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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 -
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 -
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