Testolactone
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| Clinical data | |
|---|---|
| Trade names | Teslac |
| Other names | 13-Hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone; SQ-9538; Fludestrin; NSC-12173; NSC-23759 |
| AHFS/Drugs.com | Consumer Drug Information |
| Routes of administration | By mouth |
| Drug class | Aromatase inhibitor;Antiestrogen |
| ATC code |
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| Pharmacokineticdata | |
| Protein binding | ~85% |
| Metabolism | Liver |
| Excretion | Urine |
| Identifiers | |
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| CAS Number | |
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| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.012.304 |
| Chemical and physical data | |
| Formula | C19H24O3 |
| Molar mass | 300.398g·mol−1 |
| 3D model (JSmol) | |
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Testolactone(INN,USAN) (brand nameTeslac) is anon-selective,irreversible,steroidalaromatase inhibitorwhich is used as anantineoplastic drugto treat advanced-stagebreast cancer.[1][2][3][4] The drug was discontinued in 2008 and is no longer available for medical use.[4][5]
Medical uses
[edit]Testolactone is mainly used for treating various types ofbreast cancerin women who have been throughmenopauseor whoseovariesno longer function.[6]It works by blocking theproductionofestrogens,which helps prevent thegrowthof breast cancers that are stimulated by estrogens. It may also preventtumor cellsfrom being activated by otherhormones.[6]Testolactone has also been used to postponeprecocious pubertybecause of its ability to block estrogen production.[7]In addition, it has been used in the treatment ofgynecomastia.[8][9]
Testolactone is used to treat breast cancer at a dosage of 250 mg four times per dayby mouthor 100 mg three times per week byintramuscular injection.[10]
Available forms
[edit]Testolactone has been provided in the form of 50 mg and 250 mgoraltablets.[11][12]
Side effects
[edit]The most common side effects include:
- Abnormal skin sensations
- Aches of the legs and arms
- General body discomfort
- Hair loss
- Loss of appetite
- Nausea[13]
- Redness of the tongue
- Vomiting[14]
Rare but serious side effects include:
- Allergic reactions
- New breast lumps
- Bone pain
- Menstrual changes, abnormal vaginal bleeding, abnormalvaginal discharge,pelvic pain or pressure
- Excessive nausea, vomiting, or thirst
- Glossitis
- Edema
- Paresthesia
- Erythema
- Alopecia[15]
Pharmacology
[edit]The principal action of testolactone is reported to be inhibition ofaromataseactivity and the reduction inestrogensynthesis that follows. Androstenedione, a 19-carbonsteroid hormoneproduced in theadrenal glandsand thegonads,is where estrone synthesis originates and is the source of estrogen inpostmenopausalwomen.In vitrostudies report that the aromatase inhibition may be noncompetitive and irreversible, and could possibly account for the persistence of this drug's effect on estrogen synthesis after drug withdrawal.[2]Testolactone at a dosage of 1,000 mg/day has been found to decrease estradiol levels in men by 25 to 50% after 6 to 10 days of use.[12]This reduction is substantially less than with second- and third-generation aromatase inhibitors.[12]
In addition to its activity as an aromatase inhibitor, testolactone also reportedly possesses some anabolic activity and weak androgenic activity via binding to and activation of theandrogen receptor(AR).[4]However, itsaffinityfor the AR is very low; in one study, it showed 0.0029% of theaffinityof theanabolic steroidmetribolone(100%) for the human AR (Ki= 41 μM and 1.18 nM, respectively).[16]In accordance, androgenic side effects such ashirsutism,acne,andvoice changeshave been reported in no women in clinical trials with testolactone.[10]
