| 词条 | Nomegestrol acetate | |||||||||||||||||||||||||
| 释义 |
| Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = [(8S,9S,10R,13S,14S,17R)-17-acetyl-6,13-dimethyl-3-oxo-1,2,8,9,10,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate | image = Nomegestrol acetate.svg | width = 235px | image2 = Nomegestrol acetate molecule ball.png | width2 = 235px | tradename = Alone: Lutenyl With {{abbr|E2|estradiol}}: Naemis, Zoely | pregnancy_AU = | pregnancy_US = | pregnancy_category = | licence_EU = yes | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = Rx-only | routes_of_administration = By mouth[1] | class = Progestin; Progestogen; Progestogen ester; Steroidal antiandrogen | bioavailability = 63%[1] | protein_bound = 97.5–98.0% (to albumin)[1] | metabolism = Liver (by hydroxylation via CYP3A3, CYP3A4, CYP2A6)[1] | metabolites = Six main metabolites, all essentially inactive[1] | elimination_half-life = ~50 hours (range 30–80 hours)[1][7] | excretion = Urine, feces[1] | CAS_number_Ref = | CAS_number = 58652-20-3 | CAS_supplemental = | ATC_prefix = G03 | ATC_suffix = DB04 | ATC_supplemental = | PubChem = 91668 | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = DB13981 | ChemSpiderID_Ref = | ChemSpiderID = 82771 | UNII = 83J78V5W05 | KEGG = D08281 | ChEBI = 135564 | ChEMBL = 1476022 | synonyms = NOMAC; NOMAc; Nomegesterol acetate; TX-066; TX-525; ORG-10486-0; Uniplant; 19-Normegestrol acetate; 6-Methyl-17α-acetoxy-δ6-19-norprogesterone; 17α-Acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione | C=23 | H=30 | O=4 | molecular_weight = 370.482 g/mol | SMILES = CC1=CC2C(CCC3(C2CCC3(C(=O)C)OC(=O)C)C)C4C1=CC(=O)CC4 | StdInChI_Ref = | StdInChI = 1S/C23H30O4/c1-13-11-20-18(17-6-5-16(26)12-19(13)17)7-9-22(4)21(20)8-10-23(22,14(2)24)27-15(3)25/h11-12,17-18,20-21H,5-10H2,1-4H3/t17-,18-,20-,21+,22+,23+/m1/s1 | StdInChIKey_Ref = | StdInChIKey = IIVBFTNIGYRNQY-YQLZSBIMSA-N }}Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders.[2][1][3][4][5][6] It is available both alone and in combination with an estrogen.[7][16] NOMAC is taken by mouth.[2] A birth control implant for placement under the skin was also developed but ultimately was not marketed.[18][19][20][21]Side effects of NOMAC include menstrual irregularities, headaches, nausea, breast tenderness, and others.[1][23] NOMAC is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[2] It has some antiandrogenic activity and no other important hormonal activity.[2]Nomegestrol, a related compound, was patented in 1975, and NOMAC was described in 1983.[26][27] NOMAC was first introduced for medical use, for the treatment of gynecological disorders and in menopausal hormone therapy, in Europe in 1986.[1][29][30] It was subsequently approved in Europe in 2011 as a component of birth control pills.[1][29][30] NOMAC is available widely throughout the world.[7][35] It is not available in the United States or Canada.[7][1][8][9]{{TOC limit|3}} Medical usesNOMAC is used alone in the treatment of gynecological disorders including menstrual disturbances (e.g., dysmenorrhea, menorrhagia, oligomenorrhea, polymenorrhea, amenorrhea), vaginal bleeding, breast pain, and premenstrual syndrome and in menopausal hormone therapy.[1][4][10] It is used in combination with estradiol as a birth control pill and in menopausal hormone therapy.[1][8][9] Available formsNOMAC is available both alone and in combination with estrogens.[7][11] The following formulations are available:[7][11]
The availability of these formulations differs by country.[7] ContraindicationsBecause NOMAC is metabolized by the liver, hepatic impairment can result in an accumulation of the medication.[12] Side effectsThe side effects of NOMAC are similar to those of other progestogens.[1] It is well-tolerated and often produces no side effects.[1] Possible side effects of NOMAC include menstrual irregularities (e.g., abnormal bleeding or spotting), headache, nausea, breast tenderness, and weight gain.[1][8][13][14][10] However, body weight is generally unchanged.[1] OverdoseThere have been no reports of serious adverse effects due to overdose of NOMAC.[6] NOMAC has been administered alone at a dosage of up to 40 times the recommended dosage, and the combination of NOMAC and estradiol has been administered in multiple doses of up to 5 times the recommended dosage to women in clinical trials, and no safety concerns or harmful effects were observed in either case.[15][6] Symptoms of NOMAC and estradiol overdose might include nausea, vomiting, and, in young girls, slight vaginal bleeding.[6] There is no antidote for NOMAC overdose and treatment of overdose should be based on symptoms.[6] InteractionsThe metabolism of NOMAC is dependent on CYP3A4, so inhibitors and inducers of this enzyme such as ketoconazole and rifampicin, respectively, as well as some anticonvulsants, may pose a clinically significant drug interaction with NOMAC.[1][7] (For a list of CYP3A4 inhibitors and inducers, see here.) PharmacologyNOMAC has progestogenic activity, antigonadotropic effects, antiandrogenic activity, and no other important hormonal activity.[2]
