الفهرس 
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Abstract
Owing to the great importance of paclitaxel in chemotherapy for the treatment of various tumor cancers, the researchers put a lot of efforts into preventing or reducing the side effects of paclitaxel (Taxol) on many organs, including the liver, kidneys and heart. The most instantaneous approach was the combination of chemotherapy medication with a powerful antioxidant herbal medicinal component as protective and chemo- prophylactic agents. This may be the most effective way to reduce the toxic side effects of the drug. To achieve this objective, the adult male albino rats used in this study were divided into five groups (10 rats per group):
1- group I (Normal group):
Rats in this group were administered orally 5 ml 1% CMC/kg b. wt every other day and 2ml isotonic saline (0.9% NaCl)/kg b. wt twice a week by intraperitoneal route for six weeks.
2- group II (paclitaxel-administered control group):
Rats in this group were administrated paclitaxel intraperitoneally at a dose of 2 mg/kg b. wt twice a week. This group was also administered orally an equivalent volume of 1% CMC (5 ml/kg b. wt) every other day for six weeks.
3- group III (paclitaxel-administered group treated with rutin):
Rats in this group were administered paclitaxel intraperitoneally like paclitaxel-administered control group and were also treated orally with rutin at a dose of 10 mg/kg (dissolved in 5 ml 1% CMC) b. wt every other day for six weeks.
4- group IV (paclitaxel-administered group treated with hesperidin):
Rats in this group were administered paclitaxel intraperitoneally like paclitaxel-administered control group and were also treated orally with hesperidin at a dose of 10 mg/kg (dissolved in 5 ml 1% CMC) b. wt every other day for six weeks.
5- group V (paclitaxel-administered group treated with the mixture of rutin and hesperidin):
Rats in this group were administered paclitaxel intraperitoneally like paclitaxel-administered control group and were also treated orally with the mixture of rutin and hesperidin at a dose of 10 mg/kg (dissolved in 5 ml 1% CMC) b. wt every other day for six weeks.
The results of the current study revealed that paclitaxel caused a marked elevation in serum parameters related to liver function, including ALT, AST, GGT and ALP activities, along with total bilirubin level, even though reduced albumin level. Accordance with these biochemical changes, remarkable histopathological alterations in liver tissue were detected in paclitaxel-administered animals in the form of congestion of the central veins and portal area blood vessels, marked degenerative including fatty changes and moderate necrotic changes with focal nuclear pyknosis in certain areas, focal leuckocytic infiltration mainly mononuclear cells and proliferation of Kupffer cells. While, most of these biochemical and histopathological changes were effectively improved by the treatment of these animals with rutin and/or hesperidin.
The obtained data from IHC staining of the liver sections in paclitaxel-administered rats, revealed a significant increase of caspase-3 activity and TNF-α concentration. On the other hand, the treatments successfully improved these changes.
Paclitaxel administration induced nephrotoxicity that was verified by elevations in serum urea, uric acid and creatinine levels, besides histopathological changes in the form of degenerative changes and nuclear pykosis of the lining epithelium of the renal tubules associated with glomerulonephrosis in most glomeruli. Focal interstitial nephritis could be found. Furthermore, congestion was found in the glomerular tuft and interstitial blood capillaries. While, the treatments declined the elevated levels of serum urea, uric acid and creatinine plus ameliorated the histological deterioration of the kidney.
Paclitaxel-induced cardiotoxicity was verified by elevations in serum CK-MB and LDH activities, furthermore, histopathological changes, including severe hyalinosis associated with focal lymphocyte infiltration, were observed in the hearts of rats administered paclitaxel. The treatment of these animals with rutin and/or hesperidin, successfully prevented most of these biochemical and histological alterations.
Regarding liver, kidney and heart oxidative stress and antioxidant defense system, the treatment of paclitaxel-administered rats with rutin and/or hesperidin reduced the elevated LPO and improved GSH content, and activities of GPx and SOD.
Conclusion:
Oral administration of rutin, hesperidin, and their combination could counteract paclitaxel-induced liver, kidney and heart damage and toxicity through strengthening the antioxidant defense system and decreasing oxidative stress and apoptosis. Additionally, it was discovered that rutin and hesperidin combined therapy was the most effective at restoring liver, kidney and heart function and histological integrity in paclitaxel-administered rat models. However, before rutin and hesperidin be used in humans, more clinical trials are necessary to evaluate their effectiveness and safety during paclitaxel administration. The Food and Drug Administration also needs to approve their use of these flavonoids in human beings. Moreover, further studies are required to scrutinize the effect on mediators of apoptosis other than caspase 3 and mediators of inflammation other TNF-α to identify other targets of rutin and hesperidin in paclitaxel-administered rat.