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Journal For Immunotherapy of Cancer Jan 2024Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can...
Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.
Topics: Humans; Abatacept; Adrenal Cortex Hormones; Colitis; Hepatitis; Immunoglobulins, Intravenous; Infliximab; Mycophenolic Acid; Myocarditis; Neoplasms; Nitriles; Pneumonia; Pyrazoles; Pyrimidines
PubMed: 38233099
DOI: 10.1136/jitc-2023-007409 -
Journal of Agricultural and Food... Nov 2023Structure optimization based on natural products has become an effective way to develop new green fungicides. In this project, thirty-two novel NPs-derived hydrazide...
Structure optimization based on natural products has become an effective way to develop new green fungicides. In this project, thirty-two novel NPs-derived hydrazide compounds were designed and synthesized by introducing the bioactive hydrazide substructure into sinapic acid and mycophenolic acid. The fungicidal bioassays indicated that the obtained hydrazide compounds showed excellent and selective fungicidal activity against specific pathogens, especially compounds , , and with EC values of 0.63, 0.56, and 0.43 μg mL against , respectively. SAR indicated that the introduction of 4-fluoro, 4-chloro, and 2,4-difluoro groups was conducive to improving the fungicidal activity, while the extension of the hydrazide bridge would affect the selectivity for inhibitory activity. Subsequently, the effects of hydrazide compounds on rice seedling and zebrafish growth were also investigated. The fungicidal mechanism implied that treatment with compound would cause significant changes in metabolites of plasma membrane-related linolenic acid metabolism, arachidonic acid metabolism, and α-linolenic acid metabolism pathways, which further led to the wrinkled hyphae and the blurred plasma membrane and cytoplasm. Finally, the frontier molecular orbitals and charge distribution were calculated to analyze the differences in bioactivity from a structural perspective. These results provide important guidance for the development and practical application of novel fungicides.
Topics: Animals; Fungicides, Industrial; Structure-Activity Relationship; Mycophenolic Acid; Zebrafish
PubMed: 37916897
DOI: 10.1021/acs.jafc.3c04641 -
International Journal of Biological... Apr 2024The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence...
The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence spectroscopy. Dynamic light scattering and scanning electron microscopy were used to figure out the structure of MPA-Complex (MPA-C). The binding affinity between MPA and BSA was determined, yielding a Kd value of (12.0 ± 0.7) μM, and establishing a distance of 17 Å between the BSA and MPA molecules. The presence of MPA prompted protein aggregation, leading to the formation of MPA-C. The cytotoxicity of MPA-C and its ability to fight Junín virus (JUNV) were tested in A549 and Vero cell lines. It was found that treating infected cells with MPA-C decreased the JUNV yield and was more effective than free MPA in both cell line models for prolonged time treatments. Our results represent the first report of the antiviral activity of this type of BSA-MPA complex against JUNV, as assessed in cell culture model systems. MPA-C shows promise as a candidate for drug formulation against human pathogenic arenaviruses.
Topics: Humans; Serum Albumin, Bovine; Mycophenolic Acid; Molecular Docking Simulation; Virus Replication; Junin virus; Antiviral Agents
PubMed: 38513897
DOI: 10.1016/j.ijbiomac.2024.131023 -
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 -
Current Opinion in Gastroenterology May 2024The primary therapy of autoimmune hepatitis (AIH) has been established for over three decades. This review focuses on updates in the evaluation and management of... (Review)
Review
PURPOSE OF REVIEW
The primary therapy of autoimmune hepatitis (AIH) has been established for over three decades. This review focuses on updates in the evaluation and management of patients with AIH.
RECENT FINDINGS
The evaluation of patients has recently been updated to include more definitive screening for other autoimmune diseases, including thyroid disease and celiac disease. Antibody detection by ELISA, an easier and more commonly available method, has been incorporated into the latest iteration of the AIH scoring system. Corticosteroids and AZA remain the backbone of AIH treatment, but there is growing evidence for mycophenolate mofetil as both first-line and second-line therapy, and growing inquiry into calcineurin inhibitors. Noninvasive markers of liver disease have now been validated in AIH, with the strongest evidence for VCTE in patients with minimal hepatic inflammation.
