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Transplantation and Cellular Therapy Sep 2023Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after... (Randomized Controlled Trial)
Randomized Controlled Trial
Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after nonmyeloablative (NMA) allogenic hematopoietic stem cell transplantation (HSCT) with an HLA-matched unrelated donor in a randomized clinical trial. We analyzed real-life data to investigate the impact of implementing the triple-drug regimen with cyclosporin, MMF and sirolimus as standard GVHD prophylaxis after NMA HSCT with an HLA-matched unrelated donor at our institution. We studied all adult patients (age ≥18 years) who underwent NMA HSCT with an HLA-matched unrelated donor at Rigshospitalet, Copenhagen University Hospital, Denmark between 2018 and 2021 and received GVHD prophylaxis with cyclosporin, MMF and sirolimus (triple-drug group [TDG]). Comparisons were made with a historical cohort who received tacrolimus and MMF as GVHD prophylaxis after HLA-matched unrelated donor NMA HSCT between 2014 and 2017 (control group [CG]). Outcomes were grade II-IV and grade III-IV acute GVHD, chronic GVHD, relapse, nonrelapse mortality (NRM) and overall survival (OS). A total of 264 patients were included (TDG, n = 137; CG, n = 127). Median age was 66 years (interquartile range [IQR], 58 to 69 years) in the TDG and 63 years (IQR, 57 to 68 years) in the CG. Acute myeloid leukemia and myelodysplastic syndrome were the most frequent indications for HSCT in both groups (TDG, 33% and 23%, respectively; CG, 36% and 22%, respectively). The cumulative incidence at day +110 of grade II-IV GVHD was 17% (95% confidence interval [CI] 11% to 23%) in the TDG versus 29% (95% CI, 21% to 37%) in the CG (P = .02, Gray's test) and that of grade III-IV acute GVHD was 3% (95% CI, 0 to 6%) versus 5% (95% CI, 1% to 8%), respectively (P = .4, Gray's test). In a Cox regression model adjusted for age, donor age and female donor to male recipient the risk of grade II-IV acute GVHD was lower in the TDG compared to the CG (hazard ratio [HR], .51; 95% CI .30 to .86; P = .01). The 2-year OS was 77% (95% CI, 70% to 84%) in the TDG and 69% (95% CI, 61% to 77%) in the CG (P = .04), and this difference remained significant after adjustment for age and Karnofsky Performance Status (HR, .65; 95% CI, .42 to .99; P = .04). The 2-year cumulative incidences of chronic GVHD, relapse and NRM were 60% (95% CI, 51% to 69%), 21% (95% CI, 13% to 28%), and 12% (95% CI, 6% to 17%), respectively, in the TDG and 62% (95% CI, 54% to 71%), 27% (95% CI, 19% to 35%) and 14% (95% CI, 8% to 20%), respectively, in the CG. Multivariable analyses revealed no difference in the risk of chronic GVHD (HR, .91; 95% CI, .65 to 1.26; P = .56), relapse (HR, .70; 95% CI, .42 to 1.15; P = .16) or NRM (HR, .56; 95% CI, .31 to 1.05; P = .07). After changing the standard GVHD prophylaxis in patients undergoing NMA HSCT with an HLA-matched unrelated donor from tacrolimus and MMF to cyclosporin, MMF and sirolimus, we observed a reduction in the incidence of grade II-IV acute GVHD and improved 2-year OS.
Topics: Adult; Humans; Male; Female; Middle Aged; Aged; Adolescent; Tacrolimus; Unrelated Donors; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Sirolimus; Mycophenolic Acid; Cyclosporine; Recurrence
PubMed: 37301257
DOI: 10.1016/j.jtct.2023.05.022 -
Virology Journal Jul 2020Reactivation of hepatitis B virus is a common complication that occurs in patients with hepatitis B virus (HBV) infection who have received cytotoxic chemotherapy or...
BACKGROUND
Reactivation of hepatitis B virus is a common complication that occurs in patients with hepatitis B virus (HBV) infection who have received cytotoxic chemotherapy or immunosuppressive therapy. This clinical phenomenon not only occurs in overt HBV infection patients but also occurs in patients with resolved HBV infection. Previous research has confirmed that epirubicin and dexamethasone can stimulate HBV replication and expression directly rather than indirectly through immunosuppression. Mitomycin and 5-fluorouracil are currently used as cytotoxic chemotherapy drugs for cancer patients. Leflunomide and mycophenolic acid are regarded as immunosuppressants for autoimmune diseases, and numerous clinical studies have reported that these drugs can reactivate HBV replication. In this study, we aimed to investigate whether mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid induce HBV reactivation directly rather than indirectly through immunosuppression.
