Finasteride

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Structural formula
Structure of finasteride
General
Non-proprietary name Finasteride
other names
  • N - tert -Butyl-3-oxo-4-aza-5 α -androst-1-ene-17 β -carbamide
  • (1 S , 3a S , 3b S , 5a R , 9a R , 9b S , 11a S ) - N - tert -Butyl-9a, 11a-dimethyl-7-oxo-1,2,3,3a, 3b, 4 , 5,5a, 6,9b, 10,11-dodecahydroindeno [5,4- f ] quinoline-1-carboxamide ( IUPAC )
  • Finasteridum ( Latin )
Molecular formula C 23 H 36 N 2 O 2
Brief description

white to almost white, crystalline, polymorphic powder

External identifiers / databases
CAS number 98319-26-7
EC number 620-534-3
ECHA InfoCard 100.149.445
PubChem 57363
DrugBank DB01216
Wikidata Q424167
Drug information
ATC code
Drug class

Enzyme inhibitors

Mechanism of action

selective inhibition of type II and type III 5α-reductase
properties
Molar mass 372.54 g · mol -1
density
  • 1.159 g cm −3 (polymorph I)
  • 1.100 g cm −3 (polymorph II)
Melting point
  • 253-256 ° C (polymorph I)
  • 257-258 ° C (Polymorph II)
solubility
  • Water: 11.7 mg l −1 (25 ° C)
  • Easily soluble in chloroform, DMSO, ethanol, methanol, 1-propanol, methylene chloride, tetrahydrofuran
  • slightly soluble in propylene glycol
  • very sparingly soluble in 0.1 M hydrochloric acid, 0.1 M sodium hydroxide solution
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302
P: no P-phrases
Toxicological data

486 mg kg −1 ( LD 50 ,  mouse ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Finasteride is a selective inhibitor of steroid 5- α -reductase type II and type III, as the drug for benign prostatic hyperplasia (BPH) and androgenetic alopecia (androgenetic alopecia, AGA) is used. Finasteride is subject to medical prescription in Germany, Austria and Switzerland .

The active ingredient is offered in a dosage of 5 mg against benign prostatic hyperplasia and as tablets with 1 mg finasteride against androgen-related hair loss.

properties

Finasteride occurs in two polymorphic crystal forms, which differ in terms of their melting point. Polymorph I crystallizes in an orthorhombic crystal lattice with space group P2 1 2 1 2 1 , Polymorph II in a monoclinic lattice with space group P2 1 . Both forms are enantiotropic to one another, the transition point being between 200 and 230 ° C. A number of hydrates and solvates are also formed, such as with tetrahydrofuran , acetic acid , ethyl acetate , isopropanol , dioxane and diethyl ether . Because of its higher stability, Form I is preferred in pharmaceutical use.

pharmacology

Mode of action

Finasteride is a 5 α -reductase inhibitor and belongs to the synthetic steroids . Due to its similarity to natural testosterone, it irreversibly blocks the 5 α -reductase and thus prevents the conversion of the sex hormone testosterone into dihydrotestosterone (DHT). According to the current state of research, certain hair follicles react to DHT by reducing the anagen phase (growth phase). This sensitivity of the hair follicles is hereditary. Finasteride inhibits the conversion of testosterone into DHT. The hair follicles can then respond by lengthening the anagen phase. However, if the hair follicle is barely active, nothing can usually be achieved. Finasteride must be taken as long as the man wants to keep his hair. Finasteride thereby postpones the onset of androgenetic hair loss in men into later years. If the treatment is interrupted, the DHT level in the blood increases and the hair follicles that have grown back can also fall out again. First successes can only be observed after an intake of 3–6 months.

The response to finasteride therapy (stopping hair loss, stimulating new hair growth) may be related to an upregulation of IGF1. In a small study of 9 people, the efficacy of finasteride correlated with the upregulation of IGF1 in some people. Androgen receptor polymorphism also appears to be important for the response to therapy.

The androgen receptor exists in two forms (A-form and B-form), which differ in their activity. The A-form with 87 kDa (the first 187 amino acids are missing due to proteolysis) is smaller than the B-form with 110 kDa. Usually about 80% of the total amount of receptor is in the B-form and only 20% in the A-form. There is evidence that androgenetic alopecia is associated with a transformation of the B-form into the A-form and that the A-form is primarily responsible for the AGA via stimulation by DHT. While people with androgenetic alopecia on the back of the head have a normal A / B ratio (more B-form receptors), there are more A-form receptors in bald areas. Finasteride is supposed to normalize the A / B ratio by transforming the receptors back from the A-form to the B-form, which is possibly related to the effectiveness.

