Trilostane

Last updated
Trilostane
Trilostane.svg
Clinical data
Trade names Vetoryl, others
Other namesWIN-24,540; 4α,5-Epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile
Routes of
administration 		By mouth [1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Metabolites 17-Ketotrilostane [1]
Elimination half-life Trilostane: 1.2 hours [1]
17-Ketotrilostane: 1.2 hours [1]
Identifiers
  • (1S,2R,6R,8S,11S,12S,15S,16S)-5,15-dihydroxy-2,16-dimethyl-7-oxapentacyclo[9.7.0.02,8.06,8.012,16]octadec-4-ene-4-carbonitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.033.743 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H27NO3
Molar mass 329.440 g·mol−1
3D model (JSmol)
  • N#C\C4=C(/O)[C@H]5O[C@]35[C@]([C@@H]2[C@H]([C@H]1[C@]([C@@H](O)CC1)(C)CC2)CC3)(C)C4
  • InChI=1S/C20H27NO3/c1-18-7-6-14-12(13(18)3-4-15(18)22)5-8-20-17(24-20)16(23)11(10-21)9-19(14,20)2/h12-15,17,22-23H,3-9H2,1-2H3/t12-,13-,14-,15-,17+,18-,19+,20+/m0/s1 Yes check.svgY
  • Key:KVJXBPDAXMEYOA-CXANFOAXSA-N Yes check.svgY
   (verify)

Trilostane, sold under the brand name Vetoryl among others, is a medication which has been used in the treatment of Cushing's syndrome, Conn's syndrome, and postmenopausal breast cancer in humans. [2] [3] [4] [5] [1] It was withdrawn for use in humans in the United States in the 1990s [6] but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing's syndrome in dogs. [7] It is taken by mouth. [1]

Contents

Medical uses

Trilostane has been used in the treatment of Cushing's syndrome (hypercortisolism), Conn's syndrome (hyperaldosteronism), and postmenopausal breast cancer in humans. [3] [1] When used to treat breast cancer, trilostane is administered in combination with a corticosteroid to prevent glucocorticoid deficiency. [1]

Veterinary uses

Trilostane is used for the treatment of Cushing's syndrome in dogs. The safety and effectiveness of trilostane for this indication were shown in several studies. [8] [9] Success was measured by improvements in both blood test results and physical symptoms (normalized appetite and activity level, and decreased panting, thirst, and urination). [8] [9]

Contraindications

Trilostane should not be used in pregnant women. [1]

Trilostane should not be given to a dog that:

Side effects

Side effects of trilostane in conjunction with a corticosteroid in humans include gastrointestinal side effects like gastritis, nausea, vomiting, and diarrhea. [1] Nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of diarrhea with trilostane. [1] Serious gastrointestinal side effects of trilostane alone or in combination with an NSAID like peptic ulcer, erosive gastritis, gastric perforation, hematemesis, and melena may occur in some individuals. [1] Reversible granulocytopenia and transient oral paresthesia may occur with trilostane. [1]

Pharmacology

Pharmacodynamics

Steroidogenesis. Trilostane inhibits 3b-HSD. Steroidogenesis.svg
Steroidogenesis. Trilostane inhibits 3β-HSD.

Trilostane is a steroidogenesis inhibitor. [1] It is specifically an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD). [1] [13] As a result of this action, trilostane blocks the conversion of Δ5-3β-hydroxysteroids, including pregnenolone, 17α-hydroxypregnenolone, dehydroepiandrosterone (DHEA), and androstenediol, into Δ4-3-ketosteroids, including progesterone, 17α-hydroxyprogesterone, androstenedione, and testosterone, respectively. [1] Consequently, trilostane inhibits the production of all classes of steroid hormones, including androgens, estrogens, progestogens, glucocorticoids, and mineralocorticoids. [1]

