Jokubaitis L A
Cardiovascular Clinical Research, Sandoz Research Institute, East Hanover, NJ 07936, USA.
Br J Clin Pract Suppl. 1996 Jan;77A:28-32.
Fluvastatin, a new synthetic inhibitor of HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, has been studied in several models to examine its effects when used in combination with other lipid-modifying agents such as derivatives of fibric acid (bezafibrate), resins (cholestyramine), and niacin. The combination of fluvastatin with bezafibrate has been studied in a double-blind trial involving patients with well-documented familial hypercholesterolaemia. Fluvastatin 40 mg/day, combined with either bezafibrate 400 mg/day or cholestyramine 8 g/day, resulted in reductions in levels of low-density lipoprotein cholesterol (LDL-C), these being indistinguishable between the groups; however, significantly greater increases in levels of high-density lipoprotein cholesterol (21.3%) and reductions in levels of triglycerides (25.1%) were seen with the fluvastatin-bezafibrate combination. No notable increases were seen in levels of serum creatine kinase, aspartate aminotransferase, or alanine aminotransferase, and no cases of myopathy were observed. In a study model that examined low-dose combinations of fluvastatin with cholestyramine, reductions in levels of LDL-C of 15.8% and 19.3% were seen with fluvastatin 10 mg and 20 mg, respectively. After an 8-week interval in which a daily dosage of cholestyramine 8 g was added, from baseline, reductions of 26.3% in the 10 mg fluvastatin-cholestyramine group and 31.2% in the 20 mg fluvastatin-cholestyramine group were observed, whereas the placebo-cholestyramine group displayed a reduction of 14.9%. Doubling the resin dosage to 16 g/day for the final 8 weeks of the study provided little additional benefit. Myotoxicity has been observed when lovastatin is coadministered with niacin, and so the combination of niacin with fluvastatin has also been studied to examine the possibility of this effect occurring. Patients were randomised to either fluvastatin 20 mg or placebo for 6 weeks, after which time open-label niacin was administered to all patients and titrated to a final dosage of 3 g/day. After 6 weeks, fluvastatin produced a 20.8% reduction in LDL-C levels from baseline. When combined with niacin, a 43.7% reduction was noted at the week 15 endpoint, against the 26.5% reduction seen with niacin monotherapy. The combination was well tolerated, with no reports of myopathy or of significant elevations in creatine kinase or liver transaminase levels. Combinations of fluvastatin with a variety of other agents have been shown to have significant effects on lipid profiles, with no evidence to date of clinically remarkable safety findings. Thus, the use of combination therapies may result in optimal management of patients with moderately severe hypercholesterolaemia and mixed dyslipidaemic profiles.
氟伐他汀是一种新型的HMGCoA（3-羟基-3-甲基戊二酰辅酶A）还原酶合成抑制剂，已在多种模型中进行研究，以考察其与其他调脂药物（如纤维酸衍生物（苯扎贝特）、树脂类（考来烯胺）和烟酸）联合使用时的效果。在一项涉及有明确家族性高胆固醇血症记录患者的双盲试验中，对氟伐他汀与苯扎贝特的联合用药进行了研究。每天服用40mg氟伐他汀，联合400mg/天的苯扎贝特或8g/天的考来烯胺，均可使低密度脂蛋白胆固醇（LDL-C）水平降低，两组间无差异；然而，氟伐他汀与苯扎贝特联合用药组的高密度脂蛋白胆固醇水平显著升高（21.3%），甘油三酯水平降低（25.1%）。血清肌酸激酶、天冬氨酸转氨酶或丙氨酸转氨酶水平未见明显升高，也未观察到肌病病例。在一项研究低剂量氟伐他汀与考来烯胺联合用药的模型中，10mg和20mg氟伐他汀分别使LDL-C水平降低了15.8%和19.3%。在间隔8周后，每天加用8g考来烯胺，与基线相比，10mg氟伐他汀-考来烯胺组降低了26.3%，20mg氟伐他汀-考来烯胺组降低了31.2%，而安慰剂-考来烯胺组降低了14.9%。在研究的最后8周将树脂剂量加倍至16g/天，未带来额外益处。洛伐他汀与烟酸合用时曾观察到肌毒性，因此也对烟酸与氟伐他汀的联合用药进行了研究，以考察这种效应发生的可能性。患者被随机分为服用20mg氟伐他汀组或安慰剂组，为期6周，之后所有患者均给予开放标签的烟酸，并滴定至最终剂量3g/天。6周后，氟伐他汀使LDL-C水平较基线降低了20.8%。与烟酸联合使用时，在第15周的终点观察到降低了43.7%，而烟酸单药治疗降低了26.5%。该联合用药耐受性良好，未报告肌病或肌酸激酶及肝转氨酶水平显著升高的情况。氟伐他汀与多种其他药物联合使用已显示对血脂谱有显著影响，迄今为止尚无临床显著安全性问题的证据。因此，联合治疗的应用可能会使中度严重高胆固醇血症和混合型血脂异常患者得到最佳治疗。
