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Journal of Gastrointestinal and Liver... Sep 2022Liver involvement in sarcoidosis may occur in up to 60% of all patients. As many patients experience only minor symptoms, a high number of undiagnosed cases must be...
BACKGROUND AND AIMS
Liver involvement in sarcoidosis may occur in up to 60% of all patients. As many patients experience only minor symptoms, a high number of undiagnosed cases must be assumed. In order to successfully identify patients with hepatic sarcoidosis, a throughout characterization of these patients and their course of disease is necessary.
METHODS
We collected 40 patients from four German centers to evaluate current treatment standards and course of disease. All of our patients underwent liver biopsy with histologically proven granulomatous hepatitis.
RESULTS
Detailed characterization of our patients showed an overall benign course of disease. Treatment was very diverse with glucocorticoids for 1 year in 55% (22/40), 5-10 years in 18% (7/40), and permanently in 18% (7/40). Other treatments included disease-modifying anti-rheumatic drugs (DMARDs), the conventional non-biological type in 53% of all patients (of these 81% received azathioprine, 46% metotrexate, 10% hydroxychloroquine, 10% mycophenolate mofetil and 10% cyclophosphamide and biologicals in 8%. Despite these very diverse treatments, patients generally showed slow progression of the disease. Two patients died. None of our patients received a liver transplantation.
CONCLUSIONS
Patients received diverse treatments and generally showed slow progression of the disease. Based on our experience, we proposed a diagnostic work up and surveillance strategy as a basis for future, prospective register studies.
Topics: Antirheumatic Agents; Azathioprine; Cyclophosphamide; Digestive System Diseases; Humans; Hydroxychloroquine; Mycophenolic Acid; Sarcoidosis
PubMed: 36112714
DOI: 10.15403/jgld-4122 -
British Journal of Clinical Pharmacology Apr 2021Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or... (Review)
Review
Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or pharmacodynamic modelling has been frequently used to characterize the fixed, random and covariate effects of MPA in adult patients. However, MPA population pharmacokinetic data in the paediatric population have not been systematically summarized. The objective of this narrative review was to provide an up-to-date critique of currently available paediatric MPA population pharmacokinetic models, with emphases on modelling techniques, pharmacological findings and clinical relevance. PubMed and EMBASE were searched from inception of database to May 2020, where a total of 11 studies have been identified representing kidney transplant (n = 4), liver transplant (n = 1), haematopoietic stem cell transplant (n = 1), idiopathic nephrotic syndrome (n = 2), systemic lupus erythematosus (n = 2), and a combined population consisted of kidney, liver and haematopoietic stem cell transplant patients (n = 1). Critical analyses were provided in the context of MPA absorption, distribution, metabolism, excretion and bioavailability in this paediatric database. Comparisons to adult patients were also provided. With respect to clinical utility, Bayesian estimation models (n = 6) with acceptable accuracy and precision for MPA exposure determination have also been identified and systematically evaluated. Overall, our analyses have identified unique features of MPA clinical pharmacology in the paediatric population, while recognizing several gaps that still warrant further investigations. This review can be used by pharmacologists and clinicians for improving MPA pharmacokinetic-pharmacodynamic modelling and patient care.
Topics: Adult; Area Under Curve; Bayes Theorem; Biological Availability; Child; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 33118201
DOI: 10.1111/bcp.14590 -
Scientific Reports Mar 2023Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively...
Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF's active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p < 0.05) affected expression of 351 genes in podocytes. Gene Ontology term enrichment analysis particularly clