生物活性

• 描述Progesterone Receptor (PGR) is a member or the steroid receptor superfamily. It mediates the physiological effects of progesterone, which plays a central role in reproductive events associated with the establishment and maintenance of pregnancy. Progesterone Receptor is involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Depending on the isoform, progesterone receptor functions as transcriptional activator or repressor. Norethindrone, also termed Norethisterone (NET) is a synthetic 19-nortestosterone derivative. Norethindrone acts as a ligand that binds to progesterone receptor. According to published data, mean of relative binding affinity (RBA) values of norethisterone to the progesterone, androgen and estrogen receptor in cytosol of human breast MCF-7 cells and to the glucocorticoid receptor in that of leukemic IM-9 cells were 21.5%, 3.2%, not binding, and 0.8%, respectively. These data were all expressed as percentage of standard ligands of Org 2058, 5a-dihydrotestosterone (DHT), estradiol (E2) and dexamethasone (Dex), respectively^[3]. Mean of relative agonistic activity (RAA) values of norethisterone to the progesterone, androgen, estrogen and glucocorticoid receptor in transactivation assays with CHO cells using Org 2058, 5a-dihydro-testosterone (DHT), estradiol (E2) and dexamethasone (Dex) as standards were also measured. The data (also expressed as percentage of standard ligands) were 12.4%, and 1.1% respectively for the progesterone and androgen receptor, while no transactivation was detected for the estrogen or glucocorticoid receptor^[3]. According to cell proliferation data measured by an ATP-chemosensitivity test, norethisterone inhibited MCF-7 cells proliferation between 23% and 41% over the concentration range of 0.01 nM to 10 μM tested. In vivo, the mean active doses (MAD) of norethisterone in progestagenic (McPhail), androgenic (Hershberger), estrogenic (Allen–Doisy) tests, and in a progestagenic and estrogenic (ovulation inhibition test) were 0.063 mg/kg, 2.5 mg/kg, 4 mg/kg and 0.235 mg/kg respectively after subcutaneous administration and 0.25 mg/kg, 20 mg/kg, 8 mg/kg and 12 mg/kg respectively after oral administration^[3].

• 动物研究
  剂量	Rat: 10 mg/kg, 50 mg/kg[3] (p.o.), 8 mg/kg[2] (p.o.); 4 mg/kg[2] (s.c.)
  给药途径	p.o., s.c.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01129102	Dysmenorrhea	Phase 3	Completed	-	-
  NCT01466114	Relapsing-remitting Multiple S... more >>clerosis Secondary-progressive Multiple Sclerosis Primary-progressive Multiple Sclerosis Collapse <<	Phase 2	Recruiting	December 2018	United States, California ... more >> University of California Los Angeles Recruiting Los Angeles, California, United States, 90095 Contact: Mike Montag, M.S.    310-206-2176    MMontag@mednet.ucla.edu    Sub-Investigator: Barbara Giesser, MD          Sub-Investigator: Callene Momtazee, MD          United States, Colorado The University of Colorado Denver Completed Aurora, Colorado, United States, 80045 United States, New Mexico The University of New Mexico Completed Albuquerque, New Mexico, United States, 87131 United States, Pennsylvania The University of Pennsylvania Recruiting Philadelphia, Pennsylvania, United States, 19104 Contact: Amber Roberts    215-662-4893    daj37@mail.med.upenn.edu    Principal Investigator: Dina Jacobs, M.D. Collapse <<
  NCT01129102	-	-	Completed	-	-

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• 参考文献

• [1] Schindler AE, Campagnoli C, et al. Classification and pharmacology of progestins. Maturitas. 2003 Dec 10;46 Suppl 1:S7-S16.

  [2] Schoonen WG, Deckers GH, et al. Hormonal properties of norethisterone, 7alpha-methyl-norethisterone and their derivatives. J Steroid Biochem Mol Biol. 2000 Nov 15;74(4):213-22.

  [3] Schoonen WG, Deckers GH, de Gooijer ME, de Ries R, Kloosterboer HJ. Hormonal properties of norethisterone, 7alpha-methyl-norethisterone and their derivatives. J Steroid Biochem Mol Biol. 2000 Nov 15;74(4):213-22. doi: 10.1016/s0960-0760(00)00125-4. PMID: 11162927.