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Clinical Journal of the American... Feb 2013Sarcopenia is common in hemodialysis patients. This study examined whether the anabolic steroid oxymetholone improves muscle mass and handgrip strength in hemodialysis... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Sarcopenia is common in hemodialysis patients. This study examined whether the anabolic steroid oxymetholone improves muscle mass and handgrip strength in hemodialysis patients and possible mechanisms that might engender such changes.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Forty-three eligible hemodialysis patients were randomly assigned to ingest oxymetholone or placebo for 24 weeks. Body composition, handgrip strength, and quality of life were measured during the study. Muscle biopsies were performed and analyzed for mRNA levels for myostatin, IGF-I, IGF binding proteins, and myosin heavy chains and protein expression. Muscle fiber types and diameter were assessed by reduced nicotinamide-adenine dinucleotide staining.
RESULTS
There was a significantly greater increase in fat-free mass and handgrip strength and decrease in fat mass in the oxymetholone compared with the placebo group. Moreover, compared with baseline values, patients given oxymetholone exhibited an increase in fat-free mass, handgrip strength, physical functioning scores, and type I muscle fiber cross-sectional area and a decrease in fat mass, whereas patients receiving placebo did not undergo changes. There was a significantly greater increase in muscle mRNA levels for myosin heavy chain 2×, IGF-I, and IGF-II receptor with oxymetholone treatment than placebo. Liver enzyme rose significantly in the oxymetholone group, but the number of values greater than three times the upper limit of normal were not different between these groups.
CONCLUSIONS
In hemodialysis patients, ingesting oxymetholone was associated with an increase in fat-free mass, handgrip strength, and muscle mRNA levels for several growth factors and a decrease in fat mass, but it also induced liver injury.
Topics: Administration, Oral; Adult; Anabolic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscle Strength; Muscle, Skeletal; Oxymetholone; Renal Dialysis
PubMed: 23124786
DOI: 10.2215/CJN.00380112 -
Drug Testing and Analysis Sep 2012The metabolism of two anabolic steroids - oxymetholone and desoxymethyltestosterone - was reinvestigated to identify new targets potentially valuable for the antidoping...
The metabolism of two anabolic steroids - oxymetholone and desoxymethyltestosterone - was reinvestigated to identify new targets potentially valuable for the antidoping analysis. Excretion urine samples from the laboratory reference collection were used in this study. Following fractionation of the urinary extract by means of high performance liquid chromatography (HPLC), each fraction was subjected to gas chromatography-mass spectrometry (GC-MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis after trimethylsilylation. About 20 metabolites were found for desoxymethyltestosterone and more than 40 for oxymetholone, with many of them being isomeric compounds. In addition to the well-known reduced and hydroxylated metabolites, 18-nor-17,17-dimethyl and 18-nor-17-hydroxymethyl-17-methyl steroids were also identified. Having evaluated all the metabolites in terms of how long they could be detected, we suggest that 18-nor-2ξ,17β-hydroxymethyl-17α-methyl-5α-androst-13-en-3α-ol is an important marker of oxymetholone abuse. In case of desoxymethyltestosterone, better detectability could be achieved if 18-nor-17,17-dimethyl-5α-androst-13-en-2ξ,3α-diol is monitored. These novel metabolites could be detected using GC-MS/MS at least for 14 days after administration of these anabolic steroids compared to 5-7 days for previously reported metabolites.
Topics: Anabolic Agents; Androgens; Androstenols; Chromatography, High Pressure Liquid; Doping in Sports; Gas Chromatography-Mass Spectrometry; Humans; Male; Oxymetholone; Substance Abuse Detection; Tandem Mass Spectrometry
PubMed: 22945829
DOI: 10.1002/dta.1407 -
Drug Testing and Analysis Jun 2013Dietary supplements and medicines are widely marketed over the Internet. Such products may be counterfeited and lack some or all of the labelled ingredients, or, in the...
Dietary supplements and medicines are widely marketed over the Internet. Such products may be counterfeited and lack some or all of the labelled ingredients, or, in the case of lifestyle supplements, illegally contain pharmacologically active substances, such as anorectic or androgenic compounds. The market control - especially in the case of customs seizures - is complex, as reference substances necessary for identification and calibration in traditional high performance liquid chromatography (HPLC) or gas chromatography-mass spectrometry (GC-MS) analysis are often unavailable, or extremely expensive. In this study, we introduce a 400 MHz (1) H NMR methodology, which allows identification and quantitative estimation even without such pure compound standards. The identification can be based on literature spectra, or if these data are unavailable, by applying computational NMR spectra prediction. For standardless NMR determination, simple peak-area comparison of the target compound with the TSP reference was used. The applicability was demonstrated for a wide range of compounds, such as mesterolone, oxymetholone, sibutramine, monacolin K, vinpocetine, evodiamine, caffeine, kavain, and dehydroepiandrosterone. The average relative standard deviations were 5.0% for peak area comparison, and 3.3% for external calibration with standard substance. The method uncertainty is therefore higher in standardless determination, but acceptable for the purpose of proving the presence or absence of pharmacologically active substances. The limit of detection of 0.5-2 mg/kg is sufficient for the purpose. NMR is ideally suited to controlling dietary supplements or illegal medicines as it provides qualitative and at least semi-quantitative information more rapidly (measurement time 20 min) than with any other currently available spectroscopic or chromatographic method.
Topics: Dietary Supplements; Internet; Magnetic Resonance Spectroscopy; Sensitivity and Specificity
PubMed: 22550015
DOI: 10.1002/dta.1367 -
Toxicologic Pathology Apr 2012From the archives of the National Toxicology Program, National Institutes of Health, kidney sections from twenty-four carcinogenicity studies (representing twenty-three...
Association of advanced chronic progressive nephropathy (CPN) with renal tubule tumors and precursor hyperplasia in control F344 rats from two-year carcinogenicity studies.
From the archives of the National Toxicology Program, National Institutes of Health, kidney sections from twenty-four carcinogenicity studies (representing twenty-three chemicals) in male and female F344 rats were histopathologically re-evaluated to grade the severity of chronic progressive nephropathy (CPN) on an expanded scale of 0-8, and to record the presence of renal tubule tumors (RTT) and their precursor, atypical tubule hyperplasia (ATH). The data were statistically analyzed using SAS software for logistic regression analysis. This histopathological survey of 2,436 F344 rats showed clear evidence of a qualitative and statistically significant association between advanced stages of CPN severity and the development of low-grade RTT and ATH. Advanced CPN severity therefore represents a risk factor for the development of RTT and appears to be an underlying basis for spontaneous occurrence of RTT in the F344 rat. The difference in incidence and severity of CPN between the sexes also explains the 9:1 male-to-female sex difference in the spontaneous occurrence of ATH and RTT observed here. The regulatory significance of this finding is that chemicals exacerbating CPN as their only renal effect are likely to show a numerical increase in RTT with dose, which does not represent a direct tumorigenic effect of the chemical.
Topics: Acetonitriles; Adenoma; Animals; Calcium Compounds; Carcinogenicity Tests; Carcinogens; Carcinoma; Chronic Disease; Disease Models, Animal; Female; Histocytochemistry; Hyperplasia; Kidney Diseases; Kidney Neoplasms; Kidney Tubules; Logistic Models; Male; Oxymetholone; Rats; Rats, Inbred F344; Risk Assessment; Silicates
PubMed: 22298794
DOI: 10.1177/0192623311431948 -
Toxicological Sciences : An Official... Apr 2012Anabolic androgenic steroids (AAS) are testosterone derivatives used either clinically, in elite sports, or for body shaping with the goal to increase muscle size and...
Anabolic androgenic steroids (AAS) are testosterone derivatives used either clinically, in elite sports, or for body shaping with the goal to increase muscle size and strength. Clinically developed compounds and nonclinically tested designer steroids often marketed as food supplements are widely used. Despite the considerable evidence for various adverse effects of AAS use, the underlying molecular mechanisms are insufficiently understood. Here, we investigated whether some AAS, as a result of a lack of target selectivity, might inhibit 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2)-dependent inactivation of glucocorticoids. Using recombinant human 11β-HSD2, we observed inhibitory effects for several AAS. Whereas oxymetholone, oxymesterone, danazol, and testosterone showed medium inhibitory potential, fluoxymesterone was a potent inhibitor of human 11β-HSD2 (half-maximal inhibitory concentration [IC(50)] of 60-100nM in cell lysates; IC(50) of 160nM in intact SW-620, and 530nM in MCF-7 cells). Measurements with rat kidney microsomes and lysates of cells expressing recombinant mouse 11β-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11β-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11β-HSD2. Structural modeling revealed similar binding modes for fluoxymesterone and cortisol, supporting a competitive mode of inhibition of 11β-HSD2-dependent cortisol oxidation by this AAS. No direct modulation of mineralocorticoid receptor (MR) function was observed. Thus, 11β-HSD2 inhibition by fluoxymesterone may cause cortisol-induced MR activation, thereby leading to electrolyte disturbances and contributing to the development of hypertension and cardiovascular disease.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Anabolic Agents; Animals; Cell Line; Enzyme Inhibitors; Fluoxymesterone; Glucocorticoids; Humans; Mice
PubMed: 22273746
DOI: 10.1093/toxsci/kfs022 -
Report on Carcinogens : Carcinogen... 2011
Topics: Androgens; Animals; Carcinogenicity Tests; Carcinogens, Environmental; Government Regulation; Guidelines as Topic; Humans; Leukemia; Molecular Structure; Neoplasms; Occupational Exposure; Oxymetholone; Rats
PubMed: 21860526
DOI: No ID Found -
Toxicologic Pathology Aug 2011The heart is increasingly recognized as a target for toxicity. As studies in laboratory rodents are commonly used to investigate the potential toxicity of various...
The heart is increasingly recognized as a target for toxicity. As studies in laboratory rodents are commonly used to investigate the potential toxicity of various agents, the identification and characterization of lesions of cardiotoxicity is of utmost importance. Although morphologic criteria have been established for degenerative myocardial lesions in rats and mice, differentiation of spontaneously occurring lesions from toxin-induced or toxin-related lesions remains difficult. A retrospective light microscopic evaluation was performed on the hearts of F344 rats and B6C3F(1) mice from National Toxicology Program (NTP) studies of six chemicals identified in the NTP database in which treatment-induced myocardial toxicity was present. Two previously defined myocardial lesions were observed: "cardiomyopathy" that occurred spontaneously or as a treatment-related effect and "myocardial degeneration" that occurred as a treatment-related effect. Both lesions consisted of the same basic elements, beginning with myofiber degeneration and necrosis, with varying amounts of inflammation, interstitial cell proliferation, and eventual fibrosis. This observation is indicative of the heart's limited repertoire of responses to myocardial injury, regardless of the nature of the inciting agent. A prominent differentiating factor between spontaneous and treatment-induced lesions was distribution and lesion onset. Once the respective lesions had undergone fibrosis, however, they generally appeared morphologically indistinguishable.
Topics: Animals; Biomedical Research; Cardiomyopathies; Cardiotoxins; Government Programs; Heart; Histocytochemistry; Mice; Microscopy; Myocardium; Myocytes, Cardiac; Oxymetholone; Rats; Rats, Inbred F344; Retrospective Studies; Toxicity Tests; United States; United States Dept. of Health and Human Services; Urethane; Vacuoles
PubMed: 21747121
DOI: 10.1177/0192623311413788 -
Anales de Pediatria (Barcelona, Spain :... Oct 2011
Topics: Androgens; Child; Humans; Male; Oxymetholone; Peliosis Hepatis
PubMed: 21733770
DOI: 10.1016/j.anpedi.2011.05.012 -
International Journal of Clinical... Dec 2010To determine the efficacy of oxymetholone, an androgenic steroid, in combination with rHuEPO on hematologic and muscle mass in CAPD patients. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To determine the efficacy of oxymetholone, an androgenic steroid, in combination with rHuEPO on hematologic and muscle mass in CAPD patients.
