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Biomedicine & Pharmacotherapy =... Sep 2023Male infertility is a global concern, with a noticeable increase in the decline of spermatogenesis and sperm quality. However, there are limited clinically effective...
Male infertility is a global concern, with a noticeable increase in the decline of spermatogenesis and sperm quality. However, there are limited clinically effective treatments available. This study aimed to investigate the potential effectiveness of puerarin in treating male infertility, which leads to gonadal changes. The results obtained from various analyses such as CASA, immunofluorescence, DIFF-Quick, hematoxylin and eosin (H&E), and periodic acid-Schiff (PAS) staining demonstrated that puerarin supplementation significantly alleviated the busulfan-induced reduction in spermatogenesis and sperm quality in both young and adult mice. Furthermore, puerarin exhibited a marked improvement in the damage caused by busulfan to the architecture of seminiferous tubules, causal epididymis, blood-testicular barrier (BTB), as well as spermatogonia and Sertoli cells. Similarly, puerarin significantly reduced the levels of total antioxidant capacity (T-AOC), malondialdehyde (MDA), and caspase-3 in the testes of busulfan-induced mice, as determined by microplate reader analysis. Additionally, RNA-seq data, RT-qPCR, and western blotting revealed that puerarin restored the abnormal gene expressions induced by busulfan to nearly healthy levels. Notably, puerarin significantly reversed the impact of busulfan on the expression of marker genes involved in spermatogenesis and oxidative stress. Moreover, puerarin suppressed the phosphorylation of p38, ERK1/2, and JNK in the testes, as observed through testicular analysis. Consequently, this study concludes that puerarin may serve as a potential alternative for treating busulfan-induced damage to male fertility by inactivating the testicular MAPK pathways. These findings may pave the way for the use of puerarin in addressing chemotherapy- or other factors-induced male infertility in humans.
Topics: Humans; Male; Animals; Mice; Busulfan; Semen; Spermatogenesis; Testis; Infertility, Male
PubMed: 37516022
DOI: 10.1016/j.biopha.2023.115231 -
American Journal of Hematology Aug 2022The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial.
The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.
Topics: Aged; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 35617104
DOI: 10.1002/ajh.26620 -
Journal of Assisted Reproduction and... Jan 2023Modeling methods for busulfan-induced oligoasthenozoospermia are controversial. We aimed to systematically review the modeling method of busulfan-induced oligospermia... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Modeling methods for busulfan-induced oligoasthenozoospermia are controversial. We aimed to systematically review the modeling method of busulfan-induced oligospermia and asthenozoospermia, and analyze changes in various evaluation indicators at different busulfan doses over time.
METHODS
We searched the Cochrane Library, PubMed databases, Web of Science, the Chinese National Knowledge Infrastructure, and the Chinese Biomedical Literature Service System until April 9, 2022. Animal experiments of busulfan-induced spermatogenesis dysfunction were included and screened. The model mortality and parameters of the evaluation indicators were subjected to meta-analysis.
RESULTS
Twenty-nine animal studies were included (control/model: 669/1829). The mortality of mice increased with busulfan dose. Significant spermatogenesis impairment occurred within 5 weeks, regardless of busulfan dose (10-40 mg/kg). Testicular weight (weighted mean difference [WMD]: - 0.04, 95% CI: - 0.05, - 0.03), testicular index (WMD: - 2.10, 95% CI: - 2.43, - 1.76), and Johnsen score (WMD: - 4.67, 95% CI: - 5.99, - 3.35) were significantly decreased. The pooled sperm counts of the model group were reduced by 32.8 × 10/ml (WMD: - 32.8, 95% CI: - 44.34, - 21.28), and sperm motility decreased by 37% (WMD: - 0.37, 95% CI: - 0.47, - 0.27). Sperm counts decreased slightly (WMD: - 3.03, 95% CI: - 3.42, - 2.64) in an intratesticular injection of low-dose busulfan (4 - 6 mg/kg), and the model almost returned to normal after one seminiferous cycle.
CONCLUSION
The model using low-dose busulfan (10 - 20 mg/kg) returned to normal after 10 - 15 weeks. However, in some spermatogenesis cycles, testicular weight reduction and testicular spermatogenic function damage were not proportional to busulfan dose. Sperm counts and motility results in different studies had significant heterogeneity. Standard protocols for sperm assessment in animal models were needed to reduce heterogeneity between studies.
Topics: Humans; Mice; Male; Animals; Oligospermia; Busulfan; Asthenozoospermia; Sperm Count; Sperm Motility; Semen
PubMed: 36508035
DOI: 10.1007/s10815-022-02674-y -
Blood Advances Sep 2023Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning...
Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning regimen, including busulfan, is commonly used in patients undergoing T-cell depletion (TCD) and allo-HCT, but data on optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target an area under the curve exposure between 55 and 66 mg × h/L over 3 days using a noncompartmental analysis model. We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (2021) and correlated it with outcomes. To define optimal exposure, univariable models were performed with P splines, wherein hazard ratio (HR) plots were drawn, and thresholds were found graphically as the points at which the confidence interval crossed 1. Cox proportional hazard and competing risk models were used for analyses. 176 patients were included, with a median age of 59 years (range, 2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg × h/L (range, 46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg × h/L). 5-year overall survival (OS) with busulfan exposure ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40% (95% CI, 53-68), respectively (P = .02), and this association remained in a multivariate analyses (HR, 0.5; 95% CI, 0.29; 0.88; P = .02). In patients undergoing TCD allo-HCT, busulfan exposure is significantly associated with OS. The use of a published popPK model to optimize exposure may significantly improve the OS.
Topics: Humans; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Busulfan; Retrospective Studies; Transplantation, Homologous; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation
PubMed: 37379285
DOI: 10.1182/bloodadvances.2023009708 -
Experimental Hematology Jan 2022Exposure of young C57BL/6 (B6) mice to two courses of busulfan (BSF) injections or two rounds of sublethal total-body irradiation (TBI) induced significant damage to the...
Exposure of young C57BL/6 (B6) mice to two courses of busulfan (BSF) injections or two rounds of sublethal total-body irradiation (TBI) induced significant damage to the function of hematopoietic stem and progenitor cells (HSPCs). Fifteen weeks after treatment, BSF- and TBI-treated mice had reduced white blood cells without significant change in red blood cells or platelets, indicating that BSF and TBI hematotoxicity was chronic, with leukocytes being the major targets. Hematopoietic damage induced by BSF or TBI persisted long term. Residual adverse effects were reflected by significantly decreased CD45R B cells and reduced recovery of total bone marrow cells, especially HSPCs carrying markers for KSL (KitSca-1Lin) cells, multipotent progenitor (MPP) cells (KSLCD34CD135), myeloid progenitor (MP) cells (KitSca-1Lin), and common lymphoid progenitor (CLP) cells 62 wk posttreatment. Transplantation of bone marrow (BM) cells from BSF and TBI donors at 49 weeks after treatment into lethally irradiated hosts resulted in decreased engraftment of CD45R B cells in blood and reduced reconstitution of BM HSPCs including KSL cells, short-term hematopoietic stem cells (KSLCD34CD135), MPP cells, and MP cell subsets. TBI donor had better reconstitution of CLP cells in recipients posttransplantation than did BSF donor, suggesting an impact of TBI and BSF on B cells at different development stages. In summary, BSF and TBI exposure produced long-lasting adverse effects on hematopoiesis with pronounced effects on mature B cells, immature ST-HSCs, and hematopoietic progenitor cells. Our results may have implications for therapy of human diseases.
Topics: Animals; Bone Marrow Cells; Bone Marrow Transplantation; Busulfan; Female; Hematopoiesis; Hematopoietic Stem Cells; Mice; Mice, Inbred C57BL; Myeloablative Agonists; Whole-Body Irradiation
PubMed: 34763024
DOI: 10.1016/j.exphem.2021.11.001 -
JBRA Assisted Reproduction Apr 2021Busulfan is one of the most common chemotherapeutic drugs and has the ability to induce apoptosis in testicular germ cells, which leads to infertility. In this study,...
OBJECTIVE
Busulfan is one of the most common chemotherapeutic drugs and has the ability to induce apoptosis in testicular germ cells, which leads to infertility. In this study, the effects of ozone therapy and melatonin were evaluated on testicular disorders induced by busulfan.
METHODS
In this study, we divided 24 male mice into four groups: control group, groups treated with busulfan, busulfan/melatonin, and busulfan/ozone. At the end of a 35-day period, blood samples were taken from the mice and their testosterone levels were measured. Both of the mice's testes were removed and weighed, afterwards, each one of them was used for evaluation of morphology by Johnson's score, as well as for measuring the diameter and thickness of seminiferous tubules. The other testis was homogenized for measuring Malondialdehyde (MDA) and antioxidant status using Catalase (CAT), Super Oxide Dismutase (SOD), and Total Antioxidant Capacity (TAC) levels. Epididymis spermatozoa were also used to evaluate motility, morphology, and sperm count.
RESULTS
Busulfan significantly reduced the testis quality (weight, sperm parameters, testosterone, CAT, SOD, and TAC levels) and increased MDA and destruction of seminiferous tubules compared to the control group. Ozone and melatonin treatments significantly increased testis quality, sperm parameters, MDA, and antioxidant status, but they did not affect the TAC level.
CONCLUSIONS
This study showed that similar to melatonin, ozone can reduce the effect of busulfan toxicity on mice testis. However, further studies are needed to understand the precise mechanism of ozone function on testis.
Topics: Animals; Busulfan; Male; Melatonin; Mice; Oxidative Stress; Ozone; Spermatozoa; Testis
PubMed: 33507719
DOI: 10.5935/1518-0557.20200081 -
Blood Oct 1994Busulfan is widely used as a component of the myeloablative therapy in bone marrow transplantation. Recent studies have shown that the drug disposition is altered in...
