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Toxicologic Pathology 1999Oxymetholone is generally assumed to be a nongenotoxic carcinogen. This assumption is based primarily on the results of an Ames test, existing data in repeat-dose...
Oxymetholone is generally assumed to be a nongenotoxic carcinogen. This assumption is based primarily on the results of an Ames test, existing data in repeat-dose toxicology studies, and the predicted results of a 2-yr National Toxicology Program (NTP) rat carcinogenicity bioassay. To provide a comprehensive assessment of its genotoxicity in a standard battery of mutagenicity assays, oxymetholone was tested in microbial and mammalian cell gene mutation assays, in an in vitro cytogenetics assay (human lymphocytes), and in an in vivo micronucleus assay. Oxymetholone was also tested in an in vitro morphologic transformation model using Syrian hamster embryo (SHE) cells. These studies were initiated and completed prior to the disclosure of the results of the NTP bioassay. Oxymetholone was tested at doses up to 5,000 microg/plate in the bacterial plate incorporation assay using 4 Salmonella strains and the WP2 uvrA (pKM101) strain of Escherichia coil. There was no induction of revertants up to the highest dose levels, which were insoluble as well as toxic. In the L5178Y tk+/- mouse lymphoma assay, doses up to 30 microg/ml reduced relative survival to approximately 30% with no increase in mutants. Male or female human lymphocytes were exposed in vitro to oxymetholone for 24 hr without S9 or 3 hr with S9 and evaluated for the induction of chromosomal aberrations. There was no increase in aberration frequency over control levels and no difference between male and female cells. Peripheral blood from Tg.AC transgenic mice treated dermally for 20 wk with 0, 1.2, 6.0, or 12.0 mg/day of oxymetholone and from p53 transgenic mice treated orally by gavage for 26 wk with 125, 625, or 1,250 mg/kg/day of oxymetholone was evaluated for micronuclei in polychromatic and normochromatic erythrocytes. There was no difference in micronuclei frequency between control and treated animals. These results confirm that oxymetholone is not genotoxic in a comprehensive battery of mutagenicity assays. In the SHE assay, oxymetholone produced a significant increase in morphologically transformed colonies at dose levels of 13-18 microg/ml. The lack of genotoxicity of oxymetholone, the positive response in the in vitro transformation assay, and the results of transgenic mouse carcinogenicity assays will provide an interesting perspective on the results of an on-going NTP rat carcinogenicity bioassay.
Topics: Anabolic Agents; Animals; Cell Transformation, Neoplastic; Cells, Cultured; Colony Count, Microbial; Cricetinae; Cytogenetic Analysis; Dose-Response Relationship, Drug; Escherichia coli; Female; Humans; Lymphocytes; Male; Mesocricetus; Mice; Micronucleus Tests; Mitotic Index; Mutagenicity Tests; Mutation; Oxymetholone; Rats; Salmonella typhimurium; Tumor Cells, Cultured
PubMed: 10528628
DOI: 10.1177/019262339902700501 -
Journal of Blood Medicine 2022Bone marrow transplantation, antithymocyte globulin/cyclosporine and eltrombopag are recommended as first-line therapy of severe aplastic anemia (SAA). However,...
BACKGROUND
Bone marrow transplantation, antithymocyte globulin/cyclosporine and eltrombopag are recommended as first-line therapy of severe aplastic anemia (SAA). However, androgens could be considered as front-line treatment among any patients ineligible for better methods although unsatisfactory efficacy is presented.
OBJECTIVE
This retrospective study aimed to evaluate response and survival rate of practical-based treatment with oxymetholone.
PATIENTS AND METHODS
This constituted an analysis of patients receiving a diagnosis of acquired aplastic anemia (AA) at the age of 15 or over and receiving oxymetholone between January 2004 and December 2018. Propensity Score Analysis (PSA) 1:1 matching was performed, according to sex, age and interval from first symptom to treatment. The primary outcome was one-year overall response (OR).
RESULTS
Seventy-four patients were successfully matched by PSA. The 1-year OR of oxymetholone in the nonsevere AA (nSAA) and SAA/very severe AA (vSAA) groups was 54.1 and 13.5%, respectively (P <0.001). With median follow-up 2.7 years, the overall survival was 59.5% in nSAA and 37.8% in SAA/vSAA (P = 0.051). Median survival in nSAA and SAA/vSAA were 7.0 years and 1.8 years, respectively (P = 0.045). However, the responders of SAA/vSAA had longer survival than nonresponders of the nSAA group.
CONCLUSION
These results revealed longer survival among the responders of patients with AA, even in the SAA/vSAA group. However, close monitoring of therapeutic responses is still performed. Switching therapy is necessary when remission is undetected after 6 months of oxymetholone treatment.
PubMed: 36514313
DOI: 10.2147/JBM.S383148 -
Blood Jul 1968
Topics: Adolescent; Anemia, Aplastic; Blood Cell Count; Child; Female; Hemoglobinometry; Humans; Male; Oxymetholone; Reticulocytes; Virilism
PubMed: 5658392
DOI: No ID Found -
Toxicologic Pathology 1999Several rodent models are under examination as possible alternatives to the classical 2-yr carcinogenicity bioassay. The Tg.AC transgenic mouse has been proposed as a...
Several rodent models are under examination as possible alternatives to the classical 2-yr carcinogenicity bioassay. The Tg.AC transgenic mouse has been proposed as a shorter term model offering the possibility of detecting nongenotoxic and genotoxic carcinogenic agents. Retrospective studies of chemicals with established carcinogenic potential have revealed a close correlation between classical bioassay results and the production of skin tumors in the Tg.AC mouse model. Oxymetholone is a synthetic testosterone derivative that is a suspected carcinogen but has shown no evidence of genotoxic activity in a comprehensive battery of genetic toxicity assays. It currently is being tested by the National Toxicology Program (NTP) in a 2-yr rat carcinogenicity bioassay. Because of its nongenotoxicity and the ongoing chronic bioassay, oxymetholone was considered an ideal candidate for a prospective evaluation of the predictive validity of the Tg.AC dermal carcinogenicity model. Consequently, a 6-mo dermal study with oxymetholone in the Tg.AC mouse model was initiated and completed prior to disclosure of the NTP rat bioassay results. In this study, male and female hemizygous Tg.AC mice, 7-8 wk old, were housed individually in suspended plastic cages. An area of dorsal skin was shaved to accommodate dermal applications of 200-microl doses of vehicle control (acetone), drug (1.2, 6.0, or 12 mg oxymetholone in dimethylsulfoxide:acetone, 20:80), or positive control (1.25 microg 12-o-tetradecanoyl-phorbol-13-acetate [TPA]) solutions. Mice received oxymetholone or acetone daily or TPA twice weekly for 20 wk followed by a 6-wk recovery period. The acetone control groups exhibited low spontaneous incidences of papillomas, whereas dermal application of oxymetholone produced dose-related increases in the numbers of papilloma-bearing mice and the numbers of papillomas per animal. Females showed a somewhat greater response to the androgen than did the males. TPA caused an unequivocal increase in papillomas, with males exhibiting a greater response than females. The results of this study indicate that this nongerotoxic androgenic compound possesses proliferative properties. The results predict that chronic systemic administration of oxymetholone will most likely be associated with increased incidences of neoplasms.
Topics: Anabolic Agents; Animals; Carcinogenicity Tests; Carcinogens; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Transgenic; Neoplasms, Experimental; Oxymetholone; Papilloma; Sex Factors; Skin Neoplasms; Survival Rate; Weight Gain
PubMed: 10528629
DOI: 10.1177/019262339902700502 -
Toxicologic Pathology 1999Oxymetholone has been identified as a suspected nongenotoxic carcinogen and has recently completed testing in a conventional National Toxicology Program (NTP) 2-yr...
Oxymetholone has been identified as a suspected nongenotoxic carcinogen and has recently completed testing in a conventional National Toxicology Program (NTP) 2-yr rodent bioassay program. As a synthetic androgen with a limited historical database in toxicology, oxymetholone is an ideal candidate for prospective examination of the performance of short-term transgenic mouse models in the detection of carcinogenic activity. In the present series of 3 articles, studies are described where oxymetholone was evaluated prior to disclosure of the results of the NTP 2-yr bioassay. The accompanying articles provide evidence showing that oxymetholone is devoid of mutagenic activity yet elicits a positive carcinogenic response in the Tg.AC transgenic mouse model. In the present study, oxymetholone was administered by oral gavage to p53 heterozygous male and female mice for 26 wk at doses of 125, 625, and 1,250 mg/kg/day. The vehicle was 0.5% aqueous methylcellulose. Positive controls consisted of mice treated daily by oral gavage with 200 or 400 mg/kg/day of p-cresidine in corn oil. The oxymetholone-treated females showed significantly increased body weight gain and clitoral enlargement attributable to drug treatment. In addition, significant alterations in kidney, liver, and testis weights were attributable to oxymetholone. However, there were no neoplastic lesions that were attributable to oxymetholone in either sex. p-Cresidine produced unequivocal bladder neoplasms in both sexes at the high dose and in males at the lower dose. The absence of a neoplastic response with oxymetholone is consistent with the selectivity of the p53-/- mouse model for detecting carcinogens that act by genotoxic mechanisms.
Topics: Anabolic Agents; Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Genes, p53; Heterozygote; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms, Experimental; Organ Size; Oxymetholone; Papilloma; Precancerous Conditions; Survival Analysis; Testis
PubMed: 10528630
DOI: 10.1177/019262339902700503 -
British Journal of Haematology Sep 1969
Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Sideroblastic; Bone Marrow Diseases; Erythropoietin; Female; Humans; Iron; Iron Isotopes; Kidney Failure, Chronic; Male; Middle Aged; Myeloproliferative Disorders; Oxymetholone
PubMed: 5806436
DOI: 10.1111/j.1365-2141.1969.tb01372.x -
Molecular and Cellular Biochemistry Jul 2006Oxymetholone is a 17alpha -alkylated anabolic-androgenic steroid. This drug can stimulate bone marrow cells and increase the blood cells in the peripheral blood vessels....
Oxymetholone is a 17alpha -alkylated anabolic-androgenic steroid. This drug can stimulate bone marrow cells and increase the blood cells in the peripheral blood vessels. It has been used for the treatment of anemia caused by low red cell production. Since oxymetholone has hematopoietic effect, we studied radioprotective effects of this drug in mice. In this study, we determined percentage of survival, dose-reduction factor (DRF) and hematological parameters in irradiated mice which treated with or without oxymetholone. Oxymetholone administrated at different doses 80, 160, 320, 640 mg/kg by gavages at 24 h before 8 Gy gamma irradiation. At 30 days after treatment, the following percentage of animals survival in each group was as: 80 mg/kg, 50%; 160 mg/kg, 50%; 320 mg/kg, 55%; 640 mg/kg, 75% and vehicle, 15%. Percentage of survival increased in all of treated groups statistically compared with irradiated-vehicle group. In the groups treated by oxymetholone, maximum protection was realized at 640 mg/kg. In order to calculate the DRF for oxymetholone, mice were exposed to whole-body gamma irradiation with dose ranges between 5.83 and 11.23 Gy. The probit line for oxymetholone-treated mice was shifted to the right with a DRF of 1.14. In mice exposed to whole-body gamma-irradiation (4 Gy), an oral administration of 640 mg/kg oxymetholone ameliorated radiation-induced decreases in circulating platelets and erythrocytes, but had a less effect on total number of WBC. These results demonstrate that oxymetholone stimulates myelopoiesis and thrombocytopenia and enhances survival in mice after ionizing radiation.
Topics: Animals; Blood Cells; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Evaluation, Preclinical; Gamma Rays; Hematopoietic System; Mice; Myelopoiesis; Oxymetholone; Radiation Injuries; Radiation-Protective Agents; Survival Rate; Thrombocytopenia
PubMed: 16532255
DOI: 10.1007/s11010-005-9111-5 -
Stem Cell Reports Jan 2015Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged...
Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.
Topics: Animals; Blood Cell Count; Bone Marrow; Cell Cycle; Cell Proliferation; Disease Models, Animal; Fanconi Anemia; Fanconi Anemia Complementation Group D2 Protein; Gene Expression Regulation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mice; Mice, Knockout; Osteopontin; Oxymetholone; Pancytopenia; Sequence Analysis, RNA; Time Factors; Transcription, Genetic
PubMed: 25434823
DOI: 10.1016/j.stemcr.2014.10.014 -
Drug and Chemical Toxicology Nov 2000Oxymetholone is a synthetic androgen, structurally related to testosterone. It is currently used to treat anemias, but has also been abused as a performance enhancing...
Oxymetholone is a synthetic androgen, structurally related to testosterone. It is currently used to treat anemias, but has also been abused as a performance enhancing anabolic steroid by the sport community. Concern about its suspected immunomodulatory properties provided the incentive for a detailed investigation into its effects on the mammalian immune system. In this study, male B6C3F1 mice were treated for 14 d with oxymetholone (0, 50, 150, and 300 mg/kg) by gastric intubation, then evaluated for immunotoxicity using a panel of immunotoxicity assays. Except for an increasing trend in kidney and liver weights, and a dose-dependent increase in serum blood urea nitrogen levels, no other signs of systemic toxicity were observed. Bone marrow DNA synthesis was reduced, though this did not translate into alterations in myeloid or monocyte colony forming units. Spleen B and T cell numbers, antibody response to sheep red blood cells, proliferative response to both mitogen and immunoglobulin receptor immunogens, and NK cell activity were all unaltered in mice treated with oxymetholone. Peritoneal macrophage activity was also unaffected by oxymetholone treatment. A 38% decrease in the spleen cell mixed leukocyte response, and a 15% decrease in cytotoxic T cell activity, measured in the highest oxymetholone treatment group, indicate that cell-mediated immunity was impaired following exposure. This immunomodulation did not however, translate into a change in host resistance to Listeria monocytogenes.
Topics: Anabolic Agents; Animals; B-Lymphocytes; Blood Chemical Analysis; Bone Marrow Cells; Cell Division; Cyclophosphamide; Hemoglobins; Humans; Immunity, Cellular; Immunity, Innate; Immunoglobulin M; Immunosuppressive Agents; Killer Cells, Natural; Listeria monocytogenes; Lymphocyte Culture Test, Mixed; Macrophages, Peritoneal; Male; Mice; Mice, Inbred DBA; Oxymetholone; Random Allocation; Spleen; T-Lymphocytes
PubMed: 11071398
DOI: 10.1081/dct-100101974 -
HIV Clinical Trials 2003Despite highly active antiretroviral therapy (HAART), chronic involuntary weight loss still remains a serious problem in the care of HIV patients due to various... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Despite highly active antiretroviral therapy (HAART), chronic involuntary weight loss still remains a serious problem in the care of HIV patients due to various alterations in energy metabolism and endocrine regulation. Previous studies in HIV-positive men undergoing androgen replacement therapy or treatment with recombinant growth hormone (rGH) have shown partial restoration of lean body mass (LBM), but these treatments have largely not been sufficiently studied in eugonadal individuals.
METHOD
A double-blind, randomized, placebo-controlled trial of 89 HIV-positive eugonadal women and men with wasting assigned to the anabolic steroid oxymetholone (50 mg bid or tid) or placebo for 16 weeks was performed. Body weight, bioimpedance measurements, quality of life parameters, and appetite were analyzed.
RESULTS
Oxymetholone led to a significant weight gain of 3.0 +/- 0.5 and 3.5 +/- 0.7 kg in the tid and bid groups, respectively (p <.05 for each treatment versus placebo), while individuals in the placebo group gained an average of 1.0 +/- 0.7 kg. Body cell mass (BCM) increased in the oxymetholone bid group (3.8 +/- 0.4 kg; p <.0001) and in the oxymetholone tid group (2.1 +/- 0.6 kg; p <.005). Significant improvements were noted in appetite and food intake, increased wellbeing, and reduced weakness by self-examination. The most important adverse event was liver-associated toxicity. Overall, 43% of patients in the tid group, 25% of patients in the bid oxymetholone group, and 8% in the placebo group had a greater than 5 times baseline increase for ALT, AST, or gamma GT, while other adverse events were not increased over placebo.
CONCLUSION
Oxymetholone can be considered an effective anabolic steroid in eugonadal male and female patients with AIDS-associated wasting. The bid (100 mg/day) regimen appeared to be equally effective to the tid (150 mg/day) regimen in terms of weight gain, LBM, and BCM and was associated with less liver toxicity.
Topics: Adult; Aged; Appetite; Body Composition; Body Weight; Double-Blind Method; Female; HIV Infections; HIV Wasting Syndrome; Hormones; Humans; Male; Middle Aged; Oxymetholone; Quality of Life
PubMed: 12815555
DOI: 10.1310/hct.2003.4.3.002