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TERMS
BADGE - Bisphenol A diglycidyl ether DMSO - Dimethyl sulfoxide GSH Glutathione MDA Malondialdehyde NF-B Nuclear factor kappa B PPAR- Peroxisome proliferator activated receptor gamma
I. APPRAISING DIRECTNESS
Patients
Rats with cisplatin induced nephrotoxicity Human renal adenocarcinoma cell lines
Exposure
Group
I: Normal control rats injected IP with0.1 mL diluted DMSO II: Cisplatin injected rats, 7mg/kg IP with Normal Saline Solution III: Pioglitazone 3mg/kg orally one hour before Cisplatin injection IV: BADGE 10 mg/kg IP one hour before Cisplatin V: 10 mg/kg BADGE half hour before oral administration of Pioglitazone 3mg/kg then one hour later, cisplatin was also injected by the same previous dose
Outcome
Reduction of cisplatin-induced nephrotoxicity Potentiation of anticancer effect of cisplatin
7. Were all patients analyzed in the groups to which they were originally randomized?
All patients/ animal subjects were analyzed prior to randomization with the following parameters Adult male Wistar rats weighing 275 + 10 g was obtained from Faculty of Veterinary Medicine, Zagazig University, Egypt. All rats were similar age of about 61-66 days.
Pioglitazone significantly reduced serum creatinine level compared to cisplatin alone at p<0.05. It also increased PPAR- gene expression and reduced NF-kB and TNF- gene expression. BADGE reduced the effect of Pioglitazone and did not have an effect on serum creatinine levels
Combination of pioglitazone and cisplatin resulted in a shift down in cell viability of ACHN cells.
A small probability of p<0.05 means that there is evidence of treatment effect. It is clinically worthwhile because aside from evidence of effect of the treatment on protection against nephrotoxicity, Pioglitazone also potentiated the anticancer effect of cisplatin.
2.
Pioglitazone increased the expression of PPAR- in the renal tissue. This mediated the nephroprotective action of pioglitazone, through the inhibition of NFB signaling pathway, TNF- expression, and macrophage infiltration and antioxidant effects in cisplatin treated rats without interfering with the anticancer effect of cisplatin.
ADDITIONAL QUESTIONS
If you have patients with nephrotoxicity caused by cisplatin, can you give pioglitazone as a treatment?
Pioglitazone can be given as a PROTECTIVE AGENT to reduce nephrotoxicity caused by Cisplatin.
The study focused on the prevention of cisplatin-induced nephrotoxicity. In the said study, pioglitazone was given orally one hour before the administration of Cisplatin. Afterwards, different parameters were used to measure nephrotoxicity of the experimental animals. The study suggests that pioglitazone protected the kidney against cisplatin-induced nephrotoxicity through its interaction with PPAR- receptors and anti-oxidant properties.
If you give pioglitazone, will you expect less toxicity? Less renal problem?
Yes. The results of the study suggest that pioglitazone had nephroprotective effect on cisplatin-induced nephrotoxicity.
The study revealed that pioglitazone decreased serum creatinine and ameliorated tubular necrosis without changing serum urea levels in cisplatin treated rats. In addition, the study also suggests that pioglitazone had antiinflammatory effect in cisplatin treated kidneys. Histopathological examination on the kidneys of the rats treated with pioglitazone showed less tubular necrosis and less glomerular necrosis which indicate that the rats had less renal damage.
In the study, pioglitazone potentiated the cytotoxic effect of cisplatin against ACHN cell lines. However, the cytotoxic effect was abolished by prior administration of BADGE. The cytotoxic effect was evaluated through in-vitro study using human renal adenocarcinoma cell lines. The results obtained were supported by different studies.
BUN - measures the amount of nitrogen contained in the urea. High BUN levels can indicate kidney dysfunction. Malondialdehyde (MDA) - is a major lipid peroxidation product that is mutagenic and tumorigenic. It is used to determine lipid peroxidation. Glutathione (GSH) used to measure antioxidant status.
Histopathological Kidney
Examination
of
the
Tubular necrosis Congestion of glomeruli, capillary and venules Tubular cast and dilatation Mononuclear infiltration in interstitium Thickened basement membrane of glomerulus Glomerular necrosis
While the in-vitro study on the human renal adenocarcinoma cells was sufficient to assess the cytotoxic property of the drugs and their effects when used in combination. The results presented were also supported by different studies. All these supporting studies confirmed current observation that Pioglitazone has nephroprotective effect and it potentiates cisplatin cytotoxic effect on human adenocarcinoma cell lines. .