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20141
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Subject: Veterinary Pharmacology and Toxicology × Author: Bhat, Mohammad Aamir × Type: Thesis ×
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    ThesisItemOpen Access
    PHARMACOLOGICAL & TOXICOLOGICAL EFFECTS OF PACLITAXEL
    (CSKHPKV, Palampur, 2014) Bhat, Mohammad Aamir; Varshneya, C.
    The present investigation was conducted to study in vitro cytotoxicity, apoptosis and changes in cell cycle kinetics induced by paclitaxel on C6 (Rattus norvegicus glioma) and CHO-K1 (Chinese hamster ovarian carcinoma) cell lines. In this study, percentage cytotoxicity against cell lines was evaluated by Sulphorhodamine (SRB) assay. The percentage of surviving cells fell after 48 hours of treatment and IC50 values were observed between 0.5 to 0.75 and 0.25 to 0.75 μg/ml in C6 and CHO-K1 cells, respectively. Cells incubated in high concentrations of paclitaxel had increased survivability compared with cells treated with lower concentrations of the drug. No significant cytotoxicity was observed after 24 hours of treatment. Paclitaxel induced apoptosis by caspase 3/7 activation and caused accumulation of cells in G2/M phase of cell cycle in both the cell lines. Upon fluorescent microscopy, both the cell lines lost their morphology, confluency and adherence after 24 hours but the effects were much more pronounced after 48 hours of treatment. In vivo toxicological studies were also conducted in adult wistar rats to evaluate the highest non toxic dose level of intra peritoneal administration of Paclitaxel-Cremophor EL formulation at 0.30 (G1), 1.20 (G2), 2.32 (G3) and 3.20 (G4) mg/kg at 7 day interval over a period of 21 days (3 times in total). In acute toxicity studies alopecia and tachypnea was observed in G4. No other signs of acute toxicity and no mortality was observed in any of the dose groups. After repeated dosing, at 21st day, serum aspartate transaminase, alanine transaminase, lactate dehydrogenase, creatinine phosphokinase levels were significantly increased in G3 and G4 and total serum protein, albumin and alkaline phosphatase levels were also increased in G4. No significant changes were observed in serum globulin levels in any of the dose groups. Red Blood cell and lymphocytic count was significantly decreased in groups G3 and G4 and white blood cell, neutrophil count, hematocrit percentage and haemoglobin concentration was also decreased in G4. Histopathological changes were observed mainly as nuclear fragmentation, apoptosis and cellular damage in liver, heart, spleen, kidney, mesenteric lymph nodes, lungs and testes in G3 and G4 but the severity of lesions was much higher in G4. The in vitro data suggested that paclitaxel will be most effective clinically when there is prolonged exposure of tumour to the drug rather than increasing concentration of drug in the biophase. Based on in vivo results, the highest non-toxic dose of formulation was estimated to be 1.20 mg/kg in rats, under this study condition and equivalent human dose was estimated to be 0.1332 mg/kg.