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Pediatric Blood & Cancer Aug 2024Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental...
Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number in Fancd2 mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2 mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p = .01) and hemoglobin levels (p < .05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [LinScac-Kit]) was significantly increased (p = .001) by long-term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials. HIGHLIGHTS: Long-term coadministration of metformin in combination with oxymetholone is well tolerated by Fancd2 mice. Hematopoietic stem cell quiescence in mutant mice was enhanced by treatment with metformin alone. Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.
Topics: Animals; Metformin; Mice; Fanconi Anemia; Oxymetholone; Disease Models, Animal; Drug Therapy, Combination; Fanconi Anemia Complementation Group D2 Protein; Mice, Knockout; Hematopoietic Stem Cells
PubMed: 38733122
DOI: 10.1002/pbc.31030 -
Food & Nutrition Research 2023A proprietary combination of fruit rind and leaf extracts (LI80020F4, CinDura) improved the physical performance and muscle strength of resistance-trained adult males.
BACKGROUND
A proprietary combination of fruit rind and leaf extracts (LI80020F4, CinDura) improved the physical performance and muscle strength of resistance-trained adult males.
OBJECTIVE
This study assessed the underlying mechanisms of the ergogenic potential of LI80020F4 in and models.
METHODS
The individual extracts and their combination (LI80020F4) were assessed for nitrite production in EAhy926 human endothelial cells. Subsequent experiments evaluated the effect of LI80020F4 in myotube formation in C2C12 mouse myoblasts, expression of mammalian target of rapamycin (mTOR) signaling proteins, myogenic factors, and mitochondrial functions in L6 rat myoblasts.Moreover, adult male ICR mice were randomly assigned ( = 15) into vehicle control (G1), exercise alone (G2), oxymetholone-16 mg/kg body weight (bw) (G3), and 75 (G4)-, 150 (G5)-, or 300 (G6) mg/kg bw of LI80020F4, orally gavaged for 28 days. G1 and G2 mice received 0.5% carboxymethylcellulose sodium. Following completion, muscle strength and physical performance were assessed on forelimb grip strength and forced swimming test (FST), respectively. Gastrocnemius (GA), tibialis anterior (TA) muscle weights, muscle fiber cross-sectional area (CSA), levels of muscle, and serum protein markers were also determined.
RESULTS
LI80020F4 increased nitrite production in EAhy926 cells in a dose-dependent manner. LI80020F4 induced C2C12 myotube formation, increased mitochondrial biogenesis, upregulated the expressions of activated mTOR and other mitochondria and myogenic proteins, and mitigated HO-induced mitochondrial membrane depolarization in the myoblast cells. In the animal study, 75, 150, and 300 mg/kg bw LI80020F4 doses significantly ( < 0.05) increased the animals' forelimb grip strength. Mid- and high-dose groups showed increased swimming time, increased muscle weight, CSA, muscle growth-related, and mitochondrial protein expressions in the GA muscles.
CONCLUSION
LI80020F4 increases nitric oxide production in the endothelial cells, mitochondrial biogenesis and function, upregulates skeletal muscle growth-related protein expressions and reduces oxidative stress; together, it explains the basis of the ergogenic potential of LI80020F4.
PubMed: 37920678
DOI: 10.29219/fnr.v67.9750 -
BioRxiv : the Preprint Server For... Aug 2023Fanconi Anemia (FA) is a disease caused by defective DNA repair which manifests as bone marrow failure, cancer predisposition, and developmental defects. Mice containing...
Fanconi Anemia (FA) is a disease caused by defective DNA repair which manifests as bone marrow failure, cancer predisposition, and developmental defects. Mice containing inactivating mutations in one or more genes in the FA pathway partially mimic the human disease. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow (BM) hematopoietic stem progenitor cells (HSPCs) number in mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of mice and wild-type controls with either MET alone, OXM alone, MET+OXM or placebo diet. Both male and female mice were treated from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=0.01) and hemoglobin levels (p<0.05). In addition, the percentage of quiescent HSC (LSK) was significantly increased (p=0.001) by long-term treatment with MET alone. However, the absolute number of progenitors, measured by LSK frequency or CFU-S, was not significantly altered by MET therapy. The combination of metformin and oxymetholone did not result in a significant synergistic effect on any parameter. Male animals on MET+OXM or MET alone were significantly leaner than controls at 18 months, regardless of genotype. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration.
