The metabolism of 17 alpha-methyl-17 beta-hydroxy-2-oxa-5 alpha-androstan-3-one (oxandrolone) in man has been investigated by gas chromatography/mass spectrometry. After oral administration of a 10 mg dose to man, five metabolites were detected in the free fraction of the urinary samples. Oxandrolone, the major compound excreted in urine, was detected within 72 hr after administration. During this period 35.8 and 8.4% of the administered dose was excreted as unchanged oxandrolone and 17-epioxandrolone, respectively. In addition, minute amounts of 16 alpha- and 16 beta-hydroxyoxandrolone and a delta-hydroxy acid resulting from the hydrolysis of the lactone group of oxandrolone were detected in the urine samples 8-60 hr after administration.
IDENTIFICATION: Oxandrolone is an anabolic steroid for systemic use. Origin of the substance: Naturally-occurring anabolic steroids are synthesized in the testis, ovary and adrenal gland from cholesterol via pregnenolone. Synthetic anabolic steroids are based on the principal male hormone testosterone, modified in one of three ways: alkylation of the 17-carbon; esterification of the 17-OH group and modification of the steroid nucleus. This steroid is a white solid crystalline material. It is soluble in water, alcohol, acetone, chloroform and ether. The only legitimate therapeutic indications for anabolic steroids are: (a) replacement of male sex steroids in men who have androgen deficiency, for example as a result of loss of both testes; (b) the treatment of certain rare forms of aplastic anemia which are or may be responsive to anabolic androgens. (c) the drugs have been used in certain countries to counteract catabolic states, for example after major trauma. HUMAN EXPOSURE: Main risks and target organs: The main risks are those of excessive androgens: menstrual irregularities and virilization in women and impotence, premature cardiovascular disease and prostatic hypertrophy in men. Both men and women can suffer liver damage with oral anabolic steroids containing a substituted 17-alpha-carbon. Psychiatric changes can occur during use or after cessation of these agents. Summary of clinical effects: Acute overdosage can produce nausea and gastrointestinal upset. Chronic usage is thought to cause an increase in muscle bulk, and can cause an exaggeration of male characteristics and effects related to male hormones. Anabolic steroids can influence sexual function. They can also cause cardiovascular and hepatic damage. Acne and male-pattern baldness occur in both sexes; irregular menses, atrophy of the breasts, and clitoromegaly in women; and testicular atrophy and prostatic hypertrophy in men. Contraindications: Known or suspected cancer of the prostate or (in men) breast. Pregnancy or breast feeding or known cardiovascular disease is a relative contraindication. Routes of exposure: Oral: Anabolic steroids can be absorbed from the gastrointestinal tract, but many compounds undergo such extensive first-pass metabolism in the liver that they are inactive. Those compounds in which substitution of the 17-carbon protects the compound from the rapid hepatic metabolism are active orally. There are preparations of testosterone that can be taken sublingually. Parenteral: Intramuscular or deep subcutaneous injection is the principal route of administration of all the anabolic steroids except the 17-alpha-substituted steroids which are active orally. Absorption by route of exposure: The absorption after oral dosing is rapid for testosterone and probably for other anabolic steroids, but there is extensive first-pass hepatic metabolism for all anabolic steroids except those that are substituted at the 17-alpha position. The rate of absorption from subcutaneous or intramuscular depots depends on the product and its formulation. Absorption is slow for the lipid-soluble esters such as the cypionate or enanthate, and for oily suspensions. Distribution by route of exposure: The anabolic steroids are highly protein bound, and is carried in plasma by a specific protein called sex-hormone binding globulin. Biological half-life by route of exposure: The metabolism of absorbed drug is rapid, and the elimination half-life from plasma is very short. The duration of the biological effects is therefore determined almost entirely by the rate of absorption from subcutaneous or intramuscular depots, and on the de-esterification which precedes it. Metabolism: Free (de-esterified) anabolic androgens are metabolized by hepatic mixed function oxidases. Elimination by route of exposure: After administration of radiolabelled testosterone, about 90% of the radioactivity appears in the urine, and 6% in the feces; there is some enterohepatic recirculation. Mode of action: Toxicodynamics: The toxic effects are an exaggeration of the normal