Aminoglutethimide

General characteristics. Structure:

Active ingredient: 250 mg of aminoglutethimide in 1 tablet.

Drug with the expressed antineoplastic and cytostatic action.

Pharmacological properties:

Pharmacodynamics. Suppresses enzymatic transformation of cholesterol in прегненолон and inhibits biosynthesis by bark of adrenal glands glyuko-and mineralokortikoid, estrogen and androgens. Blocks various modes of formation of steroids: a hydroxylation of side chains at 11, 18 both 21 carbon atoms and the hydroxylation necessary for aromatization of androgens in estrogen (contacts P450 cytochrome). Decrease in adrenal secretion of cortisol kompensatorno increases secretion of AKTG a hypophysis (it can be suppressed by co-administration of a hydrocortisone); inhibits thyroxine synthesis by a thyroid gland and by the principle of feedback increases secretion of thyritropic hormone. Has anticonvulsant activity.

Action (oppression of function of bark of adrenal glands) is shown in 3–5 days. Recovery of normal basal secretion of adrenal glands and reaction to a stress is usually noted during 72 h after cancellation of a combination therapy аминоглутетимид / a hydrocortisone; for recovery of function of bark of adrenal glands after prolonged treatment (for example 1 year and more) more long time can be required.

At patients with an Icenco-Cushing syndrome reduces the increased cortisone level in blood, and, respectively, expressiveness of symptomatology. Reduces the level of estrogen in blood and suppresses their biosynthesis in tumoral fabric, promotes regression of tumoral process at women with hormonedependent malignant tumors of a mammary gland in the period of a menopause. It is effective for therapy of the progressing tumors, including at the progressing prostate carcinoma, at development of metastasises in soft tissues and bones. There are data on a possibility of use as a part of complex therapy of an idiopathic hypertensia.

Carcinogenicity, mutagenicity, influence on fertility. In the biennial research of carcinogenicity of an aminoglutetimid conducted on rats when using doses of 10-60 mg/kg/days (about 0,04-0,2 MRDCh in terms of mg/sq.m), statistically reliable dozozavisimy tendency of development of high-quality and malignant new growths of bark of adrenal glands and follicular cells of a thyroid gland was found in animal both floors. Statistically significant increase (0,05 level) in the frequency of developing of ovarian tubular adenomas was observed at a dose of 60 mg/kg/days. Statistically significant dozozavisimy tendency of emergence of papillomas of a bladder in males is shown.

Aminoglutetimid changes fertility at females of rats: at the doses equivalent 0,5-1,25 MRDCh, decrease in frequency of implantation of an oospore is revealed. The importance of these data for the person is unknown.

In researches on rats it is shown what аминоглутетимид in doses, in Zraza of the exceeding MRDCh, increases the frequency of fetalis death and has teratogenic effect, including a false hermaphroditism.

Aminoglutetimid passes through a placenta. In early researches among about 5000 patients 2 cases of a pseudohermaphroditism at chest girls whose mothers at the same time accepted antikonvulsant were recorded.

Pharmacokinetics. After intake it is quickly and completely soaked up, bioavailability — 92–98%. Tmax on average is 1,5 h. Linkng with proteins of plasma — 21–25%; concentration in blood cells — is 1,4-1,7 times higher than plasma. In the range of doses of 125-1000 mg the size of equilibrium concentration in blood is proportional to a dose; at doses of 500 and 1000 mg a day, daily within 3 months of size of equilibrium concentration make 4,5 and 9,5 mkg/ml respectively. The main metabolite — N-atsetilaminoglutetimid is metabolized in a liver (oxidation and acetylation of an aromatic amino group) to inactive or low-active metabolites; at some patients genetic variability of speed of acetylation is possible. Distribution volume — 76 l. T1/2 after reception of a single dose is 12,5 h; after long reception (2–32 weeks) — decreases to 7 h since аминоглутетимид is the inductor of microsomal enzymes of system of P450 cytochrome of a liver that leads to increase in speed of own metabolism. It is removed by kidneys (34–54% — in not changed look during 48 h) and with bile (3–7%). Is removed at a hemodialysis.

Indications to use:

Hypercorticoidism: the Icenco-Cushing syndrome caused by tumors (adenoma and a carcinoma of bark of adrenal glands, including in to - and the postoperative period, inoperable kortikosteroma), a hyperplasia of bark of adrenal glands, ectopic products of AKTG. Cancer of chest gland (at men is after castration); the progressing breast cancer (at women in a postmenopause, after an ovariektomiya); estrogenzavisimy tumors. The metastasizing prostate cancer (palliative treatment). Hyper aldosteronism.

Route of administration and doses:

Inside, during food. The dose is established individually depending on a disease and a condition of the patient. Adults: an Icenco-Cushing syndrome — on 250 mg 2–3 times (adenoma of adrenal glands), 2–4 times (a carcinoma of adrenal glands), 4–7 times (ectopic products of AKTG) a day; at a hyper aldosteronism of 3-6 times a day. At the metastasizing breast cancer at women and the metastasizing prostate cancer — on 125 mg 2 times a day (usually in 8–9 h and v16-18 h), if necessary — 4 times a day with an interval not less than 6 h, under constant control (it is preferable — monitoring) the plasma maintenance of cortisol, before achievement of desirable level of adrenal suppression; at inadequate decrease in level of cortisol the dose is gradually increased — by 250 mg of weekly bucketed 1–2 weeks before achievement of well tolerable dose (not bolee1 in days); the maximum dose — 2 g a day.

