Algestone acetophenide explained

Algestone acetophenide, also known more commonly as dihydroxyprogesterone acetophenide (DHPA) and sold under the brand names Perlutal and Topasel among others, is a progestin medication which is used in combination with an estrogen as a form of long-lasting injectable birth control.[1] [2] [3] [4] It has also been used alone, but is no longer available as a standalone medication. DHPA is not active by mouth and is given once a month by injection into muscle.

Side effects of DHPA are similar to those of other progestins. DHPA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has no other important hormonal activity.

DHPA was discovered in 1958 and was introduced for medical use in the 1960s. It was not introduced in the United States, but it is marketed widely throughout Latin America. It was also previously available alone in Italy and as a combined injectable contraceptive in Portugal and Spain, but has been discontinued in these countries.

Medical uses

DHPA is used in combination with estradiol enantate (E2-EN) or estradiol benzoate butyrate (EBB) as a once-monthly combined injectable contraceptive for women in Latin America, Hong Kong, and Singapore. It was also previously marketed for use alone in Italy. DHPA has reportedly been used to treat acne.[5] [6] E2-EN/DHPA is used by transgender women in some places of South America as feminizing hormone therapy.[7] [8]

Available forms

See also: Estradiol enantate/algestone acetophenide and Estradiol benzoate butyrate/algestone acetophenide.

The following forms of DHPA in combination with an estrogen are or have been available for use:[9] [10] [11] [12]

A 90 mg DHPA and 6 mg estradiol enantate formulation was also studied, but was never marketed.[13] [14] The combination of DHPA and estradiol enantate has also been studied at other doses ranging from 75 to 200 mg DHPA and 5 to 50 mg estradiol enantate.[15]

Side effects

Side effects of the combination of DHPA and estradiol enantate have reportedly included dysmenorrhea, breast tenderness, headache, edema, bloating, changes in libido, depression, anxiety, and injection site pain. The half-dose formulation of DHPA and estradiol enantate retains contraceptive effects but causes severe disruption of menstrual bleeding patterns.[16] Likewise, the formulation of DHPA in combination with estradiol benzoate butyrate has been associated with poor control of menstrual bleeding.

Overdose

DHPA has been studied at high doses of 900 mg/week by intramuscular injection in women with endometrial cancer.[17]

Pharmacology

Pharmacodynamics

DHPA is a progestogen, or an agonist of the progesterone receptor. It is said to be both more potent and longer-acting than the related progestogen hydroxyprogesterone caproate.[18] The progestogenic potency of DHPA is about 2 to 5 times that of progesterone in animals. The medication has no androgenic, antiandrogenic, estrogenic, antiestrogenic, glucocorticoid, or antimineralocorticoid activities, and hence is a pure progestogen with no off-target activity.[19] [20] [21]

Clinical studies have found that, on the basis of endometrial changes, E2-EN/DHPA appears, at the doses used, to be an estrogen-dominant combination.

An effective ovulation-inhibiting dose of DHPA is 100 mg when given alone.[22]

Pharmacokinetics

The pharmacokinetics of DHPA have been studied, albeit limitedly.[23] [24] One study in women observed an elimination half-life of DHPA and its metabolites of 24 days and found that it remained detectable in the circulation for up to 60 days following a single intramuscular injection. In another study, the duration of action of DHPA was reported to be more than 100 days after a single subcutaneous injection, although it was unspecified as to whether this was in humans or animals. DHPA is excreted preferentially in feces via the biliary route.[25]

Chemistry

See also: List of progestogens.

DHPA, also known as 16α,17α-dihydroxyprogesterone acetophenide, as well as 16α,17α-dihydroxypregn-4-ene-3,20-dione cyclic acetal with acetophenone or as (R)-16α,17-[(1-phenylethylidene)dioxy]pregn-4-ene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone.[26] [27] [28] It is specifically a derivative of 17α-hydroxyprogesterone with an additional hydroxyl group at the C17α position, or of algestone (16α,17α-dihydroxyprogesterone), and with the two hydroxyl groups cyclized into an acetophenide moiety (a cyclic acetal with acetophenone). Analogues of DHPA include other 17α-hydroxyprogesterone derivatives such as algestone acetonide (dihydroxyprogesterone acetonide), chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and segesterone acetate.

Synthesis

Chemical syntheses of DHPA have been published.[29]

History

DHPA was first described in the literature in 1958 and was patented in 1960.[30] [31] It was developed in combination with estradiol enantate as a long-lasting combined injectable contraceptive under the tentative brand names Deladroxate and Droxone by Squibb and was studied in women starting in 1964.[32] [33] [34] [35] Development was discontinued by Squibb in the United States in the late 1960s due to concerns of toxicological findings in animals, including mammary gland tumors in beagle dogs and pituitary hyperplasia in rats, as well as possible accumulation of estradiol enantate in the body with continued use.[36] Subsequent research has shed doubt that these animal findings are applicable to humans and that the dosages required for contraception would pose any risks. Although the medication was not marketed in the United States, its development was continued elsewhere and it went on to be introduced and widely used in Latin America and Spain. A standalone version of DHPA was introduced in Italy in 1982 under the brand names Neolutin Depo and Neolutin Depositum. This single-drug formulation has since been discontinued. DHPA remains available in Latin America, but is no longer marketed in Europe.

Society and culture

Generic names

Algestone acetophenide are the English generic name of the drug and its and, while dihydroxyprogesterone acetophenide (DHPA) is a commonly used synonym.[37] [38] [39] Its generic names in other languages are as follows:

DHPA is also known by its former developmental code name SQ-15101. It has been referred to as deladroxone, droxone, alfasone acetophenide, and alphasone acetophenide as well.[40]

Brand names

DHPA has been marketed alone and in combination with estrogens under a wide variety of brand names. It was marketed alone under the brand name Neolutin Depositum, but this preparation was discontinued. The medication was developed under the developmental code names Deladroxone and Droxone, but these brand names were never used commercially.[41] DHPA has been marketed in combination with estradiol enantate (E2-EN) as a combined injectable contraceptive in a few different preparations, with varying doses of E2-EN and DHPA. These formulations all have different brand names, which include the following († = discontinued):[42]

The combination of E2-EN 10 mg and DHPA 150 mg was developed under the developmental brand name Deladroxate, but this brand name was never used commercially.

In addition to E2-EN, DHPA is marketed in combination with estradiol benzoate butyrate (EBB) as a combined injectable contraceptive under the brand names Neolutin N, Redimen, Soluna, and Unijab. This combination was developed under the developmental brand name Unimens, but this brand name was never used commercially.[43]

DHPA has also been used in veterinary medicine in cows under the brand name Bovitrol.[44] [45] [46] [47]

Availability

DHPA has been available for use both alone and in combination with estrogens.[48] [49] It was marketed alone under the brand name Neolutin Depositum in Italy, but this preparation was discontinued. DHPA has been marketed in combination with estradiol enantate (E2-EN) as a combined injectable contraceptive in at least 19 countries, mostly in Latin America.[50] [51] A few different preparations, with varying doses of E2-EN and DHPA and varying availability, have been introduced. These formulations have the following approval and availability († = discontinued in this country):

In addition to E2-EN, DHPA is marketed in combination with estradiol benzoate butyrate (EBB) as a combined injectable contraceptive in Peru and Singapore. EBB has a shorter duration than E2-EN of about 3 weeks and hence EBB/DHPA was developed because it was thought that it would be more suitable for use as a once-monthly combined injectable contraceptive than E2-EN/DHPA.

Usage

E2-EN/DHPA is the most widely used combined injectable contraceptive in Latin America.[52] It was estimated in 1995 that E2-EN/DHPA was used as a combined injectable contraceptive in Latin America by at least 1 million women. However, combined injectable contraceptives like E2-EN/DHPA are unlikely to constitute a large proportion of contraceptive use in the countries in which they are available.

Research

DHPA was studied by its developer Squibb for use as a progestogen-only injectable contraceptive at a dose of 100 mg once per month by intramuscular injection under the developmental code name and tentative brand name Deladroxone.[25] It was associated with poor cycle control and was never marketed for this indication.