pharmacological effects. Pharmacodynamics: Anabolic steroids bind to specific receptors present especially in reproductive tissue, muscle and fat. The anabolic steroids reduce nitrogen excretion from tissue breakdown in androgen deficient men. They are also responsible for normal male sexual differentiation. The ratio of anabolic body-building effects to androgenic (virilizing) effects may differ among the members of the class, but in practice all agents possess both properties to some degree. There is no clear evidence that anabolic steroids enhance overall athletic performance. Carcinogenicity: Precocious prostatic cancer has been described after long-term anabolic steroid abuse. Cases where hepatic cancers have been associated with anabolic steroid abuse have been reported. Teratogenicity: Androgen ingestion by a pregnant mother can cause virilization of a female fetus. Main adverse effects: The adverse effects of anabolic steroids include weight gain, fluid retention, and abnormal liver function as measured by biochemical tests. Administration to children can cause premature closure of the epiphyses. Men can develop impotence and azoospermia. Women are at risk of virilization. Acute poisoning: Ingestion: Nausea and vomiting can occur. Parenteral exposure: Patients are expected to recover rapidly after acute overdosage, but there are few data. Body-builders use doses many times the standard therapeutic doses for these compounds but do not suffer acute toxic effects. Chronic poisoning: Ingestion: Hepatic damage, manifest as derangement of biochemical tests of liver function and sometimes severe enough to cause jaundice; virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes; psychiatric disturbances can occur during or after prolonged treatment. Parenteral exposure: Virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes. Psychiatric disturbances can occur during or after prolonged treatment. Hepatic damage is not expected from parenteral preparations. Course, prognosis, cause of death: Patients with symptoms of acute poisoning are expected to recover rapidly. Patients who persistently abuse high doses of anabolic steroids are at risk of death from premature heart disease or cancer, especially prostatic cancer. Non-fatal but long lasting effects include voice changes in women and fusion of the epiphyses in children. Other effects are reversible over weeks or months. Systematic description of clinical effects: Cardiovascular: Chronic ingestion of high doses of anabolic steroids can cause elevations in blood pressure, left ventricular hypertrophy and premature coronary artery disease. Neurological: Central nervous system: Stroke has been described in a young anabolic steroid abuser. Mania and psychotic symptoms of hallucination and delusion have been described in anabolic steroid abusers. They also described depression after withdrawal from anabolic steroids. There is also considerable debate about the effects of anabolic steroids on aggressive behavior and on criminal behavior. Mood swings were significantly more common in normal volunteers during the active phase of a trial comparing methyltestosterone with placebo. Gastrointestinal: Acute ingestion of large doses can cause nausea and gastrointestinal upset. Hepatic: Orally active (17-alpha substituted) anabolic steroids can cause abnormalities of hepatic function, manifest as abnormally elevated hepatic enzyme activity in biochemical tests of liver function, and sometimes as overt jaundice. The histological abnormality of peliosis hepatis has been associated with anabolic steroid use. Angiosarcoma and a case of hepatocellular carcinoma in an anabolic steroid user has been reported. Urinary: Men who take large doses of anabolic steroids can develop prostatic hypertrophy. Prostatic carcinoma has been described in young men who have abused anabolic steroids. Endocrine and reproductive systems: Small doses of anabolic steroids are said to increase libido, but larger doses lead to azoospermia and impotence. Testicular atrophy is a common clinical feature of long-term abuse of anabolic steroids, and gynecomastia can occur. Women develop signs of virilism, with increased facial hair, male pattern baldness, acne, deepening of the voice, irregular menses and clitoral enlargement. Eye, ear, nose, throat: local effects: Changes in the larynx in women caused by anabolic steroids can result in a hoarse, deep voice. The changes are irreversible. Hematological: Anabolic androgens stimulate erythropoiesis. Metabolic: Fluid and electrolyte disturbances: Sodium and water retention can occur, and result in edema; hypercalcemia is also reported. Insulin resistance with a fall in glucose tolerance, and hypercholesterolemia with a fall in high density lipoprotein cholesterol, have been reported.
