Research and Development Center, Santen Pharmaceutical Co. Ltd., Ikoma, Nara, Japan.
J Ocul Pharmacol Ther. 2011 Aug;27(4):353-60. doi: 10.1089/jop.2010.0177. Epub 2011 May 16.
Glucocorticoids exert their actions via the glucocorticoid receptor through at least 2 intracellular mechanisms, known as transrepression and transactivation. It has been hypothesized that transrepression is the basis of their anti-inflammatory effects, whereas transactivation has been assumed to cause their side effects. ZK209614, a recently identified, novel selective glucocorticoid receptor agonist, exerts strong transrepression and weak transactivation. The objective of this study was to determine whether its pharmacological effects can be dissociated from its side effects. For this, we employed in vitro assays and topical in vivo models.
ZK209614 and dexamethasone were used in in vitro transrepression and transactivation assays. To evaluate anti-inflammatory and antiallergic activities in vivo, ZK209614 and betamethasone phosphate were tested in the carrageenan-induced conjunctivitis model and allergic conjunctivitis model in rats. To evaluate side effects in vivo, treatments with ZK209614 and betamethasone phosphate were tested for the ocular hypertensive effects in a feline model, each drug being administered topically.
ZK209614 showed strong transrepression and weak transactivation in the in vitro assays. When given as eyedrops, ZK209614 and betamethasone phosphate each had an inhibitory effect on edema weight in the rat carrageenan-induced conjunctivitis model. In the rat allergic conjunctivitis model, ZK209614 reduced the elevated vascular permeability at a concentration of 0.1%. In the feline intraocular pressure (IOP)-elevation experiment, topically administered betamethasone phosphate elevated IOP, but ZK209614 had no effect on IOP.
The present investigations suggest that ZK209614 eyedrops have both anti-inflammatory and antiallergic effects, but no unwanted IOP-elevating effect. On that basis, ZK209614 might be a promising candidate as an ophthalmic drug with a better therapeutic index than classic glucocorticoids.
糖皮质激素通过至少两种细胞内机制，即转录阻遏和转录激活，发挥其作用。据推测，转录阻遏是其抗炎作用的基础，而转录激活则被认为会产生其副作用。ZK209614 是一种最近发现的新型选择性糖皮质激素受体激动剂，具有强大的转录阻遏作用和较弱的转录激活作用。本研究旨在确定其药理作用是否与其副作用分离。为此，我们采用了体外和体内模型。
ZK209614 和地塞米松用于体外转录阻遏和转录激活试验。为了评估体内抗炎和抗过敏活性，在大鼠角叉菜胶性结膜炎模型和过敏性结膜炎模型中，分别检测了 ZK209614 和倍他米松磷酸酯的作用。为了评估体内副作用，采用猫模型进行了 ZK209614 和倍他米松磷酸酯的眼内压升高作用的治疗试验，两种药物均局部给药。
ZK209614 在体外试验中表现出强大的转录阻遏和较弱的转录激活作用。当作为滴眼剂使用时，ZK209614 和倍他米松磷酸酯均对大鼠角叉菜胶性结膜炎模型中的水肿重量有抑制作用。在大鼠过敏性结膜炎模型中，ZK209614 在 0.1%浓度下可降低升高的血管通透性。在猫眼内压升高实验中，局部给予倍他米松磷酸酯可升高眼内压，但 ZK209614 对眼内压无影响。
本研究表明，ZK209614 滴眼剂具有抗炎和抗过敏作用，但不会引起眼压升高。在此基础上，ZK209614 可能成为一种有前途的眼科药物，其治疗指数优于经典糖皮质激素。