The mechanism of action of trilostane in Cushing's syndrome and Conn's syndrome is by inhibiting the production of corticosteroids such as cortisol and aldosterone in the adrenal glands. [14] [15] Trilostane has also been used as an abortifacient due to its inhibition of progesterone synthesis. [1] [16]

Trilostane is not an aromatase inhibitor and hence does not inhibit the conversion of androgens like androstenedione and testosterone into estrogens like estrone and estradiol. [1] However, trilostane may nonetheless inhibit estrogen synthesis by inhibiting androgen synthesis. [1]

In addition to steroidogenesis inhibition, trilostane has been found to act as a noncompetitive antiestrogen, via direct and presumably allosteric interactions with the estrogen receptor. [1] [17] [18] The effectiveness of trilostane in postmenopausal breast cancer may relate to this apparent antiestrogenic activity. [1] [17] [18] Trilostane has also been found to act as an agonist of the androgen receptor. [19] As such, its use in men with prostate cancer may warrant caution. [1]

Pharmacokinetics

Trilostane is metabolized in the liver. [1] The major metabolite of trilostane is 17-ketotrilostane. [1] The conversion of trilostane into 17-ketotrilostane is reversible, suggesting that trilostane and 17-ketotrilostane undergo interconversion in the body. [1] 17-Ketotrilostane circulates at 3-fold higher levels than trilostane and is more active than trilostane as a 3β-HSD inhibitor. [1] The elimination half-lives of trilostane and 17-ketotrilostane are both 1.2 hours, with both compounds cleared from the blood within 6 to 8 hours of a dose of trilostane. [1] 17-Ketotrilostane is excreted by the kidneys. [1]

Chemistry

Trilostane, also known as 4α,5-epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile, is a synthetic androstane steroid and a derivative of 5α-reduced androstane derivatives like 3α-androstanediol, 3β-androstanediol, and dihydrotestosterone. [2]

Synthesis

Trilostane is prepared from testosterone in a four-step synthesis.[ citation needed ]

History

Trilostane was withdrawn from human use in the United States market in April 1994. [20] [21] [6] It continued to be available in the United Kingdom for use in humans under the brand name Modrenal for the treatment of Cushing's disease and breast cancer in humans, but was eventually discontinued in this country as well. [6] [22] [23] [8]

Trilostane was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl. [24] It was available by prescription in the United Kingdom for dogs under the Vetoryl brand name for some time before it was approved in the United States. [10] The drug is also used to treat the skin disorder Alopecia X in dogs. [20] [25] [26]

Trilostane was the first drug approved to treat both pituitary- and adrenal-dependent Cushing's in dogs.[ citation needed ] Only one other drug, Anipryl (veterinary brand name) selegiline, is FDA-approved to treat Cushing's disease in dogs, but only to treat uncomplicated, pituitary-dependent Cushing's. [27] The only previous treatment for the disease was the use of mitotane (brand name Lysodren) off-label. [9] [28]

A number of compounding pharmacies in the United States sell trilostane for dogs.[ citation needed ] Since the United States approval of Vetoryl in December 2008, [24] compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl. [29]

Society and culture

Generic names

Trilostane is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [2] [3] Its developmental code name was WIN-24,540. [2] [3]

Brand names

Trilostane has been marketed under a number of brand names including Desopan, Modrastane, Modrenal, Trilox, Vetoryl, Oncovet TL and Winstan. [2] [3]

Availability

Trilostane is available for veterinary use in many countries throughout the world. [30]

Related Research Articles

<span class="mw-page-title-main">Cushing's syndrome</span> Symptoms from excessive exposure to glucocorticoids such as cortisol

Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a round red face due to facial plethora, a fat lump between the shoulders, weak muscles, weak bones, acne, and fragile skin that heals poorly. Women may have more hair and irregular menstruation. Occasionally there may be changes in mood, headaches, and a chronic feeling of tiredness.

Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic hormone therapy, hormone replacement therapy, androgen replacement therapy (ART), oral contraceptive pills, and transgender hormone therapy.

<span class="mw-page-title-main">Ketoconazole</span> Antifungal chemical compound

Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.