SUMMARY
Recent research of alternative immunosuppressant therapies, noninvasive markers of fibrosis, and updated society guidelines, have improved our ability to evaluate, treat, and follow patients with AIH.
Topics: Humans; Hepatitis, Autoimmune; Immunosuppressive Agents; Mycophenolic Acid; Liver Diseases
PubMed: 38363233
DOI: 10.1097/MOG.0000000000001014 -
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 -
Frontiers in Microbiology 2023Mycophenolic acid (MPA)-induced colitis was still a severe side effect and challenge faced by solid transplant recipients. We aimed to explore the function and mechanism...
BACKGROUND
Mycophenolic acid (MPA)-induced colitis was still a severe side effect and challenge faced by solid transplant recipients. We aimed to explore the function and mechanism of probiotics in the treatment of MPA-induced colitis.
METHODS
In this study, 15 mice (C57BL/6) were randomly assigned into three groups: control (CNTL) group ( = 5), MPA group ( = 5) and the MPA + Probiotic group ( = 5). Bifid Triple Viable capsules, which were drugs for clinical use and consisted of , , and , were used in Probiotic group. Body weight change, stool scores, colon histopathology and morphology were used to evaluate the disease severity. The intestinal mucosal barrier function was assessed by measuring the expression level of secretory immunoglobulin A (sIgA), Zonula occludens-1 (ZO-1) and Occludin. Finally, 16S rDNA sequencing and bioinformatics analysis were performed on mice feces to compare the different intestinal microbial composition and diversity among three groups.
RESULTS
Compared with the CNTL group, the mice in MPA group showed a significantly decreased body weight, increased stool scores, shortened colon length and severe colon inflammation. However, probiotics treated MPA mice reversed the disease severity, indicating that probiotics ameliorated MPA-induced colitis in mice. Mechanistically, probiotics improved the intestinal barrier function by up-regulating the expression of sIgA, ZO-1 and Occludin. Moreover, MPA-induced colitis led to intestinal microbiota dysbiosis, including the change of / ratio, α- and β-diversity. But probiotic treated group showed mild change in these microbial features. Additionally, we found that was the most significantly different microbiota flora in MPA group.
CONCLUSION
Probiotics treatment ameliorated MPA-induced colitis by enhancing intestinal barrier function and improving intestinal microbiota dysbiosis. might be the dominant functional intestinal microflora and serve as the potential therapy target in MPA-induced colitis.
PubMed: 37533828
DOI: 10.3389/fmicb.2023.1153188 -
Pharmaceutics Sep 2023Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA...
BACKGROUND
Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA concentrations in peripheral blood mononuclear cells (PBMCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) and to evaluate and validate the performance of the methodology. A prospective follow-up cohort study was conducted to determine whether intracellular concentrations were associated with adverse outcomes in renal transplants.
METHODS
PBMCs were prepared using the Ficoll separation technique and purified with erythrocyte lysis. The cells were counted using Sysmex XN-3100 and then packaged and frozen according to a 50 µL volume containing 1.0 × 10 cells. TAC and MPA were extracted using MagnaBeads and quantified using an LC-MS/MS platform. The chromatography was run on a reversed-phase Waters Acquity UPLC BEH C18 column (1.7 µm, 50 mm × 2.1 mm) for gradient elution separation with a total run time of 4.5 min and a flow rate of 0.3 mL/min. Mobile phases A and B were water and methanol, respectively, each containing 2 mM ammonium acetate and 0.1% formic acid. Renal transplant recipients receiving TAC and MPA in combination were selected for clinical validation and divided into two groups: a stable group and an adverse outcome group. The concentrations were dynamically monitored at 5, 7, 14, and 21 days (D5, D7, D14, and D21) and 1, 2, 3, and 6 months (M1, M2, M3, and M6) after operation.