Anticoagulant effect may be increased during concurrent use with anabolic steroids, especially 17-alpha-alkylated compounds, because of decreased procoagulant factor concentration caused by alteration of procoagulant factor synthesis or catabolism and increased receptor affinity for the anticoagulant; anticoagulant dosage adjustment based on prothrombin time determinations may be required during and following concurrent use. /Anabolic steroids/
Anabolic steroids may decrease blood glucose concentrations; diabetic patients should be closely monitored for signs of hypoglycemia and dosage of hypoglycemic agent adjusted as necessary. /Anabolic steroids/
Concurrent use /of glucocorticoid corticosteroids, especially with significant mineralocorticoid activity; mineralocorticoid corticosteroids; corticotropin, especially prolonged therapeutic use; or sodium-containing medications or foods/ with anabolic steroids may increase the possibility of edema; in addition, concurrent use of glucocorticoids or corticotropin with anabolic steroids may promote development of severe acne. /Anabolic steroids/
Compounds according to the formula A-B-Z-W, wherein
A is selected from (C
6
-C
10
)aryl-, or (C
1
-C
9
)heteroaryl-, which groups may be optionally substituted;
B is selected from
(a) O, NH, NR
10
, —(CH
2
)
k
—O—, —(CH
2
)
k
—N—, and —(CH
2
)
k
—NR
10
—, where R
10
is (C
1
-C
6
)alkyl and where k is 1 to 6 in each case, or
1
where said group (i) through (iv) is optionally substituted by 1 to 4, preferably 1 to 2, groups selected from (C
1
-C
6
)alkyl, halo, and (C
1
-C
6
)alkyl optionally substituted by 1 to 3 halo atoms wherein one of carbon atoms C
1
, C
2
, C
3
and C
4
of said piperidine or piperazine group is optionally replaced by a carbonyl group;
Z and W are as herein described; and pharmaceutically acceptable salts, solvates or hydrates thereof; pharmaceutical compositions thereof; and methods useful to facilitate secretion of growth hormone(GH) in mammels.
Somatostatin antagonists and agonists that act at the SST subtype 2 receptor
申请人：——
公开号：US20020091125A1
公开（公告）日：2002-07-11
Compounds according to the formula A-Z-W as herein described, wherein A is selected from the groups consisting of: A′—(CH
2
)
n
—, A′—(CH
2
)
n
SO
2
—, and A′—(CH
2
)
n
CO—, where n is
0
to
4;
and A′ is selected from
(a) (C
6
-C
10
)aryl-, or
(b) (C
1
-C
9
)heteroaryl-; which groups may be optionally substituted; and pharmaceutically acceptable salts, solvates or hydrates thereof; pharmaceutical compositions thereof; and methods useful to facilitate secretion of growth hormone(GH) in mammals.
[EN] DRUG COMBINATIONS FOR THE TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY<br/>[FR] COMBINAISONS DE MÉDICAMENTS POUR LE TRAITEMENT DE LA DYSTROPHIE MUSCULAIRE DE DUCHENNE
申请人：SUMMIT CORP PLC
公开号：WO2009019504A1
公开（公告）日：2009-02-12
Combinations comprising (or consisting essentially of) one or more compounds of formula (1) with one or more ancillary agents, to processes for preparing the combinations, and to various therapeutic uses of the combinations. Also provided are pharmaceutical compositions containing the combinations as well as a method of treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia using the combinations.
Somatostatin antagonists and agonists that act at the sst subtype 2 receptor
申请人：——
公开号：US20020016298A1
公开（公告）日：2002-02-07
Compounds according to the formula:
1
and pharmaceutically acceptable salts, solvates or hydrates thereof; wherein group Ar is optionally substituted (C
6
-C
10
)aryl or (C
1
-C
9
)heteroaryl; X is a direct link, —CH
2
—, —SO
2
—, —CO—, —CHR
1
— where R
1
is(C
1
-C
6
) alkyl, or —CR
1′
R
1″
— where both R
1′
and R
1
″ are, independently, (C
1
-C
6
)alkyl; Y is N or CH; and Z and W are as herein defined, and pharmaceutical compositions thereof, and methods useful to facilitate secretion of growth hormone(GH) in mammals.
Drug Combinations for the Treatment of Duchenne Muscular Dystrophy
申请人：Wynne Graham Michael
公开号：US20110195932A1
公开（公告）日：2011-08-11
Combinations comprising (or consisting essentially of) one or more compounds of formula (1) with one or more ancillary agents, to processes for preparing the combinations, and to various therapeutic uses of the combinations. Also provided are pharmaceutical compositions containing the combinations as well as a method of treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia using the combinations.
