Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix

Article Article scientifique Article Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix eng 2002 author Broqua Pierre 117612 author Riviere Pierre-Marie 768096 author Conne Pierre 701070 author Rivier Jean E author Aubert Michel 25310 author Junien Jean-Louis 95-102 10.1124/jpet.301.1.95 11907162 0022-3565 http://jpet.aspetjournals.org/content/301/1/95.long 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. Animals Female Gonadal Steroid Hormones/physiology Gonadotropin-Releasing Hormone/antagonists & inhibitors Gonads/drug effects/physiology Histamine Release/drug effects Hormone Antagonists/administration & dosage/pharmacokinetics/pharmacology Injections, Intravenous Injections, Subcutaneous Luteinizing Hormone/blood Macaca mulatta Male Mast Cells/drug effects/metabolism Oligopeptides/administration & dosage/pharmacokinetics/pharmacology Orchiectomy Pituitary Gland/drug effects/physiology Rats Rats, Sprague-Dawley Testosterone/blood Dewey 618 58 Département de pédiatrie, gynécologie et obstétrique 223 false The Journal of pharmacology and experimental therapeutics 301 1 ecf879e0-5de9-47a4-b212-9691a11a6bbc Article (Published version) Public J Pharmacol Exp Ther-2002-Broqua-95-102.pdf 250743 application/pdf openAccess Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

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Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix	The Journal of pharmacology and experimental therapeutics			2002	603	923

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Riviere, Pierre-Marie