In the course of several years of international studies, 80 to 90% of the users were able to stop the progressive hair loss and in around 65% even a thickening of the scalp hair by thickening previously shrunk hair. Contrary to previous assumptions, a study from 2003 showed that finasteride also has a significant effect on users between the ages of 41 and 60.

Side effects

Side effects of finasteride occurred occasionally at the low dose of 1 mg per day (ie in 0.1% to 1% of the treated patients), but frequently (ie in 1% to 10% of the treated patients) at a higher dose of 5 mg per day decreased libido and erectile dysfunction ( erectile dysfunction , decreased ejaculate volume ). These do not always completely disappear after the end of therapy. Occasionally, patients report that erectile dysfunction persists after discontinuing treatment with 1 mg finasteride per day. Testicular pain and infertility, occasionally depressive moods, were also reported occasionally. Persistent side effects after therapy are described as post-finasteride syndrome .

In one study, depression occurred while taking it. However, it is not a placebo-controlled study.

Another study found evidence of an association between the administration of finasteride and a malfunction of the meibomian gland . As a result, the eye should no longer be able to produce an oily liquid, which serves to protect the tear film from drying out, so that patients often complained of dry eyes or visual disturbances as a result .

In patients who took finasteride for a long time, occasionally increased levels of the liver enzyme γ-GT were observed. In individual cases, the breast may become enlarged ( gynecomastia ). The prostate becomes smaller and the hormone-dependent body hair becomes sparse.

In a 2009 study published by the British Medicines and Healthcare products Regulatory Agency (MHRA), an increased incidence of breast cancer was found, namely 7.8 per 100,000 patient-years with 5 mg finasteride daily compared to 3.8 per 100,000 patient-years without ingestion. The possible connection between breast cancer and the use of finasteride was not significant, but according to the MHRA it cannot be ruled out either.

A meta-analysis published in 2015 of 34 clinical studies on the safety and side effects of finasteride when used in the treatment of androgenetic hair loss (AGA), which among other things led to the approval of finasteride in this area of ​​application, showed systematic biases in favor of safety and side effects . According to the meta-analysis, the study results provide insufficient information on the safety profile of finasteride in this application area.

Another study from 2015 advised prescribing doctors to speak intensively with patients about the risks and possible permanent side effects of finasteride when used against AGA.

On July 5, 2018, the BfArM published a Rote-Hand-Brief to provide information about persistent side effects of finasteride that can occur during or after taking the drug. This includes the risk of sexual dysfunction (including erectile dysfunction, ejaculation disorder and decreased libido), which - based on individual case reports of patients - can persist for more than 10 years even after treatment has been discontinued. It also warns against mental disorders such as mood changes (including depressive mood, depression and suicidal ideation). It should also be noted that, on the recommendation of the European Medicines Agency, “Anxiety” will be included as a new side effect in the product information for finasteride.

There are no known interactions with other drugs.

Contraindications

Finasteride should not be taken by women and persons under the age of 18 and those who urinate frequently. Finasteride taken during pregnancy leads to malformations of the external genital organs of male fetuses. Therefore, women who are pregnant or possibly pregnant should avoid any contact with this substance. Finasteride in semen poses no danger to the male fetus. Calculations have shown that a woman would have to come into contact with at least three liters of semen per day in order for any measurable changes in her DHT levels to occur. However, as a safety precaution, the use of condoms is recommended if the sexual partner is pregnant.

Due to the potential harm to a fetus in a blood transfusion to women, blood donation should not be made if finasteride is taken regularly. The US FDA recommends stopping use for a month to bring DHT levels to normal.

doping

Finasteride is not performance-enhancing, but makes it difficult to detect performance-enhancing agents such as anabolic steroids . Until 2008 it was therefore classified as banned by the World Anti-Doping Agency WADA . With effect from January 1, 2009, however, it was removed from the doping list because the detection methods for performance-enhancing substances were so refined that finasteride is no longer effective as a masking agent .

In the field of the DFB , the game TSV 1860 Munich against Wacker Burghausen was canceled in 2005 and intended to be repeated because the Serbian player Nemanja Vučićević had taken finasteride. The footballer was banned for six months. The game Kickers Emden - Fortuna Düsseldorf was rated 2-0 and three points for Düsseldorf, because the player Falk Schindler had taken the preparation "Carboxy Finasteride". He was also banned for six months. The Brazilian soccer player Romário has also been convicted of “finasteride doping”. He tested positive on October 28, 2007 after his club Vasco da Gama’s first division match against Palmeiras Sao Paulo. The 1994 world champion admitted that he had taken the substance finasteride to prevent hair loss.

During the XIII. In 2008 Paralympics, the German national wheelchair basketball player Ahmet Coskun was banned for taking finasteride as a hair restorer.

