Mitotane

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Mitotane
Mitotane.svg
Mitotane-(2S)-enantiomer-from-xtal-3D-bs-17.png
Clinical data
Trade names Lysodren
Other names1,1-(Dichlorodiphenyl)-2,2-dichloroethane; o,p'-DDD
AHFS/Drugs.com Monograph
MedlinePlus a608050
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 40%
Protein binding 6%
Elimination half-life 18–159 days
Identifiers
  • (RS)-1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)-ethyl]-benzene
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.152 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H10Cl4
Molar mass 320.03 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 76 to 78 °C (169 to 172 °F)
  • Clc1ccccc1C(c2ccc(Cl)cc2)C(Cl)Cl
  • InChI=1S/C14H10Cl4/c15-10-7-5-9(6-8-10)13(14(17)18)11-3-1-2-4-12(11)16/h1-8,13-14H Yes check.svgY
  • Key:JWBOIMRXGHLCPP-UHFFFAOYSA-N Yes check.svgY
   (verify)

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. [4] [5] [6] [7] It is a derivative of the early insecticide DDT and an isomer of p,p'-DDD Tooltip dichlorodiphenyldichloroethane (4,4'-dichlorodiphenyldichloroethane) and is also known as 2,4'-(dichlorodiphenyl)-2,2-dichloroethane (o,p'-DDD). [8]

Contents

Medical uses

Mitotane has been produced by Bristol Myers Squibb but it is marketed as an orphan drug for adrenocortical carcinoma due to the small number of patients in need of it. Its main use is in those patients who have persistent disease despite surgical resection, those who are not surgical candidates, or those who have metastatic disease. In a 2007 retrospective study of 177 patients from 1985 to 2005 showed a significant increase in the recurrence-free interval after radical surgery followed by mitotane when compared to surgery alone. [9] The drug is also sometimes used in the treatment of Cushing's syndrome. [6]

Side effects

The use of mitotane is unfortunately limited by side effects, [10] which, as reported by Schteingart et al., include anorexia and nausea (88%), diarrhea (38%), vomiting (23%), decreased memory and ability to concentrate (50%), rash (23%), gynecomastia (50%), arthralgia (19%), and leukopenia (7%). [11]

Pharmacology

Pharmacodynamics

Mitotane is an inhibitor of the adrenal cortex. It acts as an inhibitor of cholesterol side-chain cleavage enzyme (P450scc, CYP11A1), and also of 11β-hydroxylase (CYP11B1), 18-hydroxylase (aldosterone synthase, CYP11B2), and 3β-hydroxysteroid dehydrogenase (3β-HSD) to a lesser extent. [4] [10] In addition, mitotane has direct and selective cytotoxic effects on the adrenal cortex, via an unknown mechanism, and thereby induces permanent adrenal atrophy similarly to DDD. [12] [13]

Chemistry

Analogues of mitotane include aminoglutethimide, amphenone B, and metyrapone.

History

Mitotane was introduced in 1960 for the treatment of adrenocortical carcinoma. [6]

Society and culture

Generic names

Mitotane is the generic name of the medication and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [7] [14]

Brand names

Mitotane is sold under the brand name Lysodren. [7]

Veterinary use

Mitotane is also used to treat Cushing's disease (pituitary-dependent Cushing's syndrome) in dogs. The medication is used in the controlled destruction of adrenal tissue, leading to a decrease in cortisol production. [15]

Related Research Articles

<span class="mw-page-title-main">Adrenocorticotropic hormone</span> Pituitary hormone

Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol and androgens by the zona fasiculata and zona reticularis, respectively. ACTH is also related to the circadian rhythm in many organisms.

<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.

<span class="mw-page-title-main">Hirsutism</span> Excessive hair growth on parts of the body where hair is usually minimal

Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin hirsutus meaning "hairy". It usually refers to a male pattern of hair growth in a female that may be a sign of a more serious medical condition, especially if it develops well after puberty. Cultural stigma against hirsutism can cause much psychological distress and social difficulty. Discrimination based on facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression.

<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">Metyrapone</span> Chemical compound

Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). It is part of the steroidogenesis inhibitor class of drugs.

<span class="mw-page-title-main">Adrenocortical carcinoma</span> Medical condition

Adrenocortical carcinoma (ACC) is an aggressive cancer originating in the cortex of the adrenal gland.

<span class="mw-page-title-main">Methylprednisolone</span> Corticosteroid medication

Methylprednisolone is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at high doses during acute flares. Methylprednisolone and its derivatives can be administered orally or parenterally.

<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.

Secondary hypertension is a type of hypertension which has a specific and identifiable underlying primary cause. It is much less common than essential hypertension, affecting only 5-10% of hypertensive patients. It has many different causes including obstructive sleep apnea, kidney disease, endocrine diseases, and tumors. The cause of secondary hypertension varies significantly with age. It also can be a side effect of many medications.

Pseudo-Cushing's syndrome or non-neoplastic hypercortisolism is a medical condition in which patients display the signs, symptoms, and abnormal cortisol levels seen in Cushing's syndrome. However, pseudo-Cushing's syndrome is not caused by a problem with the hypothalamic-pituitary-adrenal axis as Cushing's is; it is mainly an idiopathic condition, however a cushingoid appearance is sometimes linked to excessive alcohol consumption. Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated.

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

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. It was withdrawn for use in humans in the United States in the 1990s but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing's syndrome in dogs. It is taken by mouth.

