Диеногест: различия между версиями

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Версия от 05:05, 29 августа 2017

Диеногест
Изображение химической структуры
Химическое соединение
ИЮПАК 2-[(8S,13S,14S,17R)-17-hydroxy-13-methyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl]acetonitrile
Брутто-формула C20H25NO2
Молярная масса 311.42 г/моль[1]
CAS 65928-58-7
PubChem 68861
DrugBank DB09123
Состав
Классификация
АТХ G03DB08,
G03AB08 G03FA15 (combinations with estrogen)
Фармакокинетика
Биодоступн. 90%[2]
Связывание с белками плазмы Albumin (90%);[2]
Free (10%)[2]
Метаболизм Hepatic (CYP3A4)[2][3]
Период полувывед. 10 hours[2]
Экскреция Urine
Способы введения
Oral
Логотип Викисклада Медиафайлы на Викискладе

Dienogest, sold under the brand names Dinagest, Natazia, Qlaira, Valette, and Visanne among others, is a progestin which is available both in combination with estrogen and by itself as an oral contraceptive and for the treatment of endometriosis.[4][5] In addition to its progestogenic effects, dienogest has antiandrogenic activity, and as a result may improve symptoms of androgen-dependent conditions such as acne.[1][6]

Medical uses

Contraception

Dienogest is used primarily as a contraceptive in combination with ethinylestradiol under the brand name Valette. It is given as a tablet containing 2 mg of dienogest and 30 μg of ethinylestradiol.[7] The drug is also available in a quadriphasic oral contraceptive pill combined with estradiol valerate, marketed as Natazia in the United States and Qlaira in some European countries and Russia. This formulation is also approved for the treatment of heavy menstrual bleeding.

Endometriosis

Dienogest is also approved under the brand names Visanne and Dinagest in various countries such as European countries, Australia, Malaysia, Singapore, and Japan for the treatment of endometriosis.[5][8][9] It has been shown to be equally effective as leuprorelin,[10] which is a second-line medication against endometriosis.

Side effects

Adverse effects associated with dienogest are the same as those expected of a progestogen.[1] These include weight gain, increased blood pressure, breast tenderness, and nausea.[11][нужен лучший источник] It produces no androgenic side effects and has little effect on metabolic and lipid hemostatic parameters.[12]

Interactions

Dienogest is metabolized mainly by the cytochrome P450 enzyme CYP3A4,[2][5] and for this reason, inhibitors and inducers of CYP3A4 can alter the amount of exposure to dienogest when administered concomitantly with it.[5] (For a list of CYP3A4 inhibitors and inducers, see here.) The strong CYP3A4 inhibitors ketoconazole and erythromycin have been found to increase exposure to dienogest by up to 3-fold, whereas the strong CYP3A4 inducer rifampicin (rifampin) was found to decrease steady-state and area-under-curve concentrations of dienogest by 50% and 80%, respectively.[5]

Pharmacology

Dienogest has relatively low affinity for the progesterone receptor (PR) in vitro in human uterus tissue, about 10% that of progesterone.[2][13] In spite of its relatively weak affinity for the PR, the drug shows strong progestogenic effects on the endometrium.[2][14] Dienogest is said to be one of the only 19-nortestosterone derivative progestins that does not have androgenic properties.[14] In fact, it actually has antiandrogen activity, about 30–40% of that of cyproterone acetate,[2][14] and can improve androgenic symptoms such as acne and hirsutism.[1][6] The drug does not interact with the estrogen, glucocorticoid, or mineralocorticoid receptor,[2] and hence has no estrogenic, glucocorticoid, or antimineralocorticoid activity.[14] However, it has limited impact on Gonadotropin Releasing Hormone, and thus does not lower LH significantly compared to other progestins.

Шаблон:Abbrlink of Dienogest and Metabolites[15]
Compound Шаблон:Abbrlink (%) Шаблон:Abbrlink (%)
Dienogest 5 10
9α,10β-Dihydrodienogest 26 13
3,5α-Tetrahydrodienogest 19 16
Шаблон:Abbrlink (promegestone = 100%), Шаблон:Abbrlink (metribolone = 100%)

Metabolites of dienogest, such as 9α,10β-dihydrodienogest and 3,5α-tetrahydrodienogest, show greater affinity for the PR and AR than does dienogest itself (see the table to the right).[15]

Inhibition of ovulation

The minimum effective dose of oral dienogest required to inhibit ovulation is 1 mg/day.[16][17] The inhibition of ovulation by dienogest reportedly occurs mainly via peripheral action as opposed to central action on gonadotropin secretion.[1]

Oral treatment of dienogest 2 mg/day in cyclical women reduced serum progesterone levels to anovulatory levels, however serum levels of luteinizing hormone and follicle-stimulating hormone are not significantly altered.[16]

Pharmacokinetics

Dienogest is rapidly absorbed and has high bioavailability of approximately 90%.[2] It is exclusively protein-bound to albumin (90%, with the remaining 10% being free), and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin.[2] The drug is metabolized in the liver mainly by CYP3A4.[2] Its metabolites are said to be inactive and to be rapidly excreted.[2]Шаблон:Contradiction-inline The terminal half-life of dienogest is 10 hours.[2][3] It reaches steady-state concentrations after 2 days of administration and does not accumulate in the body.[2]

Chemistry

См. также: List of steroidal progestogens и List of steroidal antiandrogens

Dienogest, also known as 17α-cyanomethyl-δ9-19-nortestosterone or as 17α-cyanomethylestra-4,9-dien-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone.[18][1][19] It is a member of the estrane subgroup of the 19-nortestosterone family of progestins, but unlike other 19-nortestosterone progestins, is not a derivative of norethisterone (17α-ethynyl-19-nortestosterone).[20][21][22] This is because it uniquely possesses a cyanomethyl group at the C17α position rather than the usual ethynyl group.[19][20] It is also unique among most 19-nortestosterone progestins in that it has a double bond between the C9 and C10 positions.[19] Dienogest is the C17α cyanomethyl derivative of the anabolic–androgenic steroid (AAS) dienolone, as well as the C17α cyanomethyl analogue of the AAS methyldienolone (17α-methyldienolone) and ethyldienolone (17α-ethyldienolone).[18]

Structure–activity relationships

In terms of structure–activity relationships, the C17α cyanomethyl group of dienogest is responsible for its unique antiandrogenic instead of androgenic activity relative to other 19-nortestosterone progestins.[19] A loss of ability to activate the AR is also seen with other testosterone derivatives with extended-length C17α substituions such as topterone (propyltestosterone) (compare to the AAS ethyltestosterone and methyltestosterone) and allylestrenol (compare to the AAS ethylestrenol).[23][24]

Studies with steroids similar to dienogest (e.g., dienolone) have found that the introduction of a double bond between the C9 and C10 positions is associated with similar/almost unchanged affinity for the PR and AR.[25] On the other hand, the C9(10) double bond of dienogest appears to inhibit metabolism via 5α-reductase and/or 5β-reductase, which is the major metabolic route for other 19-nortestosterone progestins like norethisterone, norgestrel, and etonogestrel, and this may serve to improve the metabolic stability and potency of dienogest.[26][27]

History

Dienogest was synthesized in 1979 in Jena, Germany under the leadership of Prof. Kurt Ponsold, was initially referred to as STS-557.[28][29] It was found that its potency was 10 times that of levonorgestrel.[30] The first product on the market to contain dienogest was a combined oral contraceptive pill (with ethinylestradiol), Valette, introduced in 1995 and made by Jenapharm.[31] In 2007, dienogest was introduced as Dinagest in Japan for the treatment of endometriosis, and it was subsequently marketed for this indication as Visanne in Europe and Australia in December 2009 and April 2010, respectively.[5] Qlaira was introduced in Europe in 2009 and Natazia was introduced in the United States in 2010.[32]

Society and culture

Generic name

Dienogest is the generic name of the drug and its Шаблон:Abbrlink, Шаблон:Abbrlink, Шаблон:Abbrlink, and Шаблон:Abbrlink.[18][33]

Brand names

Dienogest is marketed for use as an oral contraceptive in combination with estradiol valerate under the brand names Natazia and Qlaira and in combination with ethinylestradiol under the brand name Valette, and is marketed by itself under the brand names Visanne and Dinagest) for the treatment of endometriosis in Europe, Australia, and Japan.[33] It is also marketed under a variety of other, lesser-known brand names.[33]

Availability

См. также: List of progestogens available in the United States

Dienogest is available both alone and in combination with estradiol or ethinylestradiol throughout much of the world, including (but not limited to) Canada and many European, South American, and Southeast Asian countries.[33] It is available only in combination with an estrogen and not as a standalone drug in the United States and the United Kingdom.[33]

