Anabolic androgen use in the management of hereditary angioedema: Not so cheap after all.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare, life-threatening disease that imposes a significant burden on affected patients. 17α-alkylated androgens (anabolic androgens) decrease attack frequency and severity but carry the risk of potentially serious dose-related adverse effects. Despite the emergence of targeted therapies for HAE, continued anabolic androgen use has been driven in part by their low cost. OBJECTIVE: To examine the hidden cost of anabolic androgen use related to the risk of developing non-HAE comorbidities. METHODS: Patients with HAE were identified in the Southern California Kaiser Permanente database using clinical and laboratory findings compatible with HAE. These patients were stratified into anabolic androgen exposed and nonexposed groups. Matched controls were selected from the Kaiser database who did not have HAE or anabolic androgen exposure. Using multivariate analysis, we determined the number of non-HAE comorbidities linked to anabolic androgen use. We next determined the association between dosing and increasing exposure to anabolic androgens and the likelihood of having various comorbidities. RESULTS: Patients with HAE exposed to anabolic androgens had a 28% increase (P = .04) in non-HAE comorbidities when compared with their matched (nonexposed) controls. With each gram per month increase in exposure, a 12% increase in non-HAE comorbidities is observed (P < .01). The most commonly occurring non-HAE comorbidities were psychiatric, muscle cramps, obesity, and hyperlipidemia. CONCLUSION: Our data suggest that long-term anabolic androgen use enhances the risk of developing comorbid health conditions, thus amplifying the cost of care. Our report provides additional support for the preferred use of newer, targeted therapies for the management of HAE.

Characterization of a non-approved selective androgen receptor modulator drug candidate sold via the Internet and identification of in vitro generated phase-I metabolites for human sports drug testing.

RATIONALE: Potentially performance-enhancing agents, particularly anabolic agents, are advertised and distributed by Internet-based suppliers to a substantial extent. Among these anabolic agents, a substance referred to as LGD-4033 has been made available, comprising the core structure of a class of selective androgen receptor modulators (SARMs). METHODS: In order to provide comprehensive analytical data for doping controls, the substance was obtained and characterized by nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography/electrospray ionization high resolution/high accuracy tandem mass spectrometry (LC/ESI-HRMS). Following the identification of 4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile, the substance was subjected to in vitro metabolism studies employing human liver microsomes and Cunninghamella elegans (C. elegans) preparations as well as electrochemical metabolism simulations. RESULTS: By means of LC/ESI-HRMS, five main phase-I metabolites were identified as products of liver microsomal preparations including three monohydroxylated and two bishydroxylated species. The two most abundant metabolites (one mono- and one bishydroxylated product) were structurally confirmed by LC/ESI-HRMS and NMR. Comparing the metabolic conversion of 4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile observed in human liver microsomes with C. elegans and electrochemically derived metabolites, one monohydroxylated product was found to be predominantly formed in all three methodologies. CONCLUSIONS: The implementation of the intact SARM-like compound and its presumed urinary phase-I metabolites into routine doping controls is suggested to expand and complement existing sports drug testing methods.

Selling androgenic anabolic steroids by the pound: identification and analysis of popular websites on the Internet.

