Stanozolol:Preparation, Pharmacodynamics, Adverse Effects, Application Studies

General Description

Stanozolol (STA) is a synthetic 17α-alkylated derivative of testosterone that exhibits a greater anabolic potency and a slower hepatic degradation than the natural male hormone.It is a synthetic anabolic-androgenic steroids with therapeutic uses in treating C1-inhibitor deficient hereditary angioedema. C1-inhibitor is a protease that inhibits the complement system (part of the innate immune system), a biochemical chain of reactions which assists the body in removing pathogens from the body. Stanozolol may help control attacks of hereditary angioedema.[1]Stanozolol is derived from testosterone, and has been abused by several high profile professional athletes and it can be administered orally or intramuscularly.[2]

Figure 1 Stanozolol powder

Preparation

To a solution of 17α-methylandrostan-17β-ol-3-one (5g, 16.4mmol) in dry freshly distilled pyridine (50ml) was cautiously added, with stirring, sodium hydride (50% dispersion in oil, 3.78g). The mixture was cooled to 0°C and ethyl formate (0.7ml) and ethyl [14C] formate (10mCi) were added, the containers being washed into the reaction vessel with dry freshly distilled pyridine (10 ml) and ethyl formate (0.7ml). The reaction mixture was stirred at 0°C for 75 min under a phosphorus pentoxide trap after which additional ethyl formate (1.4ml) was added and the reaction mixture was allowed to warm to room temperature and left to stand for 24 h. The reaction mixture was cooled in an ice water bath and distilled water (100ml) was added cautiously. The solution was made just acid by the addition of concentrated hydrochloric acid and allowed to stir for 1 h. The yellow crystalline solid which separated was collected by filtration, washed with distilled water until the washings were neutral and then dried in vacuo. The crude hydroxymethylene compound(2) was dissolved in absolute ethanol (150ml) and hydrazine hydrate (1.81g) added. under reflux for 6h. treated with charcoal (0.5g) and then heated under reflux for a further 15 min. The charcoal was removed by filtration and the solution was concentrated under reduced pressure to give the crude product. Recrystallisation of this solid from absolute ethanol gave [14C) stanozolol with a weight of 3.31 g (62%).[3]

Pharmacodynamics

Stanozolol is a synthetic anabolic-androgenic steroid (AAS), which promotes cell growth (anabolism) and development/maintenance of masculine characteristics (androgenism).[4]

Mechanisms

Stanozolol binds to androgen receptors, such as membrane bound receptor proteins LAGS and stanozolol-binding protein (STBP).Glucocorticoid binding proteins includes low-affinity glucocorticoid binding proteins (LAGS) and stanozolol binding proteins (STBP) are included as targets for this drug.A group of glucocorticoid binding proteins in humans, including low-affinity glucocorticoid binding proteins (LAGS) and stanozolol binding protein (STBP).[5]

Metabolism

Stanozolol is excreted as a conjugate but is metabolized to a large extent. All identified metabolites are hydroxylated, namely at C-3 of the pyrazole ring and at C-4β, C-16α and C-16β of the steroid. Less than 5% of the metabolites are found in the unconjugated urine fraction:3-hydroxy-stanozolol and 3-hydroxy-17-epistanozolol.[6]

Adverse Effects

Adverse side effects included hirsutism, weight gain, menstrual irregularities or postmenopausal bleeding, acne, and mood changes. Liver enzyme assays revealed no persistent abnormalities. But, Stanozolol is a safe and effective drug for the longterm management of hereditary angioedema. No interruption in stanozolol therapy was required because symptoms subsided with a reduction in the stanozolol dosage.However, the chronic use of supraphysiological doses of stanozolol induced bradycardia and increased cardiac superoxide dismutase and catalase activities. Stanozolol combined with swimming led to an increase in systolic and diastolic blood pressure, relative heart weight and left cardiac axis deviation.[7]Use of anabolic steroids by athletes is not recommended. Objective evidence is conflicting and inconclusive as to whether these medications significantly increase athletic performance by increasing muscle strength. Weight gains reported by athletes are due in part to fluid retention, which is a potentially hazardous side effect of anabolic steroid therapy. The risk of other unwanted effects, such as testicular atrophy and suppression of spermatogenesis in males; menstrual disturbances and virilization, such as deepening of voice, development of acne, and unnatural growth of body hair in females; peliosis hepatis or other hepatotoxicity; and hepatic cancer outweigh and possible benefit received from anabolic steroids and make their use in athletes inappropriate.[8]

Application

Stanozolol is effective in raising hemoglobin concentrations in some cases of aplastic anemia (congenital or idiopathic) andit is indicated in the prophylaxis of hereditary angioedema to decrease the frequency and severity of attacks.Stanozolol is also indicated in the treatment of conditions associated with decreased fibrinolytic activity due to antithrombin III deficiency or excess fibrinogen. These conditions may include cutaneous vasculitis, scleroderma of Raynauds disease, vasculitis of Behcets disease, and complications of deep vein thrombosis such as venous lipodermatosclerosis. Stanozolol is indicated in the prevention of recurrent venous thrombosis associated with antithrombin III deficiency.Stanozolol may be of benefit in patients susceptible to or with a history of thromboembolism for the treatment of vascular disorders associated with these forms of reduced fibrinolytic activity.[9]

Effect on environment

The stanozolols former production and use as an androgen and possible use as a performance enhancement drug in athletes may have resulted in its release to the environment through various waste streams(SRC).If released to air,stanozolol will exist solely in the particulate phase in the atmosphere.Particulate-phase stanozolol will be removed from the atmosphere by wet and dry deposition. If released to soil, stanozolol is expected to have no mobility. Stanozolol will not volatilize from dry soil surfaces based upon its vapor pressure. If released into water, stanozolol is expected to adsorb to suspended solids and sediment. bioconcentration in aquatic organisms is high. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions.[10]

Reference

[1]Guilarte M, et al. Acquired angioedema associated with hereditary angioedema due to C1 inhibitor deficiency[J]. Journal of Investigational Allergology and Clinical Immunology. 2008, 18(2): 126.

[2]Thevis M, et al. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators[J]. Doping in Sports: Biochemical Principles, Effects and Analysis, 2010: 99-126.

[3]Duncan DR, Johnston D. Synthesis of [14C] stanozolol[J]. Journal of Labelled Compounds and Radiopharmaceuticals, 1983, 20(11): 1227-1228.

[4]Thevis M, et al. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators[J]. Doping in Sports: Biochemical Principles, Effects and Analysis, 2010: 99-126.

[5]Betancor-Hernandez E, et al.Photoaffinity labeling identification of thyroid hormone-regulated glucocorticoid-binding peptides in rat liver endoplasmic reticulum: an oligomeric protein with high affinity for 16beta-hydroxylated stanozolol[J]. The Journal of Steroid Biochemistry and Molecular Biology. 2003, 87(4-5): 253-264.

[6]Schanzer W et al, J Steroid Biochem. 1990.36 (1-2):153-74.

[7]Sloane DE,et al.Hereditary angioedema: Safety of long-term stanozolol therapy[J]. Allergy Clin Immunol. 2007,120(3):654-8.

[8]Thomson, et al. Drug Information for the Health Care Professional[J].Greenwood Village.2005.

[9]Thomson, et al. Drug Information for the Health Care Professional[J].Greenwood Village.2005.

[10]Oeil MJ, ed; The Merck Index. 13th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 1566 (2001) (2) Donahue JL, Lowenthal DT; Am J Ther 7: 365-73 (2000)