In weight training and body-building Finasteride is used to testosterone and its derivatives to combat often occurring hair loss.

Trade names

Monopreparations

Alofın (Tr), Androfin (A), Finapil (D), Crinormin (A), FinaHAIR (D), Finamed (D), Finascar (D), Finastad (A), Finasterax (CH), Finural (D), Prezepa (A), Propecia (D, A, CH), Proscar (D, A, CH), Prosmin (D), numerous generics (D, A, CH)

literature

Individual evidence

  1. ^ A b The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th edition. Merck & Co., Inc., Whitehouse Station, NJ, USA 2006, ISBN 0-911910-00-X .
  2. ^ A b c d e I. Gana, R. Ceolon, IB Rietveld: Phenomenology of polymorphism: The topological pressure-temperature phase relationships of the dimorphism of finasteride. In: Thermochim. Acta . 546, 2012, pp. 134-137, doi: 10.1016 / j.tca.2012.07.030 .
  3. ↑ a b Entry on finasteride in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  4. ↑ a b Fomasterode data sheet (PDF; 349 kB) from Santa Cruz Biotechnology, accessed on January 8, 2012.
  5. ↑ AC Moffat, MD Osselton, B. Widdop: Analysis of Drugs and Poisons - Finasteride.
  6. ↑ a b Finasteride data sheet at Sigma-Aldrich , accessed on April 1, 2011 ( PDF ).
  7. ↑ Faris Azzouni, Alejandro Godoy, Yun Li, James Mohler: The 5α-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases. In: Advances in Urology. 2012, Article ID 530121. doi: 10.1155 / 2012/530121 . PMC 3253436 (free full text).
  8. ↑ Kazutoshi Yamana, Fernand Labrie, Van Luu-The: Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride. ( Memento of the original from July 21, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Hormone Molecular Biology and Clinical Investigation. Volume 2 (3), 2010, doi: 10.1515 / HMBCI.2010.035 . @1@ 2Template: Webachiv / IABot / www.deepdyve.com
  9. ↑ a b L. Magalhães da Silva, C. Martiniano Montanari, OM Martins Santos, EC Laignier Cazedey, M. Lopes Ângelo, M. Benjamin de Araújo: Quality evaluation of the Finasteride polymorphic forms I and II in capsules. In: J. Pharm. Biomed. Anal . 105, 2015, pp. 24-31, doi: 10.1016 / j.jpba.2014.11.045 .
  10. ↑ a b A. Othman, JSO Evans, IR Evans, RK Harris, P. Hodgkinson: Structural study of polymorphs and solvates of finasteride. In: J. Pharm. Sci. 96, 2007, pp. 1380-1397, doi: 10.1002 / jps.20940 (free full text).
  11. ↑ I. Wawrzycka, K. Stqpniak, p Matyjaszczyk, AE Koziol, T. Lis, KA Abboud: Structural characterization of polymorphs and molecular complexes of finasteride. In: J. Mol. Struct. 474, 1999, pp. 157-166, doi: 10.1016 / S0022-2860 (98) 00569-9 .
  12. ^ National Library of Medicine - Medical Subject Headings Finasteride.
  13. ↑ Roger S. Rittmaster, Lida Antonian, Maria I. New, Elizabeth Stoner: Effect of Finasteride on Adrenal Steroidogenesis in Men . In: Journal of Andrology . tape 15 , no. 4 , July 1994, pp. 300 , section Conclusion , doi : 10.1002 / j.1939-4640.1994.tb00453.x .
  14. ↑ David A. Williams: Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins, 2002, ISBN 0-683-30737-1 , p. 112 ( limited preview in Google book search).
  15. ↑ Herb G. Bull et al .: Irreversible inhibition of human 5th alpha-reductase
  16. ↑ Thomas F. Woolf: Handbook of Drug Metabolism. Taylor & Francis, 1999, ISBN 0-8247-0229-8 , p. 206 ( limited preview in Google book search).
  17. ↑ Liren Tang, Olga Bernardo, Chantal Bolduc, Harvey Lui, Shabnam Madani, Jerry Shapiro: The expression of insulin-like growth factor 1 in follicular dermal papillae correlates with therapeutic efficacy of finasteride in androgenetic alopecia . In: Journal of the American Academy of Dermatology . tape 49 , no. 2 , August 2003, p. 229-233 , doi : 10.1067 / S0190-9622 (03) 00777-1 .