Internet websites offering androgenic anabolic steroids (AAS) were identified and available products were examined. Keywords for the website search were: "anabolic steroids," "anabolic steroids buy," "anabolic steroid purchase." The first 10 websites offering AAS in the first 10 pages of results were considered. At least two AAS-containing products per website were selected. Thirty AAS-selling websites were identified, mainly located in the United States (46.7%) and Europe (30%). Most websites sold other anabolic/ergogenic products (clenbuterol, 76.7%; GH/IGF, 60.0%; thyroid hormones, 46.7%; erythropoietin, 30.0%; insulin, 20.0%) or products for AAS-related adverse effects (mainly: estrogen antagonists, 63.3%; products for erectile dysfunction, 56.7%; 5α-reductase inhibitors, 33.3%; anti-acne products, 33.3%). AAS were sold as medicines (69.6%) or as dietary supplements (30.4%). AAS in medicines were mainly: nandronole (20.4%), methandrostenolone (18.4%), and testosterone (12.2%). Dietary supplements contained mainly DHEA and included several fake compounds. Manufacturers were declared for 97.9% of medicines and 66.7% of dietary supplements; however, several manufacturers were not found on the Internet. Described benefits were usually few adverse effects and no estrogenicity. Toxicity was seldom reported and presented as mild. Recommended doses were two-fourfold higher than current medical recommendations. In conclusion, misleading information and deceiving practices were common findings on AAS-selling websites, indicating their deleterious potential for public health.

New insights into the role of anabolic interventions in dialysis patients with protein energy wasting.

PURPOSE OF REVIEW: Patients on maintenance dialysis commonly develop protein-energy wasting (PEW), which is associated with poor survival. There have been several advances in anabolic interventions aimed at improving PEW in these patients in recent years. RECENT FINDINGS: Oral or parenteral nutritional supplementation, especially if administered during dialysis, improves net protein anabolism in chronic hemodialysis patients. These beneficial effects have been extended to long-term benefits in recent clinical trials. Resistance exercise, alone or combined with intradialytic oral nutrition supplementation, also improves net protein balance in the acute setting although recent studies indicated a limited beneficial effect of long-term exercise alone on muscle protein accretion in chronic hemodialysis patients. Anabolic agents such as growth hormone and androgens have been shown to exert significant benefits on visceral protein stores, muscle mass and strength. Ghrelin, a hormone with combined orexigenic and anti-inflammatory effects, is a potential new nutritional intervention in maintenance dialysis patients. SUMMARY: Existing anabolic therapeutic strategies have proven to be effective in improving PEW in maintenance dialysis patients. Combined anabolic interventions and several new and established anabolic hormones represent further promising nutritional interventions. Large-scale randomized controlled trials examining the effects of anabolic interventions on mortality and morbidity are still lacking.

Teriparatide: a review of its use in osteoporosis.

Recombinant teriparatide (Forteo; Forsteo) is an anabolic (bone forming) agent. Studies have shown that subcutaneous teriparatide 20 microg/day is effective in women with postmenopausal osteoporosis, men with idiopathic or hypogonadal osteoporosis and patients with glucocorticoid-induced osteoporosis. Teriparatide improves bone mineral density (BMD) and alters the levels of bone formation and resorption markers; histomorphometric studies showed teriparatide-induced effects on bone structure, strength and quality. Subcutaneous teriparatide 20 microg/day administered over a treatment period of 11-21 months was effective in reducing the risk of fractures in and in improving BMD in men with idiopathic or hypogonadal osteoporosis, women with postmenopausal osteoporosis and patients with glucocorticoid-induced osteoporosis. Furthermore, the beneficial effects of teriparatide on vertebral fracture prevention and BMD appear to persist following treatment cessation. Teriparatide is generally well tolerated and treatment compliance rates are favourable. However, current limitations on the length of treatment and the high acquisition cost mean that teriparatide is best reserved for the treatment of patients with osteoporosis at high risk of fracture, or for patients with osteoporosis who have unsatisfactory responses to or intolerance of other osteoporosis therapies.

Cost-effectiveness of clinical interventions for AIDS wasting.

