The aim of the paper is to investigate the effects of adiponectin in diabetic nephropathy; we used an adenovirus to over-express adiponectin (Ad-Adipo) in streptozotocin (STZ)-induced diabetic rats. ...Animals were injected with either Ad-Adipo or control Ad-lacZ at 10 weeks after STZ treatment, and at two weeks postadenovirus injection, renal function was assessed. The degree of proteinuria was significantly reduced in Ad-Adipo rats compared with Ad-lacZ rats. Consistent with this, the mRNA expression levels of nephrin and transforming growth factor β (TGF-β) were significantly increased and decreased in the renal cortex of Ad-Adipo rats, respectively. Moreover, adiponectin over-expression in STZ rats decreased markers of endothelial dysfunction, a feature of diabetic nephropathy disease progression. Endothelin 1 (ET-1), plasminogen activator inhibitor 1 (PAI-1) and inducible nitric oxide synthase (iNOS) mRNA expression levels were significantly reduced in the renal cortex of Ad-Adipo rats, respectively. Concurrently, mRNA expression levels of endothelial nitric oxide synthase (eNOS), a positive regulator of endothelial function, were significantly increased in the renal cortex of Ad-Adipo rats. We have shown that chronic hyperadiponectinemia significantly alleviated the progression of proteinuria in early stage diabetic nephropathy. The mechanism whereby adiponectin decreases proteinuria involves an increase in nephrin expression, and an improvement of the endothelial dysfunction due to decreases in ET-1 and PAI-1, and an increase in eNOS expression in the renal cortex. Thus, over-expression of adiponectin has beneficial effects on early stage diabetic nephropathy.
Etoposide {4'-demethylepipodophyllotoxin-9 (4, 6-O-ethylidene-β-D-glucopyranoside)}, an anticancer drug, is a semisynthetic derivative of podophyllotoxin, and it is claimed to be effective in a lung ...and testis cancer and in lymphoma. We have studied the tissue and organ distribution of 3H-Etoposide by whole body autoradiography and quantitative determination of radioactivity in the tissues and organs of rats. 3H-Etoposide distributed mainly in the liver, intestine and kidney. It was in good agreement with the fact that 3H-Etoposide was mainly excreted into the bile in the case of rat. No 3H-Etoposide was found in the brain after a single administration, it was regarded that Etoposide almost did not penetrate through the blood-brain barrier. Only a slight radioactivity was found in the brain after the consecutive p.o. administration for 10 days. When 3H-Etoposide was administered to the pregnant rats, radioactivity was found in the fetus in concentration about 1/10 of maternal blood level. In the consecutive administration, the concentration in most tissues and organs was higher than that after single administration, whereas the half-lives in these organs (β-phase) were not prolonged. One may conclude, concerning the above fact, that Etoposide did not accumulate in tissues and organs.
Etoposide {4'-demethylepipodophyllotoxin-9 (4, 6-O-ethylidene-β-D-glucopyranoside)}, an anticancer drug, is a semisynthetic derivative of podophyllotoxin, and it is claimed to be effective in a lung ...and testis cancer and in a lymphoma. We have synthesized a tritium labeled Etoposide (3H-Etoposide) for the pharmacokinetics study. The blood concentration of 3H-Etoposide in dog was decreased relatively fast in a tri-exponential pattern following i.v. injection. The blood level of 3H-Etoposide in dog reached to a maximum level i.v. or p.o. administration, and then it diminished relatively rapidly in a biexponential manner from the blood. Bioavailability in dog after p.o. administration was 13.1 % calculated from the AUC after i.v. and p.o. administration. Cumulative excretion following i.v. and p.o. administration were 75 and 86 %, respectively. The blood concentration of 3H-Etoposide was same both in rats and dogs, and bioavailability was 14.1 % obtained from the AUC data. The half-life of β-phase after the consecutive i.v. injection was prolonged to about 2 times than that after a single injection. The total excreted amounts to urine and feces were 95 % during 72 hours after a single and consecutive injection, indicating that excreted amount (% of administered dose) was not changed by the consecutive administration. 3H-Etoposide was mainly excreted into the bile in rats, and 68.1 and 33.8 % of it was excreted into the bile after i.v. and p.o., respectively, during 72 hours after administration. The reabsorption rate of 3H-Etoposide in rat was 9.3% of i.v. administered dose and 12.5 % after p.o. administration. The absorption rate of 3H-Etoposide in rat was about 40 % calculated from the total excretion in urine and bile after p.o. administration. 3H-Etoposide was also excreted into the milk to higher extent than to the blood. This was regarded to be due to the high lipophilicity of Etoposide.
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