PharmacodynamicsProgestogenic activityNOMAC is a potent and pure progestogen, acting as a selective, high-affinity full agonist of the progesterone receptor (PR) (Ki = 3 nM, 67–303% of the {{abbr|RBA|relative binding affinity}} of progesterone),[16] and is said to have higher potency and substantially improved selectivity for the PR relative to medroxyprogesterone acetate (the 6-hydrogenated or non-6-7-double bonded analogue of megestrol acetate and the most widely used progestin).[3][17][18] In accordance, NOMAC is a potent antigonadotropin and exhibits no androgenic, estrogenic,[19] glucocorticoid, or antimineralocorticoid activity,[1] but does possess some antiandrogenic activity (see below).[16][20] Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and antiestrogenic effects when administered at sufficiently high dosages.[1] The ovulation-inhibiting dosage of NOMAC is 1.5 to 5 mg/day.[1][2][21] Due to its high antigonadotropic activity and its long elimination half-life, the contraceptive effectiveness of NOMAC is maintained even when a dose is missed; clinical studies found no increased incidence of pregnancy with one missed pill of Zoely or even with two missed pills during days 8 to 17 of the menstrual cycle.[22] Like many other progestogens,[23][24] NOMAC has been assessed and found in vitro to inhibit the conversion of estrone sulfate to estrone (via inhibition of steroid sulfatase) and estrone to estradiol (via inhibition of {{abbrlink|17β-HSD|17β-hydroxysteroid dehydrogenase}}) at high concentrations (0.5–50 μM) and to stimulate the conversion of estrone into estrone sulfate (via activation of estrogen sulfotransferase activity) at low concentrations (0.05–0.5 μM), whilst not affecting aromatase activity at any tested concentration (up to 10 μM).[1][4] These activities appear to be PR-dependent, as NOMAC is more potent in producing them in PR-rich cell lines (e.g., T47-D vs. MCF-7) and they can be blocked by the PR antagonist mifepristone (RU-486).[4] Although the clinical implications of these actions are unclear and they have yet to be confirmed in vivo or assessed in clinical studies, it has been suggested that NOMAC and certain other progestins may be useful in the treatment of {{abbrlink|ER|estrogen receptor}}-positive breast cancer by decreasing levels of estrogens in breast tissue.[23][24] In accordance with this notion, in vitro, NOMAC does not have proliferative effects on breast tissue, does not stimulate breast cell proliferation via {{abbrlink|PGRMC1|progesterone receptor membrane component 1}} (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium.[25] Antiandrogenic activityNOMAC has weak or moderate antiandrogenic activity (5 to 20 times less than that of cyproterone acetate (a strong antiandrogen),[16][20] with approximately 12 to 31% of the {{abbr|RBA|relative binding affinity}} of testosterone for the androgen receptor).[3][18][26] It is said to be a weaker antiandrogen than dienogest (another commonly used progestin with antiandrogen activity).[22][27] However, Kuhl (2006, 2009) has reported that NOMAC has about 90% of the antiandrogenic activity of cyproterone acetate in rats, relative to 30 to 40% for dienogest.[2][28] It may be useful in helping to alleviate acne, seborrhea, and other androgen-dependent symptoms in women.[22][27] PharmacokineticsNOMAC is well-absorbed, with an oral bioavailability of 63%.[1] It is 97.5 to 98% protein-bound, to albumin, and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin.[1] The medication is metabolized hepatically via hydroxylation by the enzymes CYP3A3, CYP3A4, and CYP2A6.[1] It has six main metabolites, all of which have no or minimal progestogenic activity.[1] The elimination half-life of NOMAC is approximately 50 hours, with a range of 30 to 80 hours.[1][22] Steady-state concentrations of NOMAC are achieved after five days of repeated administration.[1] As Zoely (2.5 mg/day NOMAC), the average circulating concentrations of NOMAC are 4.5 ng/mL at steady-state, with minimum and maximum concentrations of 3.1 ng/mL and 12.3 ng/mL, respectively.[22] The medication is eliminated via urine and feces.[1] Chemistry{{See also|List of progestogens|Progestogen ester|List of progestogen esters|Steroidal antiandrogen|List of steroidal antiandrogens}}NOMAC, also known as 17α-acetoxy-6-methyl-δ6-19-norprogesterone or as 17α-acetoxy-6-methyl-19-norpregna-4,6-diene-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone belonging to the 19-norprogesterone and 17α-hydroxyprogesterone groups.