4. Discussion

Intravenous lipid emulsion is presented as a lifesaving treatment of lipophilic drug intoxications (12,14,15). ‘Lipid sink’ theory is the most emphasized theory explaining how ILE works, was first introduced by Weinberg et al. in 1998 (12). According to this theory, by administering ILE intravenously, expansion in the lipid compartment of blood is provided. The drug, which is at a toxic level, first migrates to the aqueous part of the plasma and then to the lipid compartment, which is subsequently dissolved, thereby reducing the amount of active drug in the target tissue. Because of these properties, it is suggested that lipid emulsions trap oil-soluble toxic substances in circulation and cause to sink in the emulsion (12). Another theory is the ‘Ion Channel Theory’. In this theory, it has been suggested that free fatty acids in lipid therapy have been shown to activate voltage-gated calcium channels and increases intracellular calcium level. These mechanism has positive inotropic effect on myocytes (21–23). The other theory is that the lipid emulsion is used as a source of cardiac energy. Fatty acids are used for myocardial ATP synthesis in normal resting cardiac tissue (24). In recent literature it is said that this cleaning effect is not only a static waste effect, but also a dynamic shuttle effect (14). The lipid compartment in the blood creates a shuttle effect by removing lipophilic drugs from organs. In this way, organs with high blood flow are detoxified from the drugs. Although the mechanism of action is not fully understood, it is thought that the effectiveness of ILE in the intoxication of local anesthetic and other lipophilic drugs depends on the combined effects of these mechanisms (15). Based on these theories we had investigated the effectiveness of ILE in reversing the unwanted effects of pioglitazone at a single dose of ½ LD50. We had used histopathological evaluation in order to test and compare the changes. Our results showed that toxic effects may occur in the liver and kidney in an acute intoxication model with a given dose of pioglitazone, and intralipid emulsion therapy is not fully effective in reversing these toxic effects. Besides, ILE itself may have nephrotoxic effects. In the literature, studies and case reports about pioglitazone generally showed that it has hepatotoxic effects both in acute or subacute overdoses which is also consistent with our study. Farley Hills et al. reported a patient who developed and died of acute hepatitis due to pioglitazone use (25). May et al. reported a case in which increased liver transaminase levels and histopathological changes in the liver due to pioglitazone use and these effects improved after discontinuing pioglitazone (26). Chase et al. reported a patient presenting with fulminant liver failure due to pioglitazone use and liver failure was recovered after discontinuing the drug (27). The mechanism for hepatotoxicity it is thought to be related with inhibition of ATP production by pioglitazone which causes cytotoxicity and oxidative stress. Reactive metabolite formation and hepatocyte mitochondrial dysfunction may occur by this way (28). On the contrary, El Gawly et al. reached a different result with their experimental studies. In their study, streptozotocin was used to generate diabetes mellitus in the animal model. For the pioglitazone dose, the maximum daily dose for humans, 4mg/kg, was used. The study showed that pioglitazone may have positive effects on the liver (29). This different result might be related with low dose of pioglitazone in this study. Our result showed a significant hepatotoxicity with ½ LD50 dose of pioglitazone. The answer to the question of whether ILE can reverse this toxic effect was negative. Elimination of pioglitazone and its excretion of metabolites are mainly from the liver. Renal clearance of pioglitazone is very low (30). Chinnam et al. showed that the acute toxicity of the pioglitazone in an animal model caused congestion in the kidney besides changes in the liver and heart tissue (8). In the study of Sai Elshama et al., subchronic toxicity was created for 90 days in an animal model of diabetes mellitus. They showed similar results with the Chinnam et al in the kidney tissues of the subjects (9). Our results about renal toxicity are consistent with the literature. ILE did not have a positive effect on reversing the toxic effects of pioglitazone on kidney according to our results. Besides, we observed toxic effects of ILE on the kidney cells in the 2nd group which we had administered only ILE. Even if the underlying mechanism is not fully understood studies showing that ILE itself is renal toxic, our findings are also consistent with the literature (31,32). Some experimental studies also showed that pioglitazone also has toxic effects on heart tissue. Yang et al. reported that pioglitazone causes cardiac muscle hypertrophy and subsequent ventricular hypertrophy in an animal model. They gave daily pioglitazone at a dose of 200 and 540 mg/kg/day for 12 weeks (33). Therefore, we had also investigated the histopathological changes on our subjects’ heart tissues. Although some changes observed in the 3rd and 4thgroup which we had administered pioglitazone, those were not found statistically significant. We thought that more long-term use might be needed in order to see a significant cardiac muscle hypertrophy. ILE did not change the heart tissue evaluations in our study.