1. [Once-a-month injectable microcapsules of leuprorelin acetate]
Y Ogawa, H Toguchi, H Okada, M Yamamoto Yakugaku Zasshi . 1991 Aug;111(8):397-409. doi: 10.1248/yakushi1947.111.8_397.
Leuprorelin (leuprolide, D-Leu6-(des-Gly10-NH2)-LH-RH ethylamide) acetate is a super-active agonist of luteinizing hormone-releasing hormone (LH-RH). We developed once-a-month injectable microcapsules of this agonist by our novel in-water drying method. This depot formulation can release the drug at an apparent zero-order rate over one month with bioerosion of copoly (lactic/glycolic acid) utilized as a wall material of the polycore microcapsules. A dramatic prolonged depression of pituitary-gonadal axis, chemical castration, was achieved by the once-a-month injection in experimental animals; it expects a reliable efficacy for treating hormone-dependent prostatic, breast cancers and endometriosis. Studies on the dosage design of this new delivery system of leuprorelin are summarized.
2. Evaluation of a stable gonadotropin-releasing hormone analog in mice for the treatment of endocrine disorders and prostate cancer
George Liapakis, John Matsoukas, Evangelos Balafas, Nikolaos Kostomitsopoulos, Theodora Katsila, Patrizia Limonta, Theodore Tselios, Constantin Tamvakopoulos, Marina Montagnani Marelli, Konstantinos Gkountelias J Pharmacol Exp Ther . 2011 Mar;336(3):613-23. doi: 10.1124/jpet.110.174375.
Gonadotropin-releasing hormone (GnRH) receptor agonists have wide clinical applications including the treatment of prostate cancer and endocrine disorders. However, such agonists are characterized by poor pharmacokinetic properties, often requiring repeated administration or special formulations. Therefore, the development of novel peptide analogs with enhanced in vivo stability could potentially provide therapeutic alternatives. The pharmacological evaluation of a bioactive peptide [Des-Gly¹⁰,Tyr⁵(OMe),D-Leu⁶,Aze-NHEt⁹]GnRH, analog 1, is presented herein and compared with leuprolide. Peptide stability was evaluated using mouse kidney membrane preparations, followed by a liquid chromatography-tandem mass spectrometry-based approach that afforded identification and quantification of its major metabolites. The analog was significantly more stable in vitro in comparison with leuprolide. In vitro and in vivo stability results correlated well, encouraging us to develop a clinically relevant pharmacokinetic mouse model, which facilitated efficacy measurements using testosterone as a biomarker. Analog 1, an agonist of the GnRH receptor with a binding affinity in the nanomolar range, caused testosterone release in mice that was acutely dose-dependent, an effect blocked by the GnRH receptor antagonist cetrorelix. Repeated dosing studies in mice demonstrated that analog 1 was well tolerated and had potency similar to that of leuprolide, based on plasma and testis testosterone reduction and histopathological findings. Analog 1 also shared with leuprolide similar significant antiproliferative activity on androgen-dependent prostate cancer (LNCaP) cells. On the basis of pharmacokinetic advantages, we expect that analog 1 or analogs based on this new design will be therapeutically advantageous for the treatment of cancer and endocrine disorders.
3. Effects of ionizing radiation and pretreatment with [D-Leu6,des-Gly10] luteinizing hormone-releasing hormone ethylamide on developing rat ovarian follicles
L Belbeck, A McMahon, J Jarrell, G O'Connell, E V YoungLai, R Barr Cancer Res . 1987 Oct 1;47(19):5005-8.
To assess the effects of a gonadotropin-releasing hormone agonist, [D-Leu6,des-Gly10] luteinizing hormone-releasing hormone ethylamide, in ameliorating the damage caused by ionizing radiation, gonadotropin-releasing hormone agonist was administered to rats from day 22 to 37 of age in doses of 0.1, 0.4, and 1.0 microgram/day or vehicle and the rats were sacrificed on day 44 of age. There were no effects on estradiol, progesterone, luteinizing, or follicle-stimulating hormone, nor an effect on ovarian follicle numbers or development. In separate experiments, rats treated with gonadotropin-releasing hormone agonist in doses of 0.04, 0.1, 0.4, or 1.0 microgram/day were either irradiated or sham irradiated on day 30 and all groups sacrificed on day 44 of age. Irradiation produced a reduction in ovarian weight and an increase in ovarian follicular atresia. Pretreatment with the agonist prevented the reduction in ovarian weight and numbers of primordial and preantral follicles but not healthy or atretic antral follicles. Such putative radioprotection should be tested on actual reproductive performance.