[26] NOMAC is the C17α acetate ester of nomegestrol and the 19-demethylated (or 19-nor) analogue of megestrol acetate, and can also be referred to as 19-normegestrol acetate.[26][3] HistoryNomegestrol was patented in 1975, and NOMAC, under the developmental code name TX-066, was first described in the literature in 1983.[26][29] It was developed by Theramex Laboratories, a pharmaceutical company in Monaco (a satellite country of France).[1] The medication was first introduced in Europe alone or in combination with estradiol under the respective brand names Lutenyl and Naemis[4] for the treatment of gynecological disorders and menopausal symptoms in 1986, and was subsequently developed and approved in 2011 in Europe as a birth control pill in combination with estradiol under the brand name Zoely.[1][8][9] As Zoely, NOMAC has been studied in over 4,000 women as a method of birth control.[22] Society and cultureGeneric namesNomegestrol acetate is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}.[30][31][7] It is also known by its former developmental code name TX-066.[30][31][7]Brand namesNOMAC is marketed in combination with estradiol as a birth control pill primarily under the brand name Zoely, in combination with estradiol for use in menopausal hormone therapy primarily under the brand name Naemis, and as a standalone medication for use in menopausal hormone therapy and the treatment of gynecological disorders primarily under the brand name Lutenyl.[7] NOMAC is also marketed alone or in combination with estradiol under a variety of other less common brand names throughout the world.[7] AvailabilityNOMAC (either alone (e.g., as Lutenyl) or in combination with estradiol (e.g., as Naemis))[4] is available for the treatment of gynecological disorders and menopausal symptoms in Argentina, Belgium, Brazil, Chile, France,[32][33] Georgia, Hong Kong, Indonesia, Italy, Lebanon, Lithuania, Malta, Monaco, the Netherlands, Peru, Poland, Portugal, Romania, Slovakia, Taiwan, Tunisia, Turkey, and Vietnam.[7][34][35][31] As a component of birth control pills with estradiol (under the brand name Zoely), NOMAC is available in Argentina, Australia, Austria, Belgium, Chile, Colombia, Croatia, Costa Rica, Denmark, the Dominican Republic, El Salvador, Finland, France, Germany, Guatemala, Honduras, Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Malaysia, Monaco, the Netherlands, New Zealand, Nicaragua, Norway, Panama, Poland, Portugal, Russia, Spain, Slovakia, Sweden, Switzerland, and the United Kingdom.[7][34][35][31] It was expected that Zoely would become available in the United States in 2010,[36] but the {{abbrlink|FDA|Food and Drug Administration}} rejected the {{abbrlink|NDA|New Drug Application}} for Zoely in 2011[37] and NOMAC ultimately has not been introduced in any form in this country.[38] ResearchUnder the tentative brand name Uniplant, NOMAC was under development by Theramex as a 38 mg or 55 mg 4 cm Silastic (silicone-plastic) subcutaneous birth control implant of one-year duration (75 ug/day or 100 μg/day release rate) in Brazil from the 1990s and was extensively studied for this purpose in clinical trials.[39][40][41][42] The clinical studies included 19,900 women-months of use and demonstrated a one-year failure rate of 0.94%. Uniplant was regarded as showing high effectiveness, and was well-tolerated.[42] In spite of this however, "[f]urther plans to make it available have been deferred by decision of the company holding the progestin patent",[43] and, although it continued to be investigated as late as 2006,[44] the implant ultimately never became commercially available.[45][46] Oral NOMAC was under development for the treatment of breast cancer and for use as a progestogen-only pill for birth control but did not complete development for these indications.[47] An estradiol and NOMAC vaginal ring was under development for use in birth control and to treat dysmenorrhea but did not complete development and was not marketed.[48] A continuous oral formulation of estradiol and NOMAC was under development for the treatment of menopausal symptoms and the treatment or prevention of postmenopausal osteoporosis but did not complete development.[49] References1. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 {{cite journal|last1=Lello|first1=Stefano|title=Nomegestrol Acetate|journal=Drugs|volume=70|issue=5|year=2010|pages=541–559|issn=0012-6667|doi=10.2165/11532130-000000000-00000|pmid=20329803}} 2. ^1 2 3 4 5 6 7 {{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}} 3. ^1 2 3 {{cite book|author1=Thomas L. 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10 : Acetate esters|Alcohols|Antigonadotropins|Diketones|Hormonal contraception|Implants (medicine)|Norpregnanes|Progestogen esters|Progestogens|Steroidal antiandrogens |
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