<span class="mw-page-title-main">Aminoglutethimide</span> Group of stereoisomers

Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications. It has also been used by bodybuilders, athletes, and other men for muscle-building and performance- and physique-enhancing purposes. AG is taken by mouth three or four times per day.

<span class="mw-page-title-main">Danazol</span> Chemical compound

Danazol, sold as Danocrine and other brand names, is a medication used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema and other conditions. It is taken by mouth.

<span class="mw-page-title-main">Mitotane</span> Chemical compound

Mitotane, sold under the brand name Lysodren, is a steroidogenesis inhibitor and cytostatic antineoplastic medication which is used in the treatment of adrenocortical carcinoma and Cushing's syndrome. It is a derivative of the early insecticide DDT and an isomer of p,p'-DDDTooltip dichlorodiphenyldichloroethane (4,4'-dichlorodiphenyldichloroethane) and is also known as 2,4'-(dichlorodiphenyl)-2,2-dichloroethane (o,p'-DDD).

<span class="mw-page-title-main">Megestrol acetate</span> Pharmaceutical drug - appetite stimulant

Megestrol acetate (MGA), sold under the brand name Megace among others, is a progestin medication which is used mainly as an appetite stimulant to treat wasting syndromes such as cachexia. It is also used to treat breast cancer and endometrial cancer, and has been used in birth control. MGA is generally formulated alone, although it has been combined with estrogens in birth control formulations. It is usually taken by mouth.

3β-Hydroxysteroid dehydrogenase/Δ5-4 isomerase (3β-HSD) is an enzyme that catalyzes the biosynthesis of the steroid progesterone from pregnenolone, 17α-hydroxyprogesterone from 17α-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone (DHEA) in the adrenal gland. It is the only enzyme in the adrenal pathway of corticosteroid synthesis that is not a member of the cytochrome P450 family. It is also present in other steroid-producing tissues, including the ovary, testis and placenta. In humans, there are two 3β-HSD isozymes encoded by the HSD3B1 and HSD3B2 genes.

17β-Hydroxysteroid dehydrogenases, also 17-ketosteroid reductases (17-KSR), are a group of alcohol oxidoreductases which catalyze the reduction of 17-ketosteroids and the dehydrogenation of 17β-hydroxysteroids in steroidogenesis and steroid metabolism. This includes interconversion of DHEA and androstenediol, androstenedione and testosterone, and estrone and estradiol.

Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.

<span class="mw-page-title-main">Abiraterone acetate</span> Chemical compound

Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer. Specifically it is used together with a corticosteroid for metastatic castration-resistant prostate cancer (mCRPC) and metastatic high-risk castration-sensitive prostate cancer (mCSPC). It should either be used following removal of the testicles or along with a gonadotropin-releasing hormone (GnRH) analog. It is taken by mouth.

Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people but also some non-transgender people, take this form of therapy according to their personal needs and preferences.

<span class="mw-page-title-main">HSD17B2</span> Protein-coding gene in the species Homo sapiens

17β-Hydroxysteroid dehydrogenase 2 (17β-HSD2) is an enzyme of the 17β-hydroxysteroid dehydrogenase (17β-HSD) family that in humans is encoded by the HSD17B2 gene.

<span class="mw-page-title-main">Chlormadinone acetate</span> Chemical compound

Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.

<span class="mw-page-title-main">Medroxyprogesterone acetate</span> Injectible form of birth control

Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of birth control and as a part of menopausal hormone therapy. It is also used to treat endometriosis, abnormal uterine bleeding, paraphilia, and certain types of cancer. The medication is available both alone and in combination with an estrogen. It is taken by mouth, used under the tongue, or by injection into a muscle or fat.