See also

Notes and References

  1. Jarquín González JD, Elda de Aguirre L, Rodríguez C, Abrego de Aguilar M, Carrillo F, León DA, Lima M, Trigueros S, Acosta R . 6 . Dihydroxyprogesterone acetophenide 150 mg + estradiol enantate 10 mg as monthly injectable contraceptives . Advances in Contraception . 12 . 3 . 213–225 . September 1996 . 8910663 . 10.1007/BF01849664 . 2522426 .
  2. Newton JR, D'arcangues C, Hall PE . A review of "once-a-month" combined injectable contraceptives . Journal of Obstetrics and Gynaecology . 4 . Suppl 1 . S1-34 . 1994 . 12290848 . 10.3109/01443619409027641 .
  3. Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S . Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control . World J Pharm Pharm Sci . 3 . 10 . 364–392 . 2014 . 2278-4357 . 2016-08-24 . https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf . 2017-08-10 . dead .
  4. Rowlands S . New technologies in contraception . BJOG . 116 . 2 . 230–239 . January 2009 . 19076955 . 10.1111/j.1471-0528.2008.01985.x . 3415547 .
  5. Book: Milne GW . Drugs: Synonyms and Properties: Synonyms and Properties. 8 May 2018. Taylor & Francis. 978-1-351-78989-9. 1565–.
  6. Book: Juo PS . Concise Dictionary of Biomedicine and Molecular Biology. 21 December 2001. CRC Press. 978-1-4200-4130-9. 57–.
  7. Book: Kulick D . Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. 12 January 2009. University of Chicago Press. 978-0-226-46101-4. 64–66.
  8. Comitê Técnico de Saúde Integral LGBTIA+ (June, 2023), “Protocolo para o cuidado integral à saúde de pessoas trans, travestis ou com vivências de variabilidade de gênero no município de São Paulo, 2ª ed.” (PDF), p. 307

    Archived from the original (PDF) on 2024-02-03.

