Broqua Pierre, Riviere Pierre J-M, Conn P Michael, Rivier Jean E, Aubert Michel L, Junien Jean-Louis
Ferring Research, Division of Biology of Growth and Reproduction, University of Geneva Medical School, Geneva, Switzerland.
J Pharmacol Exp Ther. 2002 Apr;301(1):95-102. doi: 10.1124/jpet.301.1.95.
We describe the pharmacological profile in rats and monkeys of degarelix (FE200486), a member of a new class of long-acting gonadotropin-releasing hormone (GnRH) antagonists. At single subcutaneous injections of 0.3 to 10 microg/kg in rats, degarelix produced a dose-dependent suppression of the pituitary-gonadal axis as revealed by the decrease in plasma luteinizing hormone (LH) and testosterone levels. Duration of LH suppression increased with the dose: in the rat, significant suppression of LH lasted 1, 2, and 7 days after a single subcutaneous injection of degarelix at 12.5, 50, or 200 microg/kg, respectively. Degarelix fully suppressed plasma LH and testosterone levels in the castrated and intact rats as well as in the ovariectomized rhesus monkey for more than 40 days after a single 2-mg/kg subcutaneous injection. In comparative experiments, degarelix showed a longer duration of action than the recently developed GnRH antagonists abarelix, ganirelix, cetrorelix, and azaline B. The in vivo mechanism of action of degarelix was consistent with competitive antagonism, and the prolonged action of degarelix was paralleled by continued presence of radioimmunoassayable degarelix in the general circulation. In contrast to cetrorelix and similarly to ganirelix and abarelix, degarelix had only weak histamine-releasing properties in vitro. These results demonstrate that the unique and favorable pharmacological properties of degarelix make it an ideal candidate for the management of sex steroid-dependent pathologies requiring long-term inhibition of the gonadotropic axis.
我们描述了新型长效促性腺激素释放激素（GnRH）拮抗剂类药物地加瑞克（FE200486）在大鼠和猴子体内的药理学特征。在大鼠中单次皮下注射0.3至10微克/千克的地加瑞克，可导致垂体-性腺轴的剂量依赖性抑制，这表现为血浆黄体生成素（LH）和睾酮水平降低。LH抑制的持续时间随剂量增加：在大鼠中，单次皮下注射12.5、50或200微克/千克的地加瑞克后，LH的显著抑制分别持续1、2和7天。单次皮下注射2毫克/千克的地加瑞克后，地加瑞克可在去势和未去势大鼠以及卵巢切除的恒河猴中完全抑制血浆LH和睾酮水平超过40天。在比较实验中，地加瑞克的作用持续时间比最近开发的GnRH拮抗剂阿巴瑞克、加尼瑞克、西曲瑞克和阿扎林B更长。地加瑞克的体内作用机制与竞争性拮抗作用一致，并且地加瑞克的延长作用与循环中可通过放射免疫测定的地加瑞克持续存在平行。与西曲瑞克不同，与加尼瑞克和阿巴瑞克相似，地加瑞克在体外仅具有较弱的组胺释放特性。这些结果表明，地加瑞克独特且有利的药理学特性使其成为治疗需要长期抑制促性腺轴的性类固醇依赖性疾病的理想候选药物。