Busulfan is widely used as a component of the myeloablative therapy in bone marrow transplantation. Recent studies have shown that the drug disposition is altered in children and is associated with less therapeutic effectiveness, lower toxicities, and higher rates of engraftment failure. We have evaluated the bioavailability of the drug in two groups of patients: eight children between 1.5 and 6 years of age and eight older children and adults between 13 and 60 years. Oral bioavailability showed a large interindividual variation. In children, the bioavailability ranged from 0.22 to 1.20, and for adults, it was within the range 0.47 to 1.03. The elimination half-life after intravenous administration in children (2.46 +/- 0.27 hours; mean +/- SD) did not differ from that obtained for adults (2.61 +/- 0.62 hours). However, busulfan clearance normalized to body weight was significantly higher in children (3.62 +/- 0.78 mL.min-1.kg-1) than that in adults (2.49 +/- 0.52 mL.min-1.kg-1). Also, the distribution volume normalized for body weight was significantly higher in children (0.74 +/- 0.10 L.kg-1) compared with 0.56 +/- 0.10 L. kg-1 in adults. The difference in clearance between children and adults was not statistically significant when normalized to body surface area, which most probably shows that busulfan dosage should be calculated on the basis of surface area rather than body weight. However, to avoid drug-related toxicities, drug monitoring and an individual dose adjustment should be considered because of the variability in busulfan bioavailability.
Topics: Administration, Oral; Adult; Age Factors; Biological Availability; Busulfan; Child, Preschool; Female; Humans; Infant; Injections, Intravenous; Male; Metabolic Clearance Rate; Middle Aged
PubMed: 7919328
DOI: No ID Found -
Transplantation and Cellular Therapy Aug 2022Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS), along with the impact...
Comparison of Pulmonary Toxicity after Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients.
Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS), along with the impact of different myeloablative conditioning regimens, remain incompletely described. Here we compared the acute and long-term incidence of pulmonary toxicity (PT) after total body irradiation (TBI)- and busulfan-based myeloablative conditioning. We conducted this retrospective cohort study of 311 consecutive pediatric patients with leukemia or MDS who underwent allo-HSCT at Dana-Farber Cancer Institute/Boston Children's Hospital between 2008 and 2018. PT was graded using Common Terminology Criteria for Adverse Events version 5.0. The primary objective was to compare the cumulative incidence of grade ≥3 and grade 5 PT after TBI-based and busulfan-based myeloablative conditioning using Gray's test. Secondary objectives were to determine factors associated with PT and overall survival (OS) using competing risk analysis and Cox regression analyses, respectively. There was no significant difference between the TBI-conditioned group (n = 227) and the busulfan-conditioned group (n = 84) in the incidence of grade ≥3 PT (29.2% versus 34.7% at 2 years; P = .26) or grade 5 pulmonary toxicity (6.2% versus 6.1% at 2 years; P = .47). Age (hazard ratio [HR], 1.70, 95% confidence interval [CI], 1.11 to 2.59; P = .01), grade ≥2 PT prior to allo-HSCT or preexisting pulmonary conditions (HR, 1.84, 95% CI, 1.24 to 2.72; P < .01), acute graft-versus-host disease (GVHD) (HR, 2.50; 95% CI, 1.51 to 4.14; P < .01), and chronic GVHD (HR, 2.61; 95% CI, 1.26 to 5.42; P = .01) were associated with grade ≥3 PT on multivariable analysis. Grade ≥3 PT was associated with worse OS (81.1% versus 61.5% at 2 years; P < .01). In pediatric allo-HSCT recipients, rates of PT were similar in recipients of TBI-based and recipients of busulfan-based myeloablative conditioning regimens. Age, the presence of PT or preexisting pulmonary conditions prior to transplantation, and the development of either acute or chronic GVHD were associated with grade ≥3 PT post-transplantation. Furthermore, the occurrence of grade 3-4 PT post-transplantation was associated with inferior OS.
Topics: Busulfan; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Myelodysplastic Syndromes; Retrospective Studies; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation
PubMed: 35623615
DOI: 10.1016/j.jtct.2022.05.028 -
Blood Advances May 2020Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic...
Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.
Topics: Animals; Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Neoplasm Recurrence, Local; Rabbits; Transplantation Conditioning
PubMed: 32384542
DOI: 10.1182/bloodadvances.2020001748 -
BMC Pediatrics Apr 2020Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial.
METHODS
Research on pertinent literature was carried out at PubMed, EMBASE, Web of science, the Cochrane Library and ClinicalTrials.gov. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 μM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events.
RESULTS
Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 μM × min, the mean AUC value of < 900 μM × min significantly increased the incidence of graft failure (RR = 3.666, 95% CI: 1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC < 1350 μM × min (RR = 0.370, 95% CI: 0.205-0.666) and < 1500 μM × min (RR = 0.409, 95% CI: 0182-0.920).
CONCLUSIONS
In children, Bu mean AUC above the cut-off value of 900 μM × min (after every 6-h dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 μM × min were associated with increased risk of VOD, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.
Topics: Adolescent; Busulfan; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Infant; Prospective Studies; Transplantation Conditioning
PubMed: 32312247
DOI: 10.1186/s12887-020-02028-6