<span class="mw-page-title-main">Adrenal tumor</span> Tumors of the adrenal gland, usually resulting in hormone overproduction

An adrenal tumor or adrenal mass is any benign or malignant neoplasms of the adrenal gland, several of which are notable for their tendency to overproduce endocrine hormones. Adrenal cancer is the presence of malignant adrenal tumors, and includes neuroblastoma, adrenocortical carcinoma and some adrenal pheochromocytomas. Most adrenal pheochromocytomas and all adrenocortical adenomas are benign tumors, which do not metastasize or invade nearby tissues, but may cause significant health problems by unbalancing hormones.

<span class="mw-page-title-main">Adrenocortical adenoma</span> Medical condition

An adrenocortical adenoma or adrenal adenoma is commonly described as a benign neoplasm emerging from the cells that comprise the adrenal cortex. Like most adenomas, the adrenocortical adenoma is considered a benign tumor since the majority of them are non-functioning and asymptomatic. Adrenocortical adenomas are classified as ACTH-independent disorders, and are commonly associated with conditions linked to hyperadrenalism such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism), which is also known as primary aldosteronism. In addition, recent case reports further support the affiliation of adrenocortical adenomas with hyperandrogenism or florid hyperandrogenism which can cause hyperandrogenic hirsutism in females. "Cushing's syndrome" differs from the "Cushing's disease" even though both conditions are induced by hypercortisolism. The term "Cushing's disease" refers specifically to "secondary hypercortisolism" classified as "ACTH-dependent Cushing's syndrome" caused by pituitary adenomas. In contrast, "Cushing's syndrome" refers specifically to "primary hypercortisolism" classified as "ACTH-independent Cushing's syndrome" caused by adrenocortical adenomas.

<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.

<span class="mw-page-title-main">Adrenal gland disorder</span> Medical condition

Adrenal gland disorders are conditions that interfere with the normal functioning of the adrenal glands. Your body produces too much or too little of one or more hormones when you have an adrenal gland dysfunction. The type of issue you have and the degree to which it affects your body's hormone levels determine the symptoms.

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.

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

Levoketoconazole, sold under the brand name Recorlev, is a steroidogenesis inhibitor that is used for the treatment of Cushing's syndrome. Levoketoconazole was approved for medical use in the United States in December 2021.

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

Osilodrostat, sold under the brand name Isturisa, is a medication for the treatment of adults with Cushing's disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. It is taken by mouth.

<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.

<span class="mw-page-title-main">Adrenalism</span>

Adrenalism describes the condition of an excessive or substandard secretion of hormones related to the adrenal glands, which are found directly superior to the kidneys. Adrenalism can be further distinguished as hyperadrenalism, referring to the excessive secretion of hormones, and hypoadrenalism, referring to the insufficient secretion of hormones.

References

  1. ↑ "Product monograph brand safety updates". Health Canada . 7 July 2016. Retrieved 3 April 2024.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  3. ↑ "Lysodren EPAR". European Medicines Agency. 12 June 2002. Retrieved 27 June 2024.
  4. 1 2 Cavagnini F, Giraldi FP (18 May 2010). "Adrenal Causes of Hypercortisolism". In Jameson JL, De Groot LJ (eds.). Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. pp. 1888–. ISBN   978-1-4557-1126-0.
  5. ↑ Hahner S, Fassnacht M (April 2005). "Mitotane for adrenocortical carcinoma treatment". Current Opinion in Investigational Drugs. 6 (4): 386–394. PMID   15898346.
  6. 1 2 3 Dang C, Trainer PJ (1 October 2010). "Medical Management of Cushing's Syndrome". In Bronstein MD (ed.). Cushing's Syndrome: Pathophysiology, Diagnosis and Treatment. Springer Science & Business Media. pp. 156–. ISBN   978-1-60327-449-4.
  7. 1 2 3 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 382–. ISBN   978-1-4757-2085-3.
  8. ↑ "Mitotane". PubChem. U.S. National Library of Medicine.
  9. ↑ Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, et al. (June 2007). "Adjuvant mitotane treatment for adrenocortical carcinoma". The New England Journal of Medicine. 356 (23): 2372–2380. doi:10.1056/NEJMoa063360. hdl: 2318/37317 . PMID   17554118.{{cite journal}}: CS1 maint: overridden setting (link)
  10. 1 2 Tzanela M, Vassiliadi DA, Tsagarakis S (24 March 2014). "Coincidental adrenal masses and adrenal cancer". In Harris PE, Bouloux PM (eds.). Endocrinology in Clinical Practice (Second ed.). CRC Press. pp. 216–. ISBN   978-1-84184-951-5.
  11. ↑ Schteingart DE, Motazedi A, Noonan RA, Thompson NW (September 1982). "Treatment of adrenal carcinomas". Archives of Surgery. 117 (9): 1142–1146. doi:10.1001/archsurg.1982.01380330010004. PMID   7115060.
  12. ↑ Sojka WS, Raizer J (28 September 2011). "Neurologic Complications of Hormonal Chemotherapies". In Lee EQ, Schiff D, Wen PY (eds.). Neurologic Complications of Cancer Therapy. Demos Medical Publishing. pp. 179–. ISBN   978-1-61705-019-0.
  13. ↑ Kannan CR (6 December 2012). "Cushing's Syndrome". The Adrenal Gland. Springer Science & Business Media. pp. 160–. ISBN   978-1-4613-1001-3.
  14. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 697–. ISBN   978-3-88763-075-1.
  15. ↑ Nichols R. "Canine Cushing's Syndrome: Diagnosis and Treatment Part 1: Typical, Atypical, and Pseudo-Cushing's Disease" (PDF). Archived from the original (PDF) on 21 October 2007.

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