METHODS
To observe the effect of mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid on HBV replication and expression, we employed HepG2.2.15 and HBV-NLuc-35 cells as a cell model. Next, by native agarose gel electrophoresis (NAGE), quantitative PCR (qPCR), luciferase assay and HBV e antigen (HBeAg) enzyme-linked immunosorbent assay (ELISA) we detected changes in HBV replication and expression induced by these drugs. We also investigated whether lamivudine could inhibit the observed phenotype. SPSS 18.0 software was employed for statistical analysis, One-way ANOVA was used to compare multiple groups.
RESULTS
Expression of HBV capsids and HBeAg in HepG2.2.15 cells was increased by increasing concentration of mitomycin, 5-fluorouracil, leflunomide, and mycophenolic acid. This phenomenon was also demonstrated in HBV-NLuc-35 cells, and the expression of capsids and luciferase activity increased in the same concentration-dependent manner. Replication levels of intracellular capsid DNA and extracellular HBV DNA in HepG2.2.15 cells gradually increased in a dose-dependent manner. In addition, although epirubicin, mitomycin, 5-fluorouracil, dexamethasone, leflunomide and mycophenolic acid enhanced HBV replication, lamivudine inhibited this process.
CONCLUSION
Our study confirmed that mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid directly upregulated HBV replication and expression in vitro. This effect was investigated not only in HepG2.2.15 cells but also in the HBV-NLuc-35 replication system. Moreover, this effect could be prevented by nucleoside analogs, such as lamivudine (LAM). Thus, for patients with HBV infection, prophylactic antiviral therapy is necessary before receiving cytotoxic chemotherapy or immunosuppressive therapy.
Topics: Antineoplastic Agents; Fluorouracil; Hep G2 Cells; Hepatitis B e Antigens; Hepatitis B virus; Humans; Immunosuppressive Agents; Leflunomide; Mitomycin; Mycophenolic Acid; Reinfection; Virus Replication
PubMed: 32611423
DOI: 10.1186/s12985-020-01339-5 -
Pharmacological Reports : PR Jun 2024Saliva sampling is one of the methods of therapeutic drug monitoring for mycophenolic acid (MPA) and its metabolite, mycophenolic acid glucuronide (MPAG). The study...
BACKGROUND
Saliva sampling is one of the methods of therapeutic drug monitoring for mycophenolic acid (MPA) and its metabolite, mycophenolic acid glucuronide (MPAG). The study describes the liquid chromatography tandem mass spectrometry (LC-MS/MS) method developed for saliva MPA and MPAG determination in children with nephrotic syndrome.
METHODS
The mobile phase consisted of methanol and water at gradient flow, both with 0.1% formic acid. Firstly, 100 µL of saliva was evaporated at 45 °C for 2 h to dryness, secondly, it was reconstituted in the mobile phase, and finally 10 µL was injected into the LC-MS/MS system. Saliva from ten children with nephrotic syndrome treated with mycophenolate mofetil was collected with Salivette.
RESULTS
For MPA and MPAG, within the 2-500 ng/mL range, the method was selective, specific, accurate and precise within-run and between-run. No carry-over and matrix effects were observed. Stability tests showed that MPA and MPAG were stable in saliva samples if stored for 2 h at room temperature, 18 h at 4 °C, and at least 5 months at - 80 °C as well as after three freeze-thaw cycles, in a dry extract for 16 h at 4 °C, and for 8 h at 15 °C in the autosampler. The analytes were not adsorbed onto Salivette cotton swabs. For concentrations above 500 ng/mL, the samples may be diluted twofold. In children, saliva MPA and MPAG were within the ranges of 4.6-531.8 ng/mL and 10.7-183.7 ng/mL, respectively.
CONCLUSIONS
The evaluated LC-MS/MS method has met the validation requirements for saliva MPA and MPAG determination in children with nephrotic syndrome. Further studies are needed to explore plasma-saliva correlations and assess their potential contribution to MPA monitoring.
