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Cholesterol absorption inhibitor (CAI) targeting Niemann-Pick C1-like1 protein was developed for the treatment of hyperlipidaemia and only ezetimibe was approved so far. For developing novel CAIs, we synthesized sixteen 2-azetidinone derivatives and thirteen 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain, and their inhibitory activity of cholesterol absorption was evaluated in Caco-2 cell line in vitro. Furthermore, top six compounds were measured by cytotoxicity and partition coefficient, and 2-azetidinone analogue 9e was selected for in vivo study. Finally, 9e considerably reduced total cholesterol, LDL-C, FFA and triglyceride in the serum and increased the rate of HDL-C to total cholesterol, suggesting it could regulate the lipid metabolism and act as a potent CAI., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

D-003 is a mixture of high molecular weight sugarcane wax aliphatic primary acids with cholesterol-lowering, anti-platelet and antioxidant effects. This study investigated the long-term oral toxicity and carcinogenicity of D-003 in Sprague Dawley rats of both sexes, randomly distributed into four groups: a control group, treated only with the vehicle, and three treated with D-003 (50, 500 and 1500 mg/kg). All treatments were given orally for 24 months. Mortality (survival analysis), clinical symptoms, weight gain, food consumption, organ weights, time-to-tumour or tumour incidence data were not shown between group differences or trends. With the exception of serum cholesterol levels, lower in D-003-treated groups (500 and 1500 mg/kg) than in the controls, no other difference in blood indicators was found. D-003 did not increase the frequency of neoplastic and non-neoplastic lesions compared with the controls. The occurrence of all malignant and mammary tumours in D-003-treated females was lower than in the controls. The lesions observed were consistent with spontaneous lesions reported in this species. In conclusion, D-003 is not toxic or carcinogenic when given orally to Sprague Dawley rats up to 1500 mg/kg for 2 years, and 1500 mg/kg was a not-observable effect dose.

Policosanol (trade name Ateromixol) is a new cholesterol-lowering drug that has been isolated and purified from sugar cane wax. The effects of policosanol (50-500 mg/kg) administered orally for 18 months to male and female Swiss mice were investigated. No differences in daily clinical observations, weight gain, food consumption and mortality (survival analysis) between groups were found. Histopathological study showed that the frequency of neoplastic (benign and malignant) lesions was similar in the control and policosanol-treated groups. The lesions observed were similar to the spontaneous lesions in Swiss mice reported in previous studies. As no drug-related increase in the occurrence of malignant or benign neoplasm was found, nor acceleration in tumour growth in any specific group observed, this study shows no evidence of policosanol-induced carcinogenicity in Swiss mice.

Three groups of beagle dogs (five/sex/group) were fed olestra, a mixture of octa-, hepta- and hexa-esters of sucrose formed with long-chain fatty acids, at 0, 5 or 10% of the diet for 20 months. The objective of the study was to assess the potential chronic toxicity of olestra in a non-rodent species. The feed was supplemented with vitamins A and E to ensure that the diets were nutritionally adequate and comparable for all groups. The levels of supplementation were established in a 91-day feeding study. Survival was 100% and growth was not affected by olestra. Olestra-fed animals consumed more feed than controls, apparently to compensate for the caloric dilution of the diet by olestra, but the increases were generally not statistically significant. No biologically significant changes were seen in haematological or serum biochemical parameters or in vitamin D and vitamin K status of the animals. Histopathology revealed no olestra-related effects. Isolated incidences of soft stools, apparently resulting from the large amounts of undigested olestra, were noted in olestra-fed animals. The results of this study indicate that olestra was not toxic when fed to dogs at up to 10% of the diet for 20 months.