Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: Degarelix
Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: Degarelix
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DOI：
10.1124/jpet.301.1.95
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发表时间：
2002-04-01
影响因子：
3.5
通讯作者：
Junien, JL
中科院分区：
文献类型：
--
作者：
Broqua, P;Riviere, PJM;Junien, JL
我们描述了degarelix （FE200486）在大鼠和猴子中的药理学特征，degarelix是一类新的长效促性腺激素释放激素（GnRH）拮抗剂。大鼠皮下单次注射0.3 ~ 10杯/千克，degarelix对垂体-性腺轴产生剂量依赖性抑制，血浆黄体生成素（LH）和睾酮水平降低。抑制黄体生成素的持续时间随着剂量的增加而增加：在大鼠中，单次皮下注射12.5、50或200马克杯/公斤的degarelix后，对黄体生成素的显著抑制持续了1、2和7天。Degarelix单次皮下注射2 mg/kg后，可完全抑制去势大鼠和完整大鼠以及去卵巢恒河猴血浆LH和睾酮水平超过40天。在对比实验中，degarelix比最近开发的GnRH拮抗剂abarelix、ganirelix、cetrorelix和azaline b显示出更长的作用时间。degarelix的体内作用机制与竞争拮抗一致，并且degarelix的延长作用与放射免疫可测定的degarelix在全身循环中的持续存在是平行的。与cetrorelix相反，与ganirelix和abarelix相似，degarelix在体外只有弱的组胺释放特性。这些结果表明，degarelix独特而有利的药理学特性使其成为需要长期抑制促性腺激素轴的性类固醇依赖性病理治疗的理想候选者。
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 mug/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 mug/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.