Economic studies of HIV/AIDS interventions are important for providing cost-effective care. This paper presents a costeffectiveness study of a three-arm clinical trial conducted at Tufts University School of Medicine/New England Medical Center in Boston, Massachusetts that treated 50 patients with AIDS wasting from March 1998 through January 2001. This study compared the costs and impacts of a nutritional counseling intervention alone (NC arm), the nutrition intervention with oxandrolone (OX arm), and the nutrition intervention with progressive resistance training (PRTarm) for the treatment of AIDS wasting. The cost of each intervention was derived for both the three-month clinical trial and a six-month estimated community model (ECM), its projected adaptation to community-based medical care. The cost determination involved obtaining and multiplying unit economic costs and quantities expended of each resource within each study arm. The ECM average cost per client in the cost-effectiveness analysis incorporated both institutional and societal perspectives. The costeffectiveness analysis compared the cost of each intervention to its quality-adjusted life-year (QALY) gain (Zeckhauser and Shepard, 1976). From a societal perspective, for the NC arm, the cost per client totaled US dollars 983 for the actual and US dollars 596 under the ECM. For the OX arm, the cost per client totaled US dollars 3,772 for the actual study and US dollars 3,385 under the ECM. For the PRT arm, the cost per client totaled US dollars 3,189 for the actual study and US dollars 2,987 under the ECM. Under the societal perspective the cost per QALY was US dollars 55,000 (range: US dollars 51,000 to US dollars 83,000) for the NC arm, US dollars 151,000 (range: US dollars 149,000 to US dollars 171,000) for the OX arm, and US dollars 65,000 (range: US dollars 44,000 to US dollars 104,000) for the PRTarm. When using only an institutional perspective, the cost per QALY was US dollars 45,000 (range: US dollars 42,000-US dollars 64,000) for the NC arm, US dollars 147,000 (range: US dollars 147,000 to US dollars 163,000) for the OX arm, and US dollars 31,000 (US dollars 21,000 to US dollars 44,000) for the PRTarm. This paper shows that cost and cost-effectiveness analyses can be adapted to a community setting by combining information from community practice and costs with data from a randomized trial. Compared to other AIDS treatments, such as highly active antiretroviral therapies, all three interventions were affordable, but their cost-effectiveness was intermediate. Oxandrolone was the least cost effective of the interventions, even compared to nutrition alone, as it included similar or somewhat greater costs for less of an increase in quality of life. PRT was the most cost-effective treatment for AIDS wasting, particularly from an institutional perspective. Third party payers should consider coverage of PRT.

A comparison of the clinical and cost-effectiveness of 3 intervention strategies for AIDS wasting.

OBJECTIVE: To compare oxandrolone (OX) or strength training with nutrition alone (NA) for AIDS wasting. SUBJECTS: Fifty patients with AIDS; 47 completing the study. INTERVENTIONS: Randomization to (1) NA with placebo pills, (2) nutrition with 10 mg of OX administered orally twice a day, or (3) nutrition with progressive resistance training (PRT) for 12 weeks. MAIN OUTCOME MEASURES: Midthigh cross-sectional muscle area (CSMA), physical functioning (PF), costs, and cost-effectiveness in dollars/quality-adjusted life-years (dollars/QALYs). RESULTS: The OX and PRT subjects had increases in CSMA (7.0% +/- 2.5%, P = 0.01; 5.0% +/- 2.0%, P = 0.04, respectively), although these increases did not differ significantly from the NA arm (NA: 1.0% +/- 1.0%; OX vs. NA: P = 0.09; PRT vs. NA: P = 0.26). Only PRT caused significant improvements in PF (mean +/- SE: 10.4 +/- 3.8 points on a 100-point scale) and 7 measures of strength (P values: 0.04 to <0.001). There were no overall differences between groups in PF change. Among patients with impaired baseline PF, however, OX was significantly less effective than NA and PRT was significantly better than NA. All treatments led to increases in protein intake and performance; NA and PRT also increased caloric intake. The institutional costs per subject in this trial were 983 dollars for NA, 3772 dollars for OX, and 3189 dollars for PRT. At a community-based level of intensity, the institutional costs per QALY were 45,000 dollars (range: 42,000 dollars-64,000 dollars) for NA, 147,000 dollars (range: 147,000 dollars-163,000 dollars) for OX, and 31,000 dollars (range: 21,000 dollars-44,000 dollars) for PRT. CONCLUSIONS: OX and PRT induce similar improvements in body composition, but PRT improves quality of life more than nutrition or OX, particularly among patients with impaired PF. PRT was the most cost-effective intervention, and OX was the least cost-effective intervention.