METHODS
A double-blinded, placebo-controlled experimental study was conducted for 6 months and 24 CAPD patients were divided into two groups. The treatment group (n = 11) received rHuEPO plus oral oxymetholone (50 mg/tablet twice daily). The placebo group (n = 13) received rHuEPO plus a placebo twice daily. The evolution of the patients' hematologic parameters and the impact of the drugs on their muscle mass were evaluated.
RESULTS
After 6 months of therapy, hematocrit and hemoglobin values of the treatment group were significantly different from those of the placebo group (38.1 ± 1.0% and 32.8 ± 0.9%, p = 0.001; 12.9 ± 0.3 g/dl and 11.0 ± 0.3 g/dl, p = 0.001 for hematocrit and hemoglobin, respectively). The increase in hematocrit and hemoglobin values observed in treatment group was statistically greater than those of the placebo group (p < 0.01). After 6 months, none of anthropometric parameters, albumin, protein or lean body mass levels, were significantly different from baseline in the placebo group. Conversely, most of the anthropometric parameters, albumin and lean body mass levels were significantly increased in the oxymetholone group (p < 0.05). The mean weight of subjects in the oxymetholone group changed from 63.82 ± 2.71 to 67.02 ± 3.26 kg (p = 0.001). The subjective global assessment score for 7 patients in the treatment group (63.6%) changed in a positive manner. A rise in liver enzymes was the main side effect observed in the treatment group.
CONCLUSIONS
Oxymetholone significantly enhances the erythropoietic effects of rHuEPO and improves the nutritional status of CAPD patients. However, significant increases in liver enzymes need to be monitored closely.
Topics: Adult; Aged; Anemia; Body Composition; Double-Blind Method; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobins; Humans; Liver; Male; Middle Aged; Muscle, Skeletal; Nutritional Status; Oxymetholone; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Serum Albumin
PubMed: 21084036
DOI: 10.5414/cpp48803 -
Journal of Korean Medical Science Nov 2010Anti-erythropoietin antibodies usually cross-react with all kinds of recombinant erythropoietins; therefore, erythropoiesis-stimulating agent (ESA)-induced pure red-cell...
Improvement in erythropoieis-stimulating agent-induced pure red-cell aplasia by introduction of darbepoetin-α when the anti-erythropoietin antibody titer declines spontaneously.
Anti-erythropoietin antibodies usually cross-react with all kinds of recombinant erythropoietins; therefore, erythropoiesis-stimulating agent (ESA)-induced pure red-cell aplasia (PRCA) is not rescued by different ESAs. Here, we present a case of ESA-induced PRCA in a 36-yr-old woman with chronic kidney disease, whose anemic condition improved following reintroduction of darbepoetin-α. The patient developed progressive, severe anemia after the use of erythropoietin-α. As the anemia did not improve after the administration of either other erythropoietin-α products or erythropoietin-β, all ESAs were discontinued. Oxymetholone therapy failed to improve the transfusion-dependent anemia and a rechallenge with ESAs continuously failed to obtain a sustained response. However, her anemia improved following reintroduction of darbepoetin-α at 3 yr after the initial diagnosis. Interestingly, anti-erythropoietin antibodies were still detectable, although their concentration was too low for titration. In conclusion, darbepoetin-α can improve ESA-induced PRCA when the anti-erythropoietin antibody titer declines and its neutralizing capacity is lost.
Topics: Adult; Anemia; Antibodies; Bone Marrow Cells; Darbepoetin alfa; Drug Hypersensitivity; Erythropoietin; Female; Glomerulonephritis, IGA; Hematinics; Humans; Kidney Failure, Chronic; Oxymetholone; Recombinant Proteins; Red-Cell Aplasia, Pure
PubMed: 21060762
DOI: 10.3346/jkms.2010.25.11.1676