References

  1. ↑ 1 2 3 4 5 6 Foster RH, Wilde MI (1998). "Dienogest". Drugs. 56 (5): 825—33, discussion 834–5. doi:10.2165/00003495-199856050-00007. PMID 9829156.
  2. ↑ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Bińkowska, Małgorzata; Woroń, Jarosław (2015). "Progestogens in menopausal hormone therapy". Menopausal Review. 14 (2): 134—143. doi:10.5114/pm.2015.52154. ISSN 1643-8876. PMC 4498031. PMID 26327902. [...] In addition to a very fast absorption rate, dienogest exhibits a very high bioavailability of around 90%. It is bound to albumins in 90%, and around 10% is in a free form. It binds neither to SHBG, nor CBG. Its metabolites are inactive and rapidly excreted. The half-life is 10 hours. Stable concentrations are achieved after two days of treatment. Dienogest does not accumulate in the body. It demonstrates a poor affinity to the PR, but has a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use. It shows antagonist activity by binding to the AR, and hence produces an antiandrogenic action equivalent to ca. 40% of the effect induced by cyproterone acetate. Dienogest does not interact with the GR, MR or ER. [...] In vivo, it has a powerful progestagenic and moderate antigonadotropic activity, without any androgenic, glucocorticoid or mineralocorticoid effects. A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. Consequently, dienogest is believed to have a weak central antigonadotropic action, but a potent direct peripheral ovulation-inhibiting effect [8]. [...] Dienogest is metabolized chiefly via the CYP3A4 isoenzyme. [...]
  3. ↑ 1 2 Stanczyk FZ (2003). "All progestins are not created equal". Steroids. 68 (10—13): 879—90. doi:10.1016/j.steroids.2003.08.003. PMID 14667980.
  4. ↑ Tommaso Falcone. Clinical Reproductive Medicine and Surgery: A Practical Guide / Tommaso Falcone, William W. Hurd. — Springer Science & Business Media, 22 May 2013. — P. 300–. — «Dienogest is a 19-nortestosterone derivative that is approved in the European Union for the treatment of endometriosis. It is not available in the United States as a separate drug. It is only available in the oral contraceptive Natazia (Bayer Pharmaceuticals, Montville, NJ, USA) (estradiol valerate/dienogest), which is a newer four-phasic pack that contains dienogest.». — ISBN 978-1-4614-6837-0.
  5. ↑ 1 2 3 4 5 6 McCormack PL (2010). "Dienogest: a review of its use in the treatment of endometriosis". Drugs. 70 (16): 2073—88. doi:10.2165/11206320-000000000-00000. PMID 20964453.
  6. ↑ 1 2 Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs. 63 (5): 463—92. doi:10.2165/00003495-200363050-00003. PMID 12600226.
  7. ↑ Wiegratz I, Mittmann K, Dietrich H, Zimmermann T, Kuhl H (2006). "Fertility after discontinuation of treatment with an oral contraceptive containing 30 microg of ethinyl estradiol and 2 mg of dienogest". Fertil. Steril. 85 (6): 1812—9. doi:10.1016/j.fertnstert.2005.11.052. PMID 16759929.
  8. ↑ Dienogest for the treatment of endometriosis (PDF). London New Drugs Group. Дата обращения: 7 декабря 2010. Архивировано из оригинала 2 октября 2011 года.
  9. ↑ Visanne (нем.). Netdoctor.de.
  10. ↑ Strowitzki, T; Marr, J; Gerlinger, C; Faustmann, T; Seitz, C (2010). "Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial". Human reproduction (Oxford, England). 25 (3): 633—41. doi:10.1093/humrep/dep469. PMID 20089522.
  11. ↑ Galbraith, Alan. Fundamentals of Pharmacology: An Applied Approach for Nursing and Health / Alan Galbraith, Shane Bullock, Elizabeth Manias … [и др.]. — United Kingdom : Pearson Education LTD, 2007. — P. 632. — ISBN 978-0-13-186901-1.
  12. ↑ Wiegratz I, Lee JH, Kutschera E, Bauer HH, von Hayn C, Moore C, Mellinger U, Winkler UH, Gross W, Kuhl H (2002). "Effect of dienogest-containing oral contraceptives on lipid metabolism". Contraception. 65 (3): 223—9. doi:10.1016/S0010-7824(01)00310-9. PMID 11929644.
  13. ↑ Oettel M, Bervoas-Martin S, Elger W, Golbs S, Hobe G, Kaufmann G, Mathieu M, Moore C, Schneider B, Puri C, Ritter P, Reddersen G, Schon R, Strauch G, Zimmermann H (1995). "A 19-norprogestin without 17α-ethinyl group II: Dienogest from a pharmacokinetic point of view". Drugs of Today. 31 (7): 499—516.