Topics: Humans; Saliva; Mycophenolic Acid; Nephrotic Syndrome; Tandem Mass Spectrometry; Child; Glucuronides; Drug Monitoring; Male; Female; Chromatography, Liquid; Child, Preschool; Adolescent; Reproducibility of Results; Immunosuppressive Agents
PubMed: 38485859
DOI: 10.1007/s43440-024-00574-9 -
BMC Microbiology May 2023Mycophenolic acid (MPA) is the active ingredient in the most important immunosuppressive pharmaceuticals. It has antifungal, antibacterial, antiviral, anti-psoriasis,...
Mycophenolic acid (MPA) is the active ingredient in the most important immunosuppressive pharmaceuticals. It has antifungal, antibacterial, antiviral, anti-psoriasis, and antitumor activities. Therefore, its overproduction in addition to gene expression analysis was our main target. Through this study, we isolated a novel potent mycophenolic acid (MPA) producer strain of the genus Penicillium from the refrigerated Mozzarella cheese and it was identified with the molecular marker ITS and benA genes as P. arizonenseHEWt1. Three MPA overproducer mutants were isolated by exposing the wild type to different doses of gamma-rays, and the fermentation conditions for the highest production of MPA were optimized. The results indicated that MPA amounts produced by the mutants MT1, MT2, and MT3 were increased by 2.1, 1.7, and 1.6-fold, respectively, compared with the wild-type. The growth of both mutant and wild-type strains on PD broth, adjusted to pH 6 and incubated at 25 °C for 15 d, were the best conditions for maximum production of MPA. In a silico study, five orthologs genes of MPA biosynthesizing gene clusters in P. brevicompactum were predicted from the genome of P. arizonense. Sequencing and bioinformatic analyses proved the presence of five putative genes namely mpaA, mpaC, mpaF, mpaG, and mpaH in the P. arizonense HEWt1 genome. Gene expression analysis by qRT-PCR indicated an increase in the transcription value of all annotated genes in the three mutants over the wild type. A highly significant increase in the gene expression of mpaC, mpaF, and mpaH was observed in P. arizonense-MT1 compared with wild-type. These results confirmed the positive correlation of these genes in MPA biosynthesis and are the first report regarding the production of MPA by P. arizonense.Kew word.Mycophenolic acid, Penicillium arizonense, mutagenesis, gene expression.
Topics: Mycophenolic Acid; Immunosuppressive Agents; Penicillium; Polymerase Chain Reaction
PubMed: 37198535
DOI: 10.1186/s12866-023-02884-z -
Frontiers in Public Health 2021Organ transplantations are difficult, complicated and very expensive interventions. In order to preserve the transplanted organs, it is necessary to provide medical...
Organ transplantations are difficult, complicated and very expensive interventions. In order to preserve the transplanted organs, it is necessary to provide medical care to the patients in terms of immunosuppression. According to the guidelines, the first-line therapy choices for achieving immunosuppression after transplantation are tacrolimus, cyclosporine, mycophenolic acid, azathioprine, sirolimus, everolimus" and corticosteroids. The aim of our study was to examine the utilization of this drugs in Montenegro and to compare the results with the ones from Finland, Croatia, and Serbia. In our investigation we used Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) methodology. Prices per DDD of drugs are presented in euros (€). In all observed countries, there is a positive trend in the consumption of all 6 drugs during the analyzed period. The prices per DDD of these drugs generally show a negative trend. Tacrolimus and mycophenolic acid in Montenegro recorded the largest reduction in the price per DDD. Price per one DDD of tacrolimus decreased from €13.28 in 2009 to €5.11 in 2019, thus by about 260%, and as regards mycophenolic acid, the price per one DDD decreased from €9.59 in 2009 to € 3.36 in 2019, thus by almost 300%. Despite the reduction in the price per DDD, drugs that are used as immunosuppressants are showing increasing costs from year to year. Since these drugs are expensive, they participate in a significant percentage in the budget for medicines in each country.
Topics: Azathioprine; Croatia; Cyclosporine; Everolimus; Finland; Humans; Montenegro; Mycophenolic Acid; Serbia; Sirolimus; Tacrolimus
PubMed: 33869136
DOI: 10.3389/fpubh.2021.671316 -
GeroScience Feb 2024In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12%...
Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used.
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.
