Cardiovascular drugs and therapy

Use of combined chemotherapy with etoposide and methotrexate, both associated to lipid nanoemulsions for atherosclerosis treatment in cholesterol-fed rabbits.

PMID 25672520


Treatment of atherosclerotic rabbits with intravenous methotrexate or etoposide carried in lipid nanoemulsions (LDE) markedly reduced the lesions in the aorta. Here, the combined treatment with LDE-methotrexate and LDE-etoposide was investigated aiming to increase the anti-atherosclerosis effect. Thirty-six male rabbits received a diet with 1xa0% cholesterol for 2xa0months. After the first month, the animals received 4 weekly intravenous injections of LDE-methotrexate (4xa0mg/kg dose), LDE-etoposide (6xa0mg/kg), or a combination of those two drugs, while the control animals were injected with LDE (n = 9 for each group). LDE-methotrexate+LDE-etoposide reduced aortic lesion areas by 95xa0% compared with controls and the intima-media ratio was reduced five-fold, whereas LDE-methotrexate reduced the lesions by 81xa0% and LDE-etoposide by 83xa0%. Compared to controls, the positive area of macrophages and MMP-9 in the arterial intima was significantly reduced in all treated groups (p < 0.001), but the MMP9 reduction was greater with the combined chemotherapy than the reduction achieved by the isolated treatments. Presence of CD3 positive cells was equal in controls and LDE-methotrexate+LDE-etoposide treated animals. However, FOXP3 positive T lymphocytes in the intima were increased in the LDE-methotrexate+LDE-etoposide rabbits. Weight, food intake evolution and the hematologic parameters suggested that the treatment had very low toxicity. Compared to the single treatments with LDE-methotrexate and LDE-etoposide, the combined treatment was more effective in reducing the atherosclerotic lesions. Because the toxicity of the novel drug-target combined scheme was low, those results favor the possibility of future clinical studies in patients with cardiovascular disease.