  14. ↑ 1 2 3 4 Kuhl, H (2009). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (sup1): 3—63. doi:10.1080/13697130500148875. ISSN 1369-7137. PMID 16112947.
  15. ↑ 1 2 Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3—63. doi:10.1080/13697130500148875. PMID 16112947.
  16. ↑ 1 2 Oettel M, Carol W, Elger W, Kaufmann G, Moore C, Romer W, Klinger G, Schneider B, Schroder J, Sobek L, Walter F, Zimmermann H (1995). "A 19-norprogestin without 17α-ethinyl group II: Dienogest from a pharmacodynamic point of view". Drugs of Today. 31 (7): 517—536.
  17. ↑ Moore C, Carol W, Gräser T, Mellinger U, Walter F (1999). "Influence of Dienogest on Ovulation in Young Fertile Women". Clinical Drug Investigation. 18 (4): 271—278. doi:10.2165/00044011-199918040-00003.
  18. ↑ 1 2 3 J. Elks. The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. — Springer, 14 November 2014. — P. 390–. — ISBN 978-1-4757-2085-3.
  19. ↑ 1 2 3 4 Bińkowska M, Woroń J (2015). "Progestogens in menopausal hormone therapy". Prz Menopauzalny. 14 (2): 134—43. doi:10.5114/pm.2015.52154. PMC 4498031. PMID 26327902.
  20. ↑ 1 2 Howard J.A. Carp. Progestogens in Obstetrics and Gynecology. — Springer, 9 April 2015. — P. 112–113. — ISBN 978-3-319-14385-9.
  21. ↑ Mary C. Brucker. Pharmacology for Women’s Health / Mary C. Brucker, Tekoa L. King. — Jones & Bartlett Publishers, 8 September 2015. — P. 368–. — ISBN 978-1-284-05748-5.
  22. ↑ Donna Shoupe. The Handbook of Contraception: A Guide for Practical Management / Donna Shoupe, Daniel R. Mishell, Jr.. — Humana Press, 28 September 2015. — P. 63–. — ISBN 978-3-319-20185-6.
  23. ↑ Singh SM, Gauthier S, Labrie F (2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Curr. Med. Chem. 7 (2): 211—47. doi:10.2174/0929867003375371. PMID 10637363.
  24. ↑ Bergink EW, Loonen PB, Kloosterboer HJ (1985). "Receptor binding of allylestrenol, a progestagen of the 19-nortestosterone series without androgenic properties". J. Steroid Biochem. 23 (2): 165—8. doi:10.1016/0022-4731(85)90232-8. PMID 3928974.
  25. ↑ Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP (1987). "Towards the mapping of the progesterone and androgen receptors". J. Steroid Biochem. 27 (1–3): 255—69. doi:10.1016/0022-4731(87)90317-7. PMID 3695484.
  26. ↑ Schubert K, Schumann G, Kaufmann G (1983). "Influence of a 9-double bond on stereospecific microbial 4,5-reductions". J. Steroid Biochem. 18 (1): 75—80. doi:10.1016/0022-4731(83)90333-3. PMID 6683343.
  27. ↑ Hobe G, Schön R, Hajek M, Undisz K, Härtl A (1998). "Studies on the hydrogenation of the progestagen dienogest in vivo and in vitro in the female rabbit". Steroids. 63 (7–8): 393—400. doi:10.1016/s0039-128x(98)00014-2. PMID 9654645.
  28. ↑ Menzenbach B; Hübner M; K. Ponsold (1984). "Untersuchungen zur Bromierung/Dehydrobromierung von 17-Cyanmethyl-17-hydroxy-östr-5(10)-en-3-on". Journal für Praktische Chemie. 326 (6): 893—898. doi:10.1002/prac.19843260606.
  29. ↑ Kaufmann G, Dautzenberg H, Henkel H, et al. (August 1999). "Nitrile hydratase from Rhodococcus erythropolis: metabolization of steroidal compounds with a nitrile group". Steroids. 64 (8): 535—40. doi:10.1016/S0039-128X(99)00028-8. PMID 10493599.
  30. ↑ Oettel M, Kurischko A (1980). "STS 557, a new orally active progestin with antiprogestational and contragestational properties in rabbits". Contraception. 21 (1): 61—9. doi:10.1016/0010-7824(80)90140-7. PMID 7357870.
  31. ↑ http://www.jenapharm.de/unternehmen/ueber-uns/geschichte/1965-1995/
  32. ↑ Guida M, Bifulco G, Di Spiezio Sardo A, Scala M, Fernandez LM, Nappi C (2010). "Review of the safety, efficacy and patient acceptability of the combined dienogest/estradiol valerate contraceptive pill". International Journal of Women's Health. 2: 279—90. doi:10.2147/IJWH.S6954. PMC 2990895. PMID 21151673.{{cite journal}}: Википедия:Обслуживание CS1 (не помеченный открытым DOI) (ссылка)
  33. ↑ 1 2 3 4 5 https://www.drugs.com/international/dienogest.html


Шаблон:Progestogens and antiprogestogens Шаблон:Androgens and antiandrogens Шаблон:Progesterone receptor modulators Шаблон:Androgen receptor modulators

Источник — https://ru.wikipedia.org/w/index.php?title=Диеногест&oldid=87314679