  9. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. International Agency for Research on Cancer. Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. 2007. World Health Organization. 978-92-832-1291-1. 431–433, 467.
  10. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer. Hormonal Contraception and Post-menopausal Hormonal Therapy. 1 January 1999. IARC. 978-92-832-1272-0. 65.
  11. Web site: Unijab Dosage & Drug Information | MIMS Singapore.
  12. Toppozada MK . Existing once-a-month combined injectable contraceptives . Contraception . 49 . 4 . 293–301 . April 1994 . 8013216 . 10.1016/0010-7824(94)90029-9 .
  13. Coutinho EM, Spinola P, Barbosa I, Gatto M, Tomaz G, Morais K, Yazlle ME, de Souza RN, Pinho Neto JS, Leal W, Leal C, Hippolito SB, Abranches AD . 6 . Multicenter, double-blind, comparative clinical study on the efficacy and acceptability of a monthly injectable contraceptive combination of 150 mg dihydroxyprogesterone acetophenide and 10 mg estradiol enanthate compared to a monthly injectable contraceptive combination of 90 mg dihydroxyprogesterone acetophenide and 6 mg estradiol enanthate . Contraception . 55 . 3 . 175–181 . March 1997 . 9115007 . 10.1016/S0010-7824(97)00018-8 .
  14. Coutinho EM, Spinola P, Tomaz G, Morais K, Nassar de Souza R, Sabino Pinho Neto J, de Barros Leal W, Bomfim Hippolito S, D'Aurea Abranches A . 6 . Efficacy, acceptability, and clinical effects of a low-dose injectable contraceptive combination of dihydroxyprogesterone acetophenide and estradiol enanthate . Contraception . 61 . 4 . 277–280 . April 2000 . 10899484 . 10.1016/S0010-7824(00)00099-8 .
  15. Koetsawang S . Once-a-month injectable contraceptives: efficacy and reasons for discontinuation . Contraception . 49 . 4 . 387–398 . April 1994 . 8013221 . 10.1016/0010-7824(94)90034-5 .
  16. Recio R, Garza-Flores J, Schiavon R, Reyes A, Diaz-Sanchez V, Valles V, Luz de la Cruz D, Oropeza G, Perez-Palacios G . 6 . Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptive . Contraception . 33 . 6 . 579–589 . June 1986 . 3769482 . 10.1016/0010-7824(86)90046-6 .
  17. Kennedy BJ . Progestogens in the treatment of carcinoma of the endometrium . Surgery, Gynecology & Obstetrics . 127 . 1 . 103–114 . July 1968 . 5657772 .
  18. Kawakami M, Sawyer CH . Effects of sex hormones and antifertility steroids in brain thresholds in the rabbit . Endocrinology . 80 . 5 . 857–871 . May 1967 . 4164655 . 10.1210/endo-80-5-857 .
  19. Lerner LJ, Brennan DM, Borman A . Biological activities of 16 alpha, 17 alpha dihydroxyprogesterone derivatives . Proceedings of the Society for Experimental Biology and Medicine . 106 . 231–234 . January 1961 . 13761080 . 10.3181/00379727-106-26296 . 89428532 .
  20. Lerner, L. J., Brennan, D. M., DePhillipo, M., & Yiacas, E. (1961). Comparison of biological activities of progesterone, norethisterone and the acetophenone derivatives of 16 alpha, 17 alpha-dihydroxyprogesterone.(Abstr.). In Federation Proceedings (Vol. 20, p. 200).
  21. Kurihara N, Tadokoro S, Ogawa H . Studies on hormonal actions of dihydroxyprogesterone acetophenide, estradiol enanthate and their mixtures . Japanese Journal of Pharmacology . 22 . 1 . 43–58 . February 1972 . 4537624 . 10.1254/jjp.22.43 . free .
  22. Bassol S, Garza-Flores J . Review of ovulation return upon discontinuation of once-a-month injectable contraceptives . Contraception . 49 . 5 . 441–453 . May 1994 . 8045131 . 10.1016/0010-7824(94)90003-5 .
  23. Garza-Flores J . Pharmacokinetics of once-a-month injectable contraceptives . Contraception . 49 . 4 . 347–359 . April 1994 . 8013219 . 10.1016/0010-7824(94)90032-9 .
  24. Gual C, Pérez-Palacios G, Perez AE, Ruiz MR, Solis J, Cervantes A, Iramain C, Schreiber EC . 6 . Metabolic fate of a long-acting injectable estrogen-progestogen contraceptive . Contraception . 7 . 4 . 1973 . 271–287 . 0010-7824 . 10.1016/0010-7824(73)90145-5.
  25. Toppozada M . The clinical use of monthly injectable contraceptive preparations . Obstetrical & Gynecological Survey . 32 . 6 . 335–347 . June 1977 . 865726 . 10.1097/00006254-197706000-00001 .
  26. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3. 27–.
  27. Book: Index Nominum 2000: International Drug Directory. 2000. Taylor & Francis. 978-3-88763-075-1. 26–.
  28. Book: William Andrew Publishing. Pharmaceutical Manufacturing Encyclopedia . 3rd . 22 October 2013 . 978-0-8155-1856-3. 153–.
  29. Book: Die Gestagene. 27 November 2013. Springer-Verlag. 978-3-642-99941-3. 8–9.
  30. Fried, J. (1960). U.S. Patent No. 2,941,997. Washington, DC: U.S. Patent and Trademark Office.
  31. Fried J, Borman A . Synthetic derivatives of cortical hormones . 16 . 303–374 . 1958 . 13625604 . 10.1016/S0083-6729(08)60320-9 . 9780127098166 . Vitamins & Hormones .
  32. Rutherford RN, Banks AL, Coburn WA . Deladroxate for the prevention of ovulation. . Fertility and Sterility . 15 . 6 . 648–652 . 1964 . 14236841 . 10.1016/s0015-0282(16)35410-3 . free .