PubMed: 37649908
DOI: 10.1101/2023.08.16.553572 -
Value in Health Regional Issues Sep 2023This study aimed to compare rabbit-antithymocyte globulin and cyclosporine (rATG/CsA) with oxymetholone in terms of direct medical expenditures and economic evaluation...
OBJECTIVES
This study aimed to compare rabbit-antithymocyte globulin and cyclosporine (rATG/CsA) with oxymetholone in terms of direct medical expenditures and economic evaluation in severe acquired aplastic anemia (SAA) and very severe acquired aplastic anemia (vSAA) patients.
METHODS
Patients with SAA/vSAA who initiated treatment with rATG/CsA or oxymetholone between 2004 and 2018 were included. Trial-based cost-effectiveness evaluation in healthcare provider perspective was performed. Direct medical costs were retrieved from hospital database, inflated, and converted to 2020 US dollar (30.01 Baht per US dollar). One-way sensitivity analysis and probabilistic sensitivity analysis by nonparametric bootstrap was performed.
RESULTS
After 2-year follow-up, the total mean (SD) direct medical expenditures per patient for oxymetholone and rATG/CsA group were $8 514.48 ($12 595.67) and $41 070.88 ($22 084.04), respectively. Nevertheless, oxymetholone had significant lower survival rate than rATG/CsA (P=.001) but higher in second-year blood transfusion need (71.4% vs 18.2%) and hospitalization (14.3% vs 0%). The incremental cost-effectiveness ratio was $45 854.08 per life-year gained when rATG/CsA was used instead of oxymetholone (95% CI $24 244.03-$143 496.67 per life-year gained). The probabilistic sensitivity analysis indicated that rATG/CsA had no chance of being cost-effective for SAA/vSAA when willingness to pay threshold of one to 3 times of national gross domestic product per capita was applied.
CONCLUSIONS
Oxymetholone remains a viable alternative in resource-limited country. Despite its high cost, the rATG/CsA is a preferred treatment option because of the significant advantages on reducing mortality, treatment complications, and hospitalization.
Topics: Animals; Rabbits; Anemia, Aplastic; Antilymphocyte Serum; Cost-Effectiveness Analysis; Cyclosporine; Oxymetholone; Thailand; Humans
PubMed: 37393722
DOI: 10.1016/j.vhri.2023.05.004 -
Diseases (Basel, Switzerland) Jun 2023Oxymetholone is one of the anabolic steroids that has widely been used among teenagers and athletes to increase their muscle bulk. It has undesirable effects on male...
Oxymetholone is one of the anabolic steroids that has widely been used among teenagers and athletes to increase their muscle bulk. It has undesirable effects on male health and fertility. In this study, the therapeutic effects of platelet-rich plasma (PRP) on oxymetholone-induced testicular toxicity were investigated in adult albino rats. During the experiments, 49 adult male albino rats were divided into 4 main groups: Group 0 (donor group) included 10 rats for the donation of PRP, Group I (control group) included 15 rats, Group II included 8 rats that received 10 mg/kg of oxymetholone orally, once daily, for 30 days, and Group III included 16 rats and was subdivided into 2 subgroups (IIIa and IIIb) that received oxymetholone the same as group II and then received PRP once and twice, respectively. Testicular tissues of all examined rats were obtained for processing and histological examination and sperm smears were stained and examined for sperm morphology. Oxymetholone-treated rats revealed wide spaces in between the tubules, vacuolated cytoplasm, and dark pyknotic nuclei of most cells, as well as deposition of homogenous acidophilic material between the tubules. Electron microscopic examination showed vacuolated cytoplasm of most cells, swollen mitochondria, and perinuclear dilatation. Concerning subgroup IIIa (PRP once), there was a partial improvement in the form of decreased vacuolations and regeneration of spermatogenic cells, as well as a reasonable improvement in sperm morphology. Regarding subgroup IIIb (PRP twice), histological sections revealed restoration of the normal testicular structure to a great extent, regeneration of the spermatogenic cells, and most sperms had normal morphology. Thus, it is recommended to use PRP to minimize structural changes in the testis of adult albino rats caused by oxymetholone.
PubMed: 37366872
DOI: 10.3390/diseases11020084 -
Molecular and Cellular Endocrinology Jun 2023Human adrenocortical H295R cells have been validated by the OECD Test Guideline 456 to detect chemicals disrupting testosterone and 17β-estradiol (estradiol)...
