Gámez Rafael, Mendoza Sarahí, Mas Rosa, Noa Miriam, Arruzazabala Lourdes, Carbajal Daysi, Castaño Gladys, Goicochea Eddy, Mesa Meilis, Mendoza Nilda
Center for Natural Products from the National Center for Scientific Research, Havana City, Cuba.
Drugs R D. 2003;4(4):219-29. doi: 10.2165/00126839-200304040-00002.
D-003 is a mixture of long-chain aliphatic primary acids isolated from sugar-cane wax and having cholesterol-lowering effects and a safety profile that have been proven in animals and in previous clinical studies in healthy volunteers. Lovastatin, the first member of the statin class, is an effective and well tolerated cholesterol-lowering drug. Some lovastatin-related adverse effects have been reported, and preclinical assessment has shown that the rabbit is the most sensitive species to lovastatin toxicity.
To compare the cholesterol-lowering effects and toxicity pattern of D-003 and lovastatin in normocholesterolaemic rabbits.
In order to study cholesterol-lowering effects, rabbits were randomly distributed into three groups (eight animals/group): one control group, only receiving the vehicle, and two groups treated with D-003 or lovastatin at 5 and 10 mg/kg/day, respectively. All treatments were orally administered for 30 days. To study toxicity, rabbits were distributed into four groups (six animals/group): one control group and three groups treated with D-003 200 and 400 mg/kg, respectively, or lovastatin 100 mg/kg.
After 30 days, D-003 5 mg/kg and lovastatin 10 mg/kg significantly (p < 0.05) and similarly lowered serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels versus baseline. D-003, but not lovastatin, increased high-density lipoprotein-cholesterol (HDL-C) significantly (p < 0.05), whereas only lovastatin decreased (p < 0.05) triglycerides. Low doses of both drugs did not change safety indicators. D-003 (200 and 400 mg/kg) and lovastatin (100 mg/kg) administered for 10 days reduced TC and LDL-C levels significantly (p < 0.05). HDL-C values increased significantly (p < 0.05) with D-003, but were unchanged with lovastatin. Neither treatment affected triglycerides. No significant changes in lipid profile were observed in the control groups of the two series. Lovastatin 100 mg/kg impaired bodyweight gain and food consumption versus the controls, while D-003 did not. Lovastatin 100 mg/kg increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values (p < 0.05 versus baseline and controls) and liver weight (p < 0.05 versus controls). D-003 200 or 400 mg/kg did not affect AST, ALT or liver weight. Lovastatin 100 mg/kg, but not D-003 200 or 400 mg/kg, induced typical hepatocellular and renal tubular necrosis in the rabbits.
D-003 5 mg/kg/day administered orally for 30 days to normocholesterolaemic rabbits lowered LDL-C and TC, as did lovastatin 10 mg/kg. D-003 was more effective in increasing HDL-C, while lovastatin was more effective in lowering triglycerides. Administration of higher doses for 10 days did not show D-003-related toxicity, but did demonstrate the typical pattern of lovastatin-induced toxicity in rabbits.
D - 003是一种从甘蔗蜡中分离出的长链脂肪族一元酸混合物，具有降胆固醇作用，其安全性已在动物实验及之前针对健康志愿者的临床研究中得到证实。洛伐他汀是他汀类药物的首个成员，是一种有效且耐受性良好的降胆固醇药物。已报道了一些与洛伐他汀相关的不良反应，临床前评估表明兔子是对洛伐他汀毒性最敏感的物种。
比较D - 003和洛伐他汀对正常胆固醇血症兔子的降胆固醇作用及毒性模式。
为研究降胆固醇作用，将兔子随机分为三组（每组8只动物）：一组为对照组，仅给予赋形剂，另外两组分别用D - 003或洛伐他汀，剂量分别为5和10 mg/kg/天。所有处理均口服给药30天。为研究毒性，将兔子分为四组（每组6只动物）：一组为对照组，另外三组分别用200和400 mg/kg的D - 003或100 mg/kg的洛伐他汀处理。
30天后，与基线相比，5 mg/kg的D - 003和10 mg/kg的洛伐他汀显著（p < 0.05）且相似地降低了血清总胆固醇（TC）和低密度脂蛋白胆固醇（LDL - C）水平。D - 003显著（p < 0.05）升高了高密度脂蛋白胆固醇（HDL - C），而洛伐他汀未升高，只有洛伐他汀降低了（p < 0.05）甘油三酯。两种药物的低剂量均未改变安全指标。给予10天的200和400 mg/kg的D - 以及100 mg/kg的洛伐他汀显著（p < 0.05）降低了TC和LDL - C水平。D - 003使HDL - C值显著升高（p < 0.05），而洛伐他汀则无变化。两种处理均未影响甘油三酯。两个系列的对照组中脂质谱均未观察到显著变化。与对照组相比，100 mg/kg的洛伐他汀损害了体重增加和食物消耗，而D - 003未出现此情况。100 mg/kg的洛伐他汀使天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）值升高（与基线和对照组相比，p < 0.05）以及肝脏重量增加（与对照组相比，p < 0.05）。200或400 mg/kg的D - 003不影响AST、ALT或肝脏重量。100 mg/kg的洛伐他汀在兔子中诱导了典型的肝细胞和肾小管坏死，而200或400 mg/kg的D - 003未出现此情况。
对正常胆固醇血症兔子口服给予30天、剂量为5 mg/kg/天的D - 003可降低LDL - C和TC，与10 mg/kg的洛伐他汀效果相同。D - 003在升高HDL - C方面更有效，而洛伐他汀在降低甘油三酯方面更有效。给予较高剂量10天未显示出与D - 003相关的毒性，但确实显示出洛伐他汀在兔子中诱导毒性的典型模式。