  18. Jump up ↑ Nagaoki Wakisaka, Yuh-ichi Taira, Masahiro Ishikawa, Yoshio Nakamizo, Kazuhiro Kobayashi, Masashi Uwabu, Yasutaka Fukuda, Yasuyuki Taguchi, Takanori Hama, Masaya Kawakami: Effectiveness of Finasteride on Patients and Patients Polymorphic Receptorphism, And Patients with Male Pattern Receptorphism . In: Journal of Investigative Dermatology Symposium Proceedings . tape 10 , no. 3 , December 2005, p. 293-294 , doi : 10.1111 / j.0022-202X.2005.10123.x .
  19. ↑ CM Wilson, MJ McPhaul: A and B forms of the androgen receptor are present in human genital skin fibroblasts . In: Proceedings of the National Academy of Sciences . tape 91 , no. 4 , February 1994, p. 1234-1238 , doi : 10.1073 / pnas.91.4.1234 .
  20. ↑ Tianshu Gao, Michael J. McPhaul: Functional Activities of the A and B forms of the Human Androgen Receptor in Response to Androgen Receptor Agonists and Antagonists . In: Molecular Endocrinology . tape 12 , no. 5 , May 1998, pp. 654-663 , doi : 10.1210 / mend.12.5.0112 .
  21. ↑ Information: Dr. Marty Sawaya, University of Miami School of Medicine, Miami.
  22. ^ DA Whiting: Efficacy and tolerability of finasteride 1 mg in men aged 41 to 60 years with male pattern hair loss. In: European Journal of Dermatology . 13, 2003, pp. 150-160. PMID 12695131 .
  23. ↑ a b Core Safety Profile: Finasteride 1 mg , basic information of the European product information, published on the website of the Federal Institute for Drugs and Medical Devices (BfArM), May 16, 2014.
  24. ↑ Propecia leaflet . (PDF; 210 kB). Merck & Co., June 2011. Retrieved September 13, 2011.
  25. ↑ Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A .: Finasteride induced depression: a prospective stud. In: BMC Clin Pharmacol. 6, October 7, 2006, p. 7. PMID 17026771 .
  26. ↑ Kathleen L. Krenzer et al: Effect of Androgen Deficiency on the Human Meibomian Gland and Ocular Surface. In: The Journal of Clinical Endocrinology & Metabolism . Vol. 85, no. 12, 2000, pp. 4874-4882. PMID 11134156 . doi: 10.1210 / jcem.85.12.7072 .
  27. ^ MHRA Public Assessment Report, The risk of male breast cancer with finasteride. ( Memento of December 7, 2009 in the Internet Archive ) December 2009; Full text (PDF) .
  28. ↑ SM Belknap, I. Aslam, T. Kiguradze, WH Temps, PR Yarnold, J. Cashy, RE Brannigan, G. Micali, B. Nardone, DP West: Adverse Event Reporting in Clinical Trials of Finasteride for Androgenic Alopecia: A Meta -analysis. In: JAMA Dermatology . 151 (6), Jun 1, 2015, pp. 600-606. doi: 10.1001 / jamadermatol.2015.36 . PMID 25830296 .
  29. ↑ MS Irwig: Safety concerns regarding 5α reductase inhibitors for the treatment of androgenetic alopecia. In: Curr Opin Endocrinol Diabetes Obes. 22 (3), Jun 2015, pp. 248-253, 151 (6), 1 Jun 2015, pp. 600-606. doi: 10.1097 / MED.0000000000000158 . PMID 25871957 .
  30. ↑ BfArM - Rote-Hand-Letters and Information Letters - Rote-Hand-Brief on Finasteride: Risk of sexual dysfunction and mental disorders. Retrieved August 3, 2018 .
  31. ↑ BfArM - Rote-Hand-Letters and Information Letters - Rote-Hand-Brief on Finasteride: Risk of sexual dysfunction and mental disorders. Retrieved August 3, 2018 .
  32. ↑ BfArM - Rote-Hand-Letters and Information Letters - Rote-Hand-Brief on Finasteride: Risk of sexual dysfunction and mental disorders. Retrieved August 3, 2018 .
  33. ↑ technical information of the company. Sandoz Finasteride, Version 010248-B726 (September 2008).
  34. ↑ H. Wolff, C. Kunte: Therapy of androgenetic alopecia in men with finasteride, 1999 . MMW Progress Med.
  35. ↑ Package insert finasteride.
  36. ↑ FDA: Recommendations for donor deferral (PDF; 9 kB), July 28, 1993.
  37. ↑ Q&A: Status of Finasteride by the World Anti-Doping Agency's (WADA) ( Memento of November 14, 2008 in the Internet Archive ) (PDF; 36 kB).
  38. ↑ D. Sinner: The Black Book - Anabolic Steroids. BMS-Verlag, Gronau 2007, ISBN 978-3-00-020944-4 , p. 108/109.