Features of use:

During pregnancy in need of use of an aminoglutetimid on vital indications or in case of a serious illness when other HP cannot be used, it is necessary to compare risk and advantage carefully. Category of action on a fruit on FDA — D. It is unknown whether gets аминоглутетимид into breast milk. Problems at the person are not registered, however for the period of reception of an aminoglutetimid it is recommended to stop breastfeeding.

Selection of a dose is recommended to be carried out in stationary conditions.

It is necessary to remember what аминоглутетимид can suppress products of Aldosteronum bark of adrenal glands and cause orthostatic or constant hypotension. In this regard at all patients at treatment through the corresponding time intervals it is necessary to carry out monitoring of the ABP. During treatment constantly control a functional condition of bark of adrenal glands, a thyroid gland and each 2 weeks, especially in the first 2–3 months — cellular composition of peripheral blood.

At the adrenal hypofunction arising during treatment or in the conditions of stressful situations (surgical intervention, an injury, an acute disease, etc.), in addition appoint glucocorticoids (hydrocortisone). At development of disturbances of a hemopoiesis and at suspicion on development of an allergic alveolitis therapy is cancelled. Emergence of skin rash, especially in an initiation of treatment, demands its temporary termination.

Patients are warned about need during a course to abstain from occupations potentially dangerous types of activity requiring special attention and speed of psychomotor reactions, to exclude the use of alcoholic beverages (alcohol can exponentiate effect of an aminoglutetimid), to refuse use of hormonal contraceptives.

Side effects:

From a nervous system and sense bodys: slackness, drowsiness, insomniya, depression, inadequate reaction to external irritants, confusion of consciousness, ataxy, headache, dizziness.

From cardiovascular system and blood (a hemopoiesis, a hemostasis): a neutropenia, a leukopenia, an agranulocytosis, thrombocytopenia, anemia (including hemolitic), a pancytopenia, decrease in level of hemoglobin and a hematocrit, arterial hypotension (up to a collapse), tachycardia.

From endocrine system: hypofunction of bark of adrenal glands up to adrenal insufficiency; a hypothyroidism, a masculinization and a hirsutism (at women), premature sexual development (at young men); hypoglycemia.

From bodies of a GIT: nausea, vomiting, diarrhea or lock, anorexia, disturbance of functional hepatic tests, including increase in level gamma глутамилтрансферазы; cholestatic hepatitis, jaundice.

Allergic reactions: rash, exfoliative dermatitis, Stephens-Johnson's syndrome, Lyell's disease; allergic, including anaphylactoid reactions — an itch, urticaria, a Quincke's edema, the allergic alveolitis which is followed by eosinophilic pulmonary infiltrates, etc.

Others: a renal failure, a hyponatremia, a hyperpotassemia, a hypercholesterolemia, fever, the increased sweating, a mialgiya.

Interaction with other medicines:

Hypnotic drugs, tranquilizers, tricyclic antidepressants, alcohol aggravate or change symptoms of acute overdose. Diuretics strengthen a hyponatremia. Aminoglutetimid stimulates (owing to activation of enzymes of a liver) biotransformation of peroral anticoagulants (monitoring of PV is necessary for correction of a dose), dexamethasone, Prednisonum, Prednisolonum, digitoxin, theophylline, a medroksiprogesteron, peroral hypoglycemic means (sulphonylurea derivatives) that leads to increase in clearance of these HP; in need of purpose of glucocorticoids the patient receiving аминоглутетимид is recommended to use a hydrocortisone. Aminoglutetimid can inhibit reaction of adrenal glands to AKTG (possibly decrease in therapeutic effect of AKTG).

Contraindications:

Hypersensitivity, including to a glutetimid; porphyria, liver failure.

Restrictions to use. Acute infectious diseases of the virus, fungal or bacterial nature, including chicken pox now or recently postponed (including recent contact with the patient), the surrounding herpes (risk of a serious generalized illness); a hypothyroidism, a renal failure, children's age (efficiency and safety of use are not established).

Overdose:

Symptoms: manifestations of reduced products of corticosteroids, including respiratory depression, a hyperventilation with the subsequent hypoventilation, hypotension, hypovolemic shock, drowsiness, a lethargy, an ataxy, dizziness, feeling of fatigue, muscular weakness, coma, nausea, vomiting; loss of sodium and water, hyponatremia, hypochloraemia, hyperpotassemia, hypoglycemia.

Treatment: a gastric lavage, at respiratory depression — an oxygenotherapy, IVL, at a hypovolemia and hypotension — a regidratation (500 ml of plasma, blood, plasma substitutes), then — in/in adrenaline of 10 mg in 500 ml of isotonic solution of sodium of chloride, at development of symptoms of deficit of glucocorticoids — in/in infusion of a hydrocortisone (100 mg of a hydrocortisone of sodium of succinate in 500 ml of isotonic solution of sodium of chloride) and 50 ml of 40% of solution of glucose during 3 h, then — in/in a hydrocortisone of 10 ml an hour constantly to a possibility of independent reception of a hydrocortisone inside. Hemoperfusion or dialysis (are effective at heavy intoxication).

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets on 250 mg, 10 tablets in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.