Topics: Female; Mice; Male; Animals; Longevity; Meclizine; Hydrogen Sulfide; Dimethyl Fumarate; Mycophenolic Acid; Phenylbutyrates; Xanthophylls; Flavonols
PubMed: 38041783
DOI: 10.1007/s11357-023-01011-0 -
Microbiology and Immunology Sep 2020In this study, the anti-severe acute respiratory syndrome coronavirus-2 (anti-SARS-CoV-2) activity of mycophenolic acid (MPA) and IMD-0354 was analyzed. These compounds...
In this study, the anti-severe acute respiratory syndrome coronavirus-2 (anti-SARS-CoV-2) activity of mycophenolic acid (MPA) and IMD-0354 was analyzed. These compounds were chosen based on their antiviral activities against other coronaviruses. Because they also inhibit dengue virus (DENV) infection, other anti-DENV compounds/drugs were also assessed. On SARS-CoV-2-infected VeroE6/TMPRSS2 monolayers, both MPA and IMD-0354, but not other anti-DENV compounds/drugs, showed significant anti-SARS-CoV-2 activity. Although MPA reduced the viral RNA level by only approximately 100-fold, its half maximal effective concentration was as low as 0.87 µ m, which is easily achievable at therapeutic doses of mycophenolate mofetil. MPA targets the coronaviral papain-like protease and an in-depth study on its mechanism of action would be useful in the development of novel anti-SARS-CoV-2 drugs.
Topics: Animals; Antiviral Agents; Benzamides; Betacoronavirus; COVID-19; Chlorocebus aethiops; Coronavirus Infections; Dengue Virus; Humans; Mycophenolic Acid; Pandemics; Pneumonia, Viral; SARS-CoV-2; Vero Cells; Virus Replication
PubMed: 32579258
DOI: 10.1111/1348-0421.12828 -
Frontiers in Immunology 2023Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.
METHODS
We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.
RESULTS
Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).
DISCUSSION
This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.
Topics: Humans; Adult; Immunosuppressive Agents; Lupus Nephritis; Network Meta-Analysis; Treatment Outcome; Cyclophosphamide; Tacrolimus; Azathioprine; Mycophenolic Acid; Glucocorticoids; Bone Marrow Diseases; Kidney Failure, Chronic; Recurrence; Herpes Zoster; Neoplasms
PubMed: 37901212
DOI: 10.3389/fimmu.2023.1232244 -
Polish Archives of Internal Medicine Sep 2022Autoimmune hepatitis (AIH) is an acute or chronic inflammatory disease of the liver caused by an immune response of unknown origin. It affects people from all ethnic... (Review)
Review
Autoimmune hepatitis (AIH) is an acute or chronic inflammatory disease of the liver caused by an immune response of unknown origin. It affects people from all ethnic groups irrespective of age or sex. AIH is characterized by hyperglobulinemia, presence of circulating autoantibodies, and liver inflammation. The clinical picture of the disease varies from asymptomatic or mild to severe acute hepatitis or liver failure. A timely and prompt diagnosis is of utmost importance to prevent progression to advanced liver disease by immediate initiation of immunosuppressive treatment. So far, several diagnostic scoring systems have been proposed, which incorporated demographic data as well as biochemical, clinical, and histological characteristics of the disease. However, due to the high heterogeneity of the disease presentation, diagnosis of AIH remains challenging. Most patients initially respond to first‑ line treatment, which consists of corticosteroids combined with azathioprine or mycophenolate mofetil. However, insufficient response to the treatment and intolerance due to side effects are common, so a significant proportion of patients require second- and / or third‑ line therapies. Herein, we review the challenges and recent advances in AIH diagnosis and management.
Topics: Autoantibodies; Azathioprine; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid
PubMed: 36093593
DOI: 10.20452/pamw.16334 -
Chinese Medical Journal Jan 2024Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, poses a substantial risk of progression to end-stage renal disease, with increased... (Review)
Review
Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, poses a substantial risk of progression to end-stage renal disease, with increased mortality. Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids, mycophenolate mofetil, and calcineurin inhibitors. Although therapeutic regimens have evolved over the years, they have inherent limitations, including non-specific targeting, substantial adverse effects, high relapse rates, and prolonged maintenance and remission courses. These drawbacks underscore the need for targeted therapeutic strategies for LN. Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity. This review provides an overview of the current evidence on targeted therapies for LN, elucidates the biological mechanisms of responses and failure, highlights the challenges ahead, and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.
Topics: Humans; Calcineurin Inhibitors; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid
PubMed: 38057972
DOI: 10.1097/CM9.0000000000002959