# Hyperlipidemic Rabbit Models for Anti-Atherosclerotic Drug Development
## 3 Hyperlipidemic Rabbit Models for the Development of Drugs
### Ezetimibe  
Ezetimibe is an inhibitor of cholesterol absorption through the targeting of Nieman Pick C1 like 1 protein at the brush border of intestinal epithelial cells. Ezetimibe is often prescribed for patients with elevated plasma TC, LDL-C, and apo B, either as monotherapy or in combination with statins [76]. The pharmacological functions of ezetimibe on atherosclerosis, thrombosis, and fatty liver disease have been investigated in rabbits (Table 2). [PERSON] et al. examined the effect of ezetimibe combined with simvastatin on cholesterol-fed rabbits with femoral artery injury. Although ezetimibe did not significantly change plasma TC levels, the intima/media ratio of the femoral artery was reduced by 13% (ezetimibe), 27% (simvastatin), and 28% (zeetinibe plus simvastatin) compared with that of control rabbits [77]. [PERSON] et al. evaluated the effect of ezetimibe on atherothrombosis [78]. Atherosclerosis was induced by cholesterol diet feeding and balloon injury, and then plaque disruption and thrombosis were triggered by [PERSON]'s viper venom and histamine. Ezetimibe treatment reduced plasma TC levels and decreased plaque size and thrombus area [78]. [PERSON] et al. recently showed that ezetimibe treatment significantly decreased thrombus occlusion in the femoral artery in angiotensin II-perfused rabbits [79]. In addition, [PERSON] et al. examined the effect of ezetimibe on rabbits with nonalcoholic steatohepatitis, which was induced by feeding a diet containing 1.25% cholesterol and 20% corn oil. Ezetimibe therapy lowered plasma TC levels and suppressed hepatic fat depositions and fibrosis [80].  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multicolumn{2}{c}{**Target Disease**} & \multicolumn{1}{c}{**Prague**} & \multicolumn{1}{c}{**Plasma TC**} & \multicolumn{1}{c}{**Outcome**} & \multicolumn{1}{c}{**Reference**} \\ \hline \multirow{4}{*}{\(\bullet\)} & Atherosclerosis & Ezetimibe (0.6 mg/kg) & 8\% \(\downarrow\) & 13\% \(\downarrow\) * & \\  & NZW (male) & Simvastatin (5 mg/kg) & 26\% \(\downarrow\) & 27\% \(\downarrow\) * & \\  & 2\% Chol, 6\% peanut oil diet & Combination (Eze + Sim) & 37\% \(\downarrow\) & 28\% \(\downarrow\) * & [77] \\  & Endothelial desiccation & for 6 weeks & (6 weeks) & (Femoral artery, & \\  & & & & intima/media ratio) & \\ \hline \multirow{4}{*}{\(\bullet\)} & Atherothrombosis & Ezetimibe (1 mg/kg) & 86\% \(\downarrow\) * & Plaque area: 38\% \(\downarrow\) * & \\  & NZW (male) & for 3 months & (6 months) & Thrombus area: 93\% \(\downarrow\) * & \\  & 1\% Chol diet (alternating & & & \\  & with normal chow every & & & & \\  & other month) & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\ \hline \multirow{4}{*}{\(\bullet\)} & Atherothrombosis & Ezetimibe (0.6 mg/kg) & 18\% \(\downarrow\) * & 51\% \(\downarrow\) * & \\  & JW (male) & Rosvastatin (1 mg/kg) & 23\% \(\downarrow\) * & 12\% \(\downarrow\) & \\  & 1\% Chol, 3\% peanut oil diet & for 2–8 weeks & (4 weeks) & (Thrombotic occlusion) & Honda [79] \\ \cline{1-1}  & Balloon injury & & & & \\ \cline{1-1}  & Angiotensin II (50 ng/kg & & & \\  & per min) infusion & & & & \\ \hline \multirow{4}{*}{\(\bullet\)} & NASH & Ezetimibe (0.6 mg/kg) & \(\approx\) 40\% \(\downarrow\) * & Lipid droplet \(\approx\)15\% \(\downarrow\) * & \\  & JW (male) & for 8 weeks & (8 weeks) & Hepatic TC: \(\approx\)26\% \(\downarrow\) * & Ogawa [80] \\ \cline{1-1}  & 1.25\% Chol, 20\% corn oil diet & & & & Hepatic TG: \(\approx\)63\% \(\downarrow\) * & \\ \hline \multicolumn{2}{c}{NZW, New Zealand white; JW, Japanese white; Chol, cholesterol; TN, nonalcoholic steatohepatitis; TC, total cholesterol; TG, triglycerides. Plasma TC and outcomes are expressed as \(\%\) compared with those of control rabbits (* \(p<0.05\)).} & & \\ \hline \hline \end{tabular}
\end{table}
Table 2: Ezetimibe in rabbit models.