemic rats treated by simvastatin (20 mg/kg) and nano-selenium (0.1 mg/kg) (HFD & SV & SeNPs), group 6: hyperlipidemic rats treated by simvastatin (20 mg/kg), nano-coQ10 (10 mg/kg) and nano-selenium (0.1 mg/kg) (HFD & SV & coQNPs & SeNPs). Hyperlipidemia was induced by feeding rats with high fat diet (HFD) for 16 weeks. Treatments were given orally starting from 13th week simultaneously with HFD for 30 days. Serum samples were separated for determination of lipid profile biomarkers [total cholesterol (T.C) - triglycerides (T.G) - high density lipoprotein (HDL) - low density lipoprotein (LDL) - atherogenic index (AIX)], glucose, insulin, liver function biomarkers [alanine aminotransferase (ALT) - aspartate aminotransferase (AST) – albumin - alkaline phosphatase (ALP)], biomarkers of muscle function [creatine kinase (CK) - myoglobin (MYO) - troponin (Tn-T)] and kidney function biomarkers [creatinine – urea - blood urea nitrogen (BUN)]. Liver was dissected to determine oxidative stress biomarkers [malondialdehyde (MDA) - glutathione (GSH) - superoxide dismutase (SOD)]. Also, histopathological and immunohistochemical examinations were estimated.
Results: hyperlipidemic rats showed significant increments in all measured biomarkers as compared to nano-vehicle control group. SV treated rats showed significant decrease in all mentioned parameters as compared to hyperlipidemic group. Histopathological findings of hyperlipidemic rats showed fatty change in liver tissue and fat droplet deposition with zenkers necrosis in quadriceps muscle tissue section. While, Histopathological findings of SV treated rats showed vacuolar degeneration with some inflammatory cells in liver tissue and also showed fatty deposition between muscle bundles with some atrophied cells in quadriceps muscle tissue. Positive caspase-3 reactivity was noticed in liver and quadriceps muscle in hyperlipidemic and SV treated rats. Treatment with SVNPs 20, SVNPs 5, combined regimen of SV & coQNPs and combined therapy of SV & SeNPs showed significant enhancement in the measured parameters and histopathological and immunohistochemical findings. The triple combination therapy of SV& coQNPs & SeNPs caused significant enhancement in lipid profile biomarkers and marked increase in the other parameters as compared to SV treated group. Histopathological findings in rat’s liver upon administration of this triple combination showed vacuolar degeneration with inflammatory cells and also fat deposition between muscle bundles and atrophy was observed in rat’s quadriceps muscle section. Also, Positive caspase-3 reactivity was noticed in liver and quadriceps muscle of rats treated by this triple combination.
Conclusion: The present results indicate that Administration of SVNPs 20 or SVNPs 5 on hyperlipidemic rats produced an anti-hyperlipidemic, anti-hyperglycemic efficacy and anti-oxidant with lower side effects and the combination therapy of SV & coQNPs and combined treatment of SV & SeNPs exhibited better therapeutic effects than treatment with simvastatin alone with hepatotoxic and myopathic side effects. Unfortunately, the concurrent administration of SV & coQNPs & SeNPs produced anti-hyperlipidemic and anti-hyperglycemic effects with higher incidence of hepatotoxicity, renotoxicity and rhabdomyolysis with regard to SV alone.
Keywords: Hyperlipidemia, simvastatin, hepatotoxicity, rhabdomyolysis, nanomedicine, lipid profile, oxidative stress, myoglobin.

Text in English, abstracts in English and Arabic.