Economic impact of tibolone compared with continuous-combined hormone replacement therapy. In the management of postmenopausal women with climacteric symptoms in the UK.

OBJECTIVE: To estimate the economic impact of using tibolone 2.5 mg compared with 17 beta-estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA) in postmenopausal women with climacteric symptoms. DESIGN AND SETTING: This was a modelling study performed from the perspective of the UK's National Health Service (NHS). METHODS: The clinical outcomes from a previously reported trial were used as the clinical basis for the analysis, which showed that 48 weeks' treatment with tibolone and E2/NETA significantly alleviated the climacteric symptoms experienced by postmenopausal women. These data were combined with resource utilisation estimates derived from a panel of 10 GPs and 3 gynaecologists, enabling us to construct a Markov model depicting changes in the health status of postmenopausal women. The model was used to estimate the expected NHS costs and consequences after 48 weeks' treatment with tibolone and E2/NETA. MAIN OUTCOME MEASURES AND RESULTS: The mean expected direct healthcare cost of using tibolone and E2/NETA to manage postmenopausal women for 48 weeks was estimated to be 260 Pounds and 239 Pounds (1997/1998 prices) per patient, respectively. Starting hormone replacement therapy (HRT) with tibolone instead of E2/NETA was equally effective in alleviating climacteric symptoms (65.9 and 62.2%, respectively; p = 0.516) over 48 weeks and significantly reduced the incidence of vaginal bleeding by 36% (p < 0.0001) and breast tenderness by 57% (p < 0.0001) for a mean additional cost of 21 Pounds (ranging between -3 Pounds and 42 Pounds) per patient. The acquisition cost of HRT was the primary cost driver for tibolone-treated patients, whereas the cost of managing adverse events was the primary cost driver for E2/NETA-treated patients. CONCLUSIONS: The true cost of prescribing tibolone and E2/NETA is impacted on by a broad range of resources, not only drug acquisition costs. Although the acquisition cost of tibolone is higher than that of E2/NETA, the difference in the expected NHS cost of the first year of treatment between the 2 HRTs is negligible. This is because of the higher incidence of adverse events among E2/NETA-treated patients, which also results in a higher continuation rate among tibolone-treated patients. Factors such as patient preferences should also be taken into consideration so that treatment choices are not decided solely on the basis of acquisition costs.

Growth response and final height in Turner syndrome after combination therapy of growth hormone and anabolic steroid.

To improve the growth of Turner syndrome patients we administered human growth hormone (GH) combined with anabolic steroid. Thirty three patients completed at least one year of GH therapy. Daily GH injection was started at a dose of 1.0 IU/kg/wk at age 12.6 +/- 2.1 years when their heights were below -3.2 +/- 2.1 standard deviation, growth velocity was less than 4 cm/year and bone age (BA) was 9.9 +/- 1.7 years. Anabolic steroid was added at 14.3 +/- 1.3 years of age when their growth velocity slowed. Their consecutive annual growth velocities were: 7.40 cm/year; 6.15 cm/year; 5.47 cm/year; 4.74 cm/year and 4.05 cm/year respectively. Growth hormone therapy was discontinued when patients grew less than 4 cm/year, their BA reached 14 years or they were satisfied with their height. After combination therapy of GH for 3.0 +/- 1.1 years and anabolic steroids for 1.9 +/- 1.0 years, the final height of 17 patients was 150.3 +/- 4.1 cm. We compared our results with worldwide reports and analyzed demographic factors related to growth response and final height. We conclude that combination therapy of GH and anabolic steroid is effective in improving growth and final height of Chinese Turner patients.