| Generation | Medication | Dosage | % inhibitiona | Classb | IC50c |
|---|---|---|---|---|---|
| First | Testolactone | 250 mg 4x/dayp.o. | ? | Type I | ? |
| 100 mg 3x/weeki.m. | ? | ||||
| Rogletimide | 200 mg 2x/dayp.o. 400 mg 2x/dayp.o. 800 mg 2x/dayp.o. |
50.6% 63.5% 73.8% |
Type II | ? | |
| Aminoglutethimide | 250 mg mg 4x/dayp.o. | 90.6% | Type II | 4,500 nM | |
| Second | Formestane | 125 mg 1x/dayp.o. 125 mg 2x/dayp.o. 250 mg 1x/dayp.o. |
72.3% 70.0% 57.3% |
Type I | 30 nM |
| 250 mg 1x/2 weeksi.m. 500 mg 1x/2 weeksi.m. 500 mg 1x/1 weeki.m. |
84.8% 91.9% 92.5% | ||||
| Fadrozole | 1 mg 1x/dayp.o. 2 mg 2x/dayp.o. |
82.4% 92.6% |
Type II | ? | |
| Third | Exemestane | 25 mg 1x/dayp.o. | 97.9% | Type I | 15 nM |
| Anastrozole | 1 mg 1x/dayp.o. 10 mg 1x/dayp.o. |
96.7–97.3% 98.1% |
Type II | 10 nM | |
| Letrozole | 0.5 mg 1x/dayp.o. 2.5 mg 1x/dayp.o. |
98.4% 98.9%–>99.1% |
Type II | 2.5 nM | |
| Footnotes:a= Inpostmenopausalwomen.b= Type I:Steroidal,irreversible(substrate-binding site). Type II:Nonsteroidal,reversible(binding to and interference with thecytochrome P450hememoiety).c= Inbreast cancerhomogenates.Sources:See template. | |||||
Chemistry
[edit]Testolactone, also known as 13-hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone, is a synthetic 18-oxasteroid and aD-homo-18-oxoanalogueofandrostenedione(androst-4-en-3,17-dione), with a six-memberedlactoneringin place of the five-memberedcarbocyclicD-ring.[4][1]
History
[edit]Testolactone was first approved for medical use in theUnited Statesin 1970.[12]
References
[edit]- ^abMilne GW (8 May 2018).Drugs: Synonyms and Properties: Synonyms and Properties.Taylor & Francis. pp. 935–.ISBN978-1-351-78989-9.
- ^abTestolactoneat DrugBank.ca
- ^Dunkel L (July 2006). "Use of aromatase inhibitors to increase final height".Molecular and Cellular Endocrinology.254–255: 207–216.doi:10.1016/j.mce.2006.04.031.PMID16766117.S2CID34706246.
- ^abcdLemke TL, Williams DA (24 January 2012).Foye's Principles of Medicinal Chemistry.Lippincott Williams & Wilkins. pp. 1362–.ISBN978-1-60913-345-0.
- ^"Testolactone Advanced Patient Information".Drugs.com.2022-03-19.Retrieved2022-07-21.
- ^abTestolactone facts and comparisons at Drugs.com
- ^Carel JC, Lahlou N, Roger M, Chaussain JL (2004)."Precocious puberty and statural growth".Human Reproduction Update.10(2): 135–147.doi:10.1093/humupd/dmh012.PMID15073143.
- ^Becker KL (2001).Principles and Practice of Endocrinology and Metabolism.Lippincott Williams & Wilkins. pp. 1206–.ISBN978-0-7817-1750-2.
- ^Bland KI, Copeland EM, Klimberg VS (9 September 2009).The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases.Elsevier Health Sciences. pp. 162–.ISBN978-1-4377-1121-9.
- ^abLupulescu A (24 October 1990)."Treatment of Hormone Dependent Cancers".Hormones and Vitamins in Cancer Treatment.CRC Press. pp. 57, 64.ISBN978-0-8493-5973-6.
- ^Medical Economics (February 1983).Physicians Desk Reference.PDR Network, LLC. pp. 1921, 1963.ISBN978-0-87489-859-0.
- ^abcdLlewellyn W (2011).Anabolics.Molecular Nutrition Llc. pp. 805–.ISBN978-0-9828280-1-4.
- ^Clark RV, Sherins RJ (1989-05-06)."Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover".Journal of Andrology.10(3): 240–247.doi:10.1002/j.1939-4640.1989.tb00094.x.PMID2663800.
- ^"Testolactone Uses, Side Effects & Warnings".Drugs.com.Retrieved2022-03-27.
- ^"Testolactone Side Effects: Common, Severe, Long Term".Drugs.com.Retrieved2022-03-27.
- ^Eil C, Edelson SK (July 1984). "The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors".The Journal of Clinical Endocrinology and Metabolism.59(1): 51–55.doi:10.1210/jcem-59-1-51.PMID6725525.