what is 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 It was withdrawn for use in humans in the United States in the 1990s[6] but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing’s syndrome in dogs. It is taken by mouth.
Medical uses
buy 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.
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. Success was measured by improvements in both blood test results and physical symptoms (normalized appetite and activity level, and decreased panting, thirst, and urination).
Contraindications
Trilostane should not be used in pregnant women.
Trilostane should not be given to a dog that:
Has kidney or liver disease
Takes certain medications used to treat cardiovascular disease
Is pregnant, nursing or intended for breeding
trilostane side effects
Side effects of trilostane in conjunction with a corticosteroid in humans include gastrointestinal side effects like gastritis, nausea, vomiting, and diarrhea. Nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of diarrhea with trilostane. 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. Reversible granulocytopenia and transient oral paresthesia may occur with trilostane.
Pharmacodynamics
Steroidogenesis. Trilostane inhibits 3β-HSD.
Trilostane is a steroidogenesis inhibitor. It is specifically an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD). 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. Consequently, trilostane inhibits the production of all classes of steroid hormones, including androgens, estrogens, progestogens, glucocorticoids, and mineralocorticoids.
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. Trilostane has also been used as an abortifacient due to its inhibition of progesterone synthesis.
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. However, trilostane may nonetheless inhibit estrogen synthesis by inhibiting androgen synthesis.
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. The effectiveness of trilostane in postmenopausal breast cancer may relate to this apparent antiestrogenic activity. Trilostane has also been found to act as an agonist of the androgen receptor. As such, its use in men with prostate cancer may warrant caution.
treatment of Cushing’s syndrome Trilostane is an inhibitor of 3β-hydroxysteroid dehydrogenase used in the treatment of Cushing’s syndrome and primary hyperaldosteronism. These are both disorders where excess amounts of corticosteroid hormones are produced in the body. Corticosteroids are essential for the body to make use of carbohydrates, fats and proteins and for a normal response to stress. They are also necessary for the regulation of salt and water balance in the body. Trilostane helps prevent the production of corticosteroids, controlling the symptoms associated with these disorders.
Trilostane can also be useful in the treatment of breast cancer that has relapsed in women who have gone through menopause.
Mechanism Breast cancer is one of hormone-dependent tumors. And estrogen is the main driving factor of the growth of breast cancer cells. Thus, one of the modern treatment of breast cancer is the major target of estrogen through inhibiting the production of estrogen or block the action of estrogen or estrogen receptor in its site of action. It has been known that estrogen receptor is only a single receptor, but recent studies have identified that there are at least two subtypes α and β. Estrogen uniting with α-estrogen can stimulate cell growth, but it uniting with β-estrogen receptor can cut α-estrogen receptors and slow the rate of cell proliferation. Research revealed that the trilostane cannot only lower the production of estrogen, but also can modulate the binding of estrogen receptors on different subtypes. And meanwhile the dual effect of α-estrogen receptor inhibitors and β-estrogen receptor appears. Finally it can block and alter the negative effect of estrogen on cancer cells. The unique mode of action of trilostane can not only set it apart from other existing anti-estrogen drugs, but also be the pharmacological basis of that it is still highly effective on breast cancer in treatment failure with other anti-estrogen therapy or resistant breast cancer.
The treatment of advanced breast cancer Breast cancer is the most common type of tumor in women. Currently, for postmenopausal patients with hormone receptor-positive or unknown, clinical treatments unanimously recommend to be the preferred antiestrogen therapy, and the role of this therapy in delaying disease progression and improving survival time also has been affirmed and confirmed in numerous studies of breast cancer.
Trilostane (trade name Modrenal) developed by the biotechnology company has already been on the market. It can be used for the treatment of postmenopausal women that hormone-selective cancer has spread outside the breast. The pharmaceutical uses two ways to slow down the disease progression. For hormone-sensitive breast cancer, estrogen promotes the growth of cancer cells by acting to the two receptors. Estrogen receptor α is cancer accelerator, and estrogen receptor β is the brake. Modrenal strengthens estrogen adsorption to the estrogen receptor β, and weakens the adsorption to estrogen receptor α. Meanwhile it also acts on another loci AP1in cell DNA to reduce cell proliferation.
Description 3β-hydroxysteroid dehydrogenase (3β-HSD) type 1 and type 2 isoforms are key enzymes for the biosynthesis of all active steroid hormones. 3β-HSD1 (type I) is expressed in placenta and peripheral tissues including breast tumors, whereas 3β-HSD2 (type 2) is expressed in the adrenal gland, ovary, and testis. Trilostane is an inhibitor of the 3β-HSDs: 3β-HSD1 and 3β-HSD2 with Ki values of 0.10 and 1.60 μM, respectively. Trilsotane has been approved for use in the treatment of Cushing’s syndrome in dogs to reduce cortisol, aldosterone, and corticosterone levels. Because human 3β-HSD (type 1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors, trilostane is also of interest for the treatment of breast cancer in postmenopausal women.
Chemical Properties Tan Crystals
Uses An inhibitor of steroid biosynthesis. Used as an adrenocortical suppressant. Used in the treatment of breast cancer.
Uses antifungal, inhibits mitosis in metaphase
Uses Trilostane has been used to evaluate its capability to regulate the sex-dependent differences in the lipopolysaccharide (LPS)-induced inflammatory responses of astrocytes.
Definition ChEBI: Trilostane is an epoxy steroid that is 3,17beta-dihydroxy-5alpha-androst-2-ene-2-carbonitrile in which the oxygen of the epoxy group is joined to the 4alpha and 5 alpha positions. It has a role as an antineoplastic agent, an abortifacient and an EC 1.1.1.210 [3beta(or 20alpha)-hydroxysteroid dehydrogenase] inhibitor. It is a 3-hydroxy steroid, a 17beta-hydroxy steroid, an androstanoid, an epoxy steroid and a nitrile.
Trade names Vetoryl, others
Other names WIN-24,540; 4α,5-Epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile
Routes of administration By mouth
ATC code H02CA01 (WHO)
trilostane powder Chemical Properties
Melting point 264 °C
alpha D25 +137.4° (c = 1 in pyridine)
Boiling point 467.02°C (rough estimate)
density 1.1213 (rough estimate)
refractive index 1.5614 (estimate)
storage temp. 2-8°C
solubility DMSO: ≥17mg/mL
form powder
pka 8.57±0.70(Predicted)
color white to tan
InChIKey KVJXBPDAXMEYOA-CXANFOAXSA-N
SMILES [C@@]123CC[C@@]4([H])[C@]5([H])CC[C@H](O)[C@@]5(C)CC[C@]4([H])[C@@]1(C)CC(C#N)=C(O)[C@@]2([H])O3 |&1:0,3,5,9,11,15,17,25,r|
CAS DataBase Reference 13647-35-3(CAS DataBase Reference)
EPA Substance Registry System Trilostane (13647-35-3)