  33. Taymor ML, Planck S, Yahia C . Ovulation inhibition with a long-acting parenteral progestogen-estrogen combination . Fertility and Sterility . 15 . 6 . 653–660 . 1964 . 14236842 . 10.1016/s0015-0282(16)35411-5 . free .
  34. Book: Artini PG, Genazzani AR, Petraglia F . Advances in Gynecological Endocrinology. 11 December 2001. CRC Press. 978-1-84214-071-0. 101–. Subsequently another formulation of 150 mg of dihydroxyprogesterone acetophenide (DHPA) with 10 mg estradiol enanthate (E2-EN) was tested in the 1960s3-6..
  35. Book: d 'Arcangues C, Snow RC . Fertility Control — Update and Trends. Injectable Contraceptives. 1999. 121–149. 10.1007/978-3-642-86696-8_6. 978-3-642-86698-2.
  36. Book: Population Reports: Injectables and implants. 1987. Department of Medical and Public Affairs, George Washington University.. K-75. In the US, Squibb Pharmaceutical Company withdrew Deladroxate from clinical testing in the late 1960s because of concerns over (1) breast tumors in beagle dogs, (2) pituitary hyperplasia in rats, and (3) possible accumulation of estradiol enanthate in the body with continued use (89, 98, 243). Subsequently, however, questions have been raised about whether such animal findings are applicable to humans. Research suggests that the adverse effects of Deladroxate on animals may occur only with doses higher than the equivalent of a contraceptive dose (2, 62, 82, 121, 272)..
  37. Web site: Archived copy . 2018-09-18 . 2018-09-18 . https://web.archive.org/web/20180918123639/https://www.drugs.com/international/algestone.html . dead .
  38. Web site: Progestin Oral, Parenteral, Vaginal Advanced Patient Information.
  39. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms. 6 December 2012. Springer Science & Business Media. 978-94-011-4439-1. 10–.
  40. Book: Kleemann A, Engel J . Pharmaceutical Substances: Syntheses, Patents, Applications. 2001. Thieme. 978-3-13-558404-1. 61.
  41. Book: Chemical Contraception. 18 June 1974. Macmillan International Higher Education. 978-1-349-02287-8. 55–.
  42. Gallo MF, Grimes DA, Lopez LM, Schulz KF, d'Arcangues C . Combination injectable contraceptives for contraception . The Cochrane Database of Systematic Reviews . 3 . CD004568 . 2013 . 23641480 . 6513542 . 10.1002/14651858.CD004568.pub3 .
  43. Book: Toppozada MK . Monthly Injectable Contraceptives . 93–103 . Goldsmith A, Toppozada M . Long-Acting Contraception . 1983 . 35018604 .
  44. Book: Negwer M . Organic-chemical Drugs and Their Synonyms: (an International Survey). 1994. Akademie Verlag. 978-3-05-500156-7. 2572. Algestone acetophenide, Alphasone acetophenide, Bovitrol, Deladroxone, Dihydroxyprogesterone acetophenide, Droxone, Neolutin depositum, SQ 15101 U Progestin, spermatogenesis inhibitor.
  45. Book: North Dakota State University. Extension Service. Circulars. 1967. XV.
  46. Book: Louisiana Agriculture. 1967. Agricultural Experiment Station, Louisiana State University and Agricultural and Mechanical College.. 38.
  47. Book: Beef Cattle Science Handbook. 1971. Agriservices Foundation.. 148.
  48. Web site: Micromedex Products: Please Login.
  49. Book: Sweetman SC . Sex hormones and their modulators . Martindale: The Complete Drug Reference . 36th . 2009 . 2082 . Pharmaceutical Press . London. 978-0-85369-840-1. https://www.medicinescomplete.com/mc/martindale/.
  50. Book: Senanayake P, Potts M . Atlas of Contraception, Second Edition. 14 April 2008. CRC Press. 978-0-203-34732-4. 50–.
  51. Book: Rabe T, Runnebaum B . Fertility Control — Update and Trends: Update and Trends. 6 December 2012. Springer Science & Business Media. 978-3-642-86696-8. 183–. Two additional monthly, combined injectable methods warrant mention. Deladroxate (commercially labelled as Perlutan, Topasel, Agurin, Horprotal and Uno-Ciclo in various countries), is a combination of 150 mg dihydroxyprogesterone acetophenide and 10 mg estradiol enanthate, and is available in many Latin American countries and Spain. The method is highly effective, without a single pregnancy reported in large clinical trials (Koetsawang 1994). Although available since the 1960s, the method has not been studied as extensively as Cyclofem or Mesigyna. The original manufacturer withdrew support due to toxicological concerns with dihydroxyprogesterone acetophenide, and clinical evaluations continue to be published. A recent dose-finding trial compared the standard available dose of 150/10 with a lower dose of 90/6, and concluded the lower dose was equally effective (Coutinho et al., 1997)..
  52. Book: Speroff L, Fritz MA . Clinical Gynecologic Endocrinology and Infertility. 2005. Lippincott Williams & Wilkins. 978-0-7817-4795-0. 969–.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Algestone acetophenide".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.