RESULTS
Method performance validation was performed according to Food and Drug Administration guidelines, showing high specificity and sensitivity. The TAC and MPA calibration curves were linear (r = 0.9988 and r = 0.9990, respectively). Both intra-day and inter-day imprecision and inaccuracy were less than 15%. Matrix effects and recoveries were satisfactory. The TAC and MPA concentrations in 304 "real" PBMC samples from 47 renal transplant recipients were within the calibration curve range (0.12 to 16.40 ng/mL and 0.20 to 4.72 ng/mL, respectively). There was a weak correlation between PBMC-C and WB-C ( < 0.05), but no correlation was found for MPA. The level of immunosuppressive intra-patient variation (IPV) was higher in PBMC at 77.47% (55.06, 97.76%) than in WB at 34.61% (21.90, 49.85%). During the dynamic change in C, PBMC-C was in a fluctuating state, and no stable period was found. PBMC-C did not show a significant difference between the stable and adverse outcome group, but the level of the adverse outcome group was generally higher than that of the stable group.
CONCLUSIONS
Compared with conventional therapeutic drug monitoring, the proposed rapid and sensitive method can provide more clinically reliable information on drug concentration at an active site, which has the potential to be applied to the clinical monitoring of intracellular immunosuppressive concentration in organ transplantation. However, the application of PBMC-C in adverse outcomes of renal transplant should be studied further.
PubMed: 37765287
DOI: 10.3390/pharmaceutics15092318 -
Clinical Journal of the American... Mar 2024In a phase 3 study of adults with active lupus nephritis, addition of voclosporin to mycophenolate mofetil (MMF) and low-dose glucocorticoids led to significant... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In a phase 3 study of adults with active lupus nephritis, addition of voclosporin to mycophenolate mofetil (MMF) and low-dose glucocorticoids led to significant improvements in the proportion of participants achieving complete and partial renal response as well as sustained reduction in proteinuria. This analysis examined the efficacy and safety of voclosporin in a subgroup of the phase 3 study with proliferative lupus nephritis and high levels of proteinuria.
METHODS
Participants were randomized to oral voclosporin (23.7 mg twice daily) or placebo for 12 months; all participants received MMF and low-dose glucocorticoids. This analysis includes participants with class III or IV (±class V) lupus nephritis and baseline urine protein-creatinine ratio (UPCR) ≥3 g/g. Efficacy end points included complete renal response (UPCR ≤0.5 g/g with stable eGFR, low-dose glucocorticoids, and no rescue medication), partial renal response (≥50% reduction from baseline UPCR), and UPCR over time. Safety outcomes were also assessed.
RESULTS
A total of 148 participants were in the voclosporin ( n =76) and control ( n =72) arms. At 12 months, 34% and 11% of participants in the voclosporin and control arms, respectively, achieved a complete renal response (odds ratio, 4.43; 95% confidence interval [CI], 1.78 to >9.99; P = 0.001). A partial renal response was achieved by 65% of the voclosporin arm and 51% of the control arm at 12 months (odds ratio, 1.60; 95% CI, 0.8 to 3.20; P = 0.18). More voclosporin- than control-treated participants achieved UPCR ≤0.5 g/g (51% versus 26%), and voclosporin-treated participants met this end point significantly earlier (hazard ratio, 2.07; 95% CI, 1.19 to 3.60; P = 0.01). The incidence of adverse events was similar between the arms; mean eGFR values remained stable and within normal range in both arms.
CONCLUSIONS
Addition of voclosporin to MMF and low-dose glucocorticoids resulted in a significantly higher proportion of participants with proliferative lupus nephritis achieving complete and partial renal responses as well as earlier reductions in proteinuria, with no evidence of worsening kidney function.
Topics: Adult; Humans; Lupus Nephritis; Immunosuppressive Agents; Cyclosporine; Mycophenolic Acid; Proteinuria; Glucocorticoids; Treatment Outcome
PubMed: 38110196
DOI: 10.2215/CJN.0000000000000297 -
Transplantation Jan 2024Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids.... (Review)
Review
Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.
Topics: Humans; Mycophenolic Acid; Abatacept; Immunosuppressive Agents; Tacrolimus; Calcineurin Inhibitors; Immunosuppression Therapy; Sirolimus; Graft Rejection
PubMed: 37309030
DOI: 10.1097/TP.0000000000004646