Human adrenocortical H295R cells have been validated by the OECD Test Guideline 456 to detect chemicals disrupting testosterone and 17β-estradiol (estradiol) biosynthesis. This study evaluated a novel approach to detect disturbances of steroidogenesis in H295R cells, exemplified by prochloraz and five anabolic steroids. Steroid profiles were assessed by an untargeted LC-MS-based method, providing a relative quantification of 57 steroids annotated according to their accurate masses and retention times. Such a panel of steroids included several mineralocorticoids, glucocorticoids, progestins and adrenal androgens. The coverage of a high number of metabolites in this extended steroid profiling facilitated grouping of chemicals with similar effects and detecting subtler differences between chemicals. It allowed, for example, distinguishing between the effects of turinabol and oxymetholone, supposed to act similarly in a previous characterization including only nine adrenal steroids. Furthermore, the results revealed that product/substrate ratios can provide superior information on altered enzyme activities compared to individual metabolite levels. For example, the 17α-hydroxypregnenolone/pregnenolone ratio was found to be a more sensitive marker for detecting 17α-hydroxylase inhibition by prochloraz than the corresponding individual steroids. These results illustrate that chemical grouping and calculation of product/substrate ratios can provide valuable information on mode-of-action and help prioritizing further experimental work.
Topics: Humans; Anabolic Androgenic Steroids; Cell Line, Tumor; Steroids; Estradiol
PubMed: 37037411
DOI: 10.1016/j.mce.2023.111929 -
Iranian Journal of Pharmaceutical... Dec 2022Using sports supplements is common among athletes. The presence of anabolic steroids in sports supplements as a hormonal contaminant can increase production efficiency....
BACKGROUND
Using sports supplements is common among athletes. The presence of anabolic steroids in sports supplements as a hormonal contaminant can increase production efficiency. Since anabolic steroids cause health problems and result in positive doping tests in athletes, it is important to investigate their presence in the supplement preparations consumed by athletes.
OBJECTIVES
This paper aims to simultaneously determine ten anabolic steroids by high-performance thin-layer chromatography (HPTLC) method in sports supplements.
METHODS
Chromatographic analysis was conducted on glass silica gel 60F254 plates. The extracts loaded on silica gel plates are subjected to programed multiple development (PMD) to separate anabolic androgenic steroids (AASs). Densitometric scanning is carried out at the wavelength of 245 and 366nm. The method was validated according to the ICH guidelines.
RESULTS
Spots at retardation factor (Rf) 0.72 (elution system 1), 0.4 (elution system 1), 0.29 (elution system 2), 0.25 (elution system 2), 0.1 (elution system 1), 0.65 (elution system 2), 0.59 (elution system 1), 0.44 (elution system 1), 0.8 (elution system 3), and 0.82 (elution system 3) values were recognized as 19-nor androstenedione, 19-nortestosterone, methyl testosterone, clostebol, stanozolol, trenbolone enanthate, oxymetholone, oxandrolone, testosterone enanthate, and nandrolone decanoate, respectively. The linear ranges were 25 - 250 μg/mL for oxymetholone, 7 - 50 μg/mL for 19-nor androstenedione, 19-nortestosterone, and oxandrolone, and 3 - 20 μg/mL for methyl testosterone, clostebol, stanozolol, trenbolone enanthate, testosterone enanthate, and nandrolone decanoate. The developed method is validated by acceptable precision (CV < 20%) and good accuracy (94% < R < 114%). The value of limit of detection (LOD) for all derivatives was in the range of 0.02 - 0.16 μg/spot (20-160 μg/g of supplement), while limit of quantitation (LOQ) was found to be in the range of 0.06 - 0.5 μg/spot (60 - 500 μg/g of supplement). Fifty sports supplement samples as real sample were collected and analyzed. None of the samples screened positive using the HPTLC method.
CONCLUSIONS
In the present study, the fast, cheap, and simple HPTLC method could be used for the multi-residue analysis of ten anabolic androgenic steroids in sports supplements.
PubMed: 36942061
DOI: 10.5812/ijpr-127444 -
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 -
Expert Review of Hematology Aug 2022Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the... (Review)
Review
BACKGROUND
Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance, and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders.
WHAT IS COVERED
Clinical features, genetics, and biology of the different subtypes. Expert view on diagnosis, treatment of the hematological complications and future.
EXPERT VIEW
As these are very pleotropic disorders affecting multiple organs, a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols. New therapies are needed where danazol/oxymetholone is ineffective and HSCT is not feasible.
Topics: Biology; Danazol; Dyskeratosis Congenita; Humans; Mutation; Oxymetholone; Telomerase; Telomere
PubMed: 35929966
DOI: 10.1080/17474086.2022.2108784