Ito B R, Zhang B-H, Cable E E, Song X, Fujitaki J M, MacKenna D A, Wilker C E, Chi B, van Poelje P D, Linemeyer D L, Erion M D
Department of Biological Sciences, Metabasis Therapeutics, Inc., La Jolla, CA, USA.
Br J Pharmacol. 2009 Feb;156(3):454-65. doi: 10.1111/j.1750-3639.2009.00038.x. Epub 2009 Jan 22.
Thyroid hormone receptor (TR) agonists are in clinical trials for the treatment of hypercholesterolaemia. As statins are the standard of clinical care, any new therapies must have adjunctive activity, when given in combination with statins. As already known for the statins, the cholesterol lowering effect of TR activation involves increased expression of the low-density lipoprotein receptor. Using animal models, we tested whether TR activation would have additive cholesterol lowering activity in the presence of effective doses of a statin.
We evaluated the activity of a liver-targeted prodrug, MB07811, of a novel TH receptor beta agonist, MB07344, as monotherapy and in combination with atorvastatin in rabbits, dogs and monkeys.
In rabbits, MB07344 (i.v.) decreased total plasma cholesterol (TPC) comparable to that achieved with a maximally effective dose of atorvastatin (p.o.). The addition of MB07344 to atorvastatin resulted in a further decrease in TPC. Similarly, the addition of MB07811 (p.o.) to atorvastatin treatment decreased TPC beyond the level achieved with either agent as monotherapy. In dogs and monkeys, atorvastatin and MB07811 were administered as monotherapy or in combination. Consistent with the rabbit studies, the combination treatment caused a greater decrease in TPC than either MB07811 or atorvastatin administered as monotherapy.
We conclude that the effects of MB07811 and atorvastatin in lowering cholesterol are additive in animals. These results would encourage and support the demonstration of similarly improved efficacy of combination versus monotherapy with such agents in the clinic.
甲状腺激素受体（TR）激动剂正处于治疗高胆固醇血症的临床试验阶段。由于他汀类药物是临床治疗的标准用药，任何新疗法在与他汀类药物联合使用时都必须具有辅助活性。正如他汀类药物已知的那样，TR激活降低胆固醇的作用涉及低密度脂蛋白受体表达的增加。我们使用动物模型测试了在有效剂量的他汀类药物存在的情况下，TR激活是否具有额外的降低胆固醇活性。
我们评估了一种新型TH受体β激动剂MB07344的肝脏靶向前药MB07811作为单一疗法以及与阿托伐他汀联合使用时在兔、犬和猴体内的活性。
在兔中，静脉注射MB07344降低总血浆胆固醇（TPC）的效果与口服最大有效剂量的阿托伐他汀相当（p.o.）。将MB07344添加到阿托伐他汀中可使TPC进一步降低。同样，在阿托伐他汀治疗中添加口服的MB07811可使TPC降低幅度超过单一使用任何一种药物所达到的水平。在犬和猴中，阿托伐他汀和MB07811作为单一疗法或联合使用。与兔的研究结果一致，联合治疗导致的TPC降低幅度大于单一使用MB07811或阿托伐他汀。
我们得出结论，MB07811和阿托伐他汀在动物体内降低胆固醇的作用是相加的。这些结果将鼓励并支持在临床上证明此类药物联合治疗与单一治疗相比同样具有更好的疗效。