<span class="mw-page-title-main">Gynecomastia</span> Endocrine system disorder of human male breast

Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Gynecomastia can cause significant psychological distress or unease.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

An androgen synthesis inhibitor is a type of drug which inhibits the enzymatic synthesis of androgens, such as testosterone and dihydrotestosterone (DHT). They include:

<span class="mw-page-title-main">Amphenone B</span> Chemical compound

Amphenone B, or simply amphenone, also known as 3,3-bis(p-aminophenyl)butan-2-one, is an inhibitor of steroid hormone and thyroid hormone biosynthesis which was never marketed but has been used as a tool in scientific research to study corticosteroids and the adrenal glands. It acts as competitive inhibitor of 11β-hydroxylase, 17α-hydroxylase, 17,20-lyase, 21-hydroxylase, and 3β-hydroxysteroid dehydrogenase, as well as of cholesterol side-chain cleavage enzyme, thereby inhibiting the production of steroid hormones including glucocorticoids, mineralocorticoids, androgens, and estrogens. In addition, amphenone B inhibits the production of thyroxine by a thiouracil-like mechanism, specifically via inhibition of organic binding of iodine and uptake of iodide by the thyroid gland.

An estrogen synthesis inhibitor is a type of drug which inhibits the enzymatic synthesis of estrogens, such as estradiol. They include:

References

  1. 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 Puddefoot JR, Barker S, Vinson GP (December 2006). "Trilostane in advanced breast cancer". Expert Opinion on Pharmacotherapy. 7 (17): 2413–2419. doi:10.1517/14656566.7.17.2413. PMID   17109615. S2CID   23940491.
  2. 1 2 3 4 5 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1245–. ISBN   978-1-4757-2085-3.
  3. 1 2 3 4 5 Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 281–. ISBN   978-94-011-4439-1.
  4. ↑ Negwer M (1987). Organic-chemical Drugs and Their Synonyms: (an International Survey). VCH Publishers. ISBN   978-0-89573-552-2. 5870 (6516) C20H2:NOs 13647-35-3 42,5-Epoxy-173-hydroxy-3-oxo-50-androstane-22carbonitrile = (22,42,52,173)-4,5-Epoxy-17-hydroxy-3-oxoandrostane-2-carbonitrile (e) S Desopan, Modrastane, Modrenal, Trilostane", Trilox, Win 24 540, Winstan U Adrenocortical suppressant (steroid biosynthesis inhibitor)
  5. ↑ Milne GW (8 May 2018). Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. pp. 34–. ISBN   978-1-351-78989-9.
  6. 1 2 3 Tung D, Ciallella J, Hain H, Cheung PH, Saha S (December 2013). "Possible therapeutic effect of trilostane in rodent models of inflammation and nociception". Current Therapeutic Research, Clinical and Experimental. 75: 71–76. doi:10.1016/j.curtheres.2013.09.004. PMC   3898193 . PMID   24465047.
  7. ↑ "Cushing's Disease in Dogs Part 3: Current & Investigative Options for Therapy". Today's Veterinary Practice. 2016-02-24. Retrieved 2021-01-04.
  8. 1 2 3 Braddock JA, Church DB, Robertson ID, Watson AD (October 2003). "Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism". Australian Veterinary Journal. 81 (10): 600–607. doi:10.1111/j.1751-0813.2003.tb12498.x. PMID   15080470.[ permanent dead link ] (PDF)
  9. 1 2 3 "Treating Cushing's Disease in Dogs". US Food and Drug Administration. Retrieved 3 April 2011.
  10. 1 2 3 "Vetoryl-Contraindications". NOAH Compendium of Animal Health-National Office of Animal Health UK. Archived from the original on 17 February 2013. Retrieved 3 April 2011.
  11. 1 2 "Dechra US Datasheet-Vetoryl" (PDF). Dechra US. Archived from the original (PDF) on 22 March 2012. Retrieved 3 April 2011. (PDF)
  12. ↑ "Cushing's Disease in Dogs". NASC LIVE. 2 February 2015. Retrieved 2021-01-04.
  13. ↑ de Gier J, Wolthers CH, Galac S, Okkens AC, Kooistra HS (April 2011). "Effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane on luteal progesterone production in the dog". Theriogenology. 75 (7): 1271–1279. doi:10.1016/j.theriogenology.2010.11.041. PMID   21295836.
  14. ↑ Reusch CE (2006). "Trilostane-5 Years of Clinical Experience for the Treatment of Cushing's Disease" (PDF). Ohio State University Endocrinology Symposium. pp. 17–19. Retrieved 5 April 2011.[ permanent dead link ] (PDF)
  15. ↑ Reusch CE (2010). "Trilostane-A Review of a Success Story". World Small Animal Veterinary Association (WSAVA). Retrieved 5 April 2011.
  16. ↑ le Roux PA, Tregoning SK, Zinn PM, van der Spuy ZM (June 2002). "Inhibition of progesterone secretion with trilostane for mid-trimester termination of pregnancy: randomized controlled trials". Human Reproduction. 17 (6): 1483–1489. doi: 10.1093/humrep/17.6.1483 . PMID   12042266.
  17. 1 2 Puddefoot JR, Barker S, Glover HR, Malouitre SD, Vinson GP (September 2002). "Non-competitive steroid inhibition of oestrogen receptor functions". International Journal of Cancer. 101 (1): 17–22. doi:10.1002/ijc.10547. PMID   12209583. S2CID   25779906.
  18. 1 2 Beatson GT (1896). "On the Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases". Transactions. Medico-Chirurgical Society of Edinburgh. 15: 153–179. PMC   5518378 . PMID   29584099.
  19. ↑ Takizawa I, Nishiyama T, Hara N, Hoshii T, Ishizaki F, Miyashiro Y, Takahashi K (November 2010). "Trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, has an agonistic activity on androgen receptor in human prostate cancer cells". Cancer Letters. 297 (2): 226–230. doi:10.1016/j.canlet.2010.05.015. PMID   20831980.
  20. 1 2 Cook AK (1 February 2008). "Trilostane: A therapeutic consideration for canine hyperadrenocorticism". DVM 360. Archived from the original on 17 February 2013. Retrieved 5 April 2011.
  21. ↑ "Trilostane consumer information". Drugs.com. 4 January 2009. Archived from the original on 12 February 2008. Retrieved 3 April 2011.
  22. ↑ "Modrenal consumer information". Drugs.com UK. Archived from the original on 14 October 2012. Retrieved 3 April 2011.
  23. ↑ "Modrenal". electronic Medicines Compendium UK. Retrieved 3 April 2011.
  24. 1 2 "Vetoryl approval information". Food and Drug Administration. 5 December 2008. Retrieved 3 April 2011.
  25. ↑ Hillier A (2006). "Alopecia: Is an Endocrine Disorder Responsible?" (PDF). Ohio State University Endocrinology Symposium. p. 12 of 67. Retrieved 8 April 2011.[ permanent dead link ] (PDF)
  26. ↑ Cerundolo R, Lloyd DH, Persechino A, Evans H, Cauvin A (October 2004). "Treatment of canine Alopecia X with trilostane" (PDF). Veterinary Dermatology. European Society of Veterinary Dermatology. 15 (5): 285–293. doi:10.1111/j.1365-3164.2004.00403.x. PMID   15500480. Archived from the original (PDF) on 1 May 2014. Retrieved 16 May 2011. (PDF)
  27. ↑ "Anipryl consumer information". Drugs.com Vet. Retrieved 3 April 2011.
  28. ↑ Reine NJ (February 2007). "Medical management of pituitary-dependent hyperadrenocorticism: mitotane versus trilostane". Clinical Techniques in Small Animal Practice. 22 (1): 18–25. doi:10.1053/j.ctsap.2007.02.003. PMID   17542193.
  29. ↑ "VETORYL (trilostane) Capsules Letter - Pharmacy Professionals". Food and Drug Administration. 11 September 2009. Retrieved 3 April 2011.
  30. ↑ "Vetoryl Capsules (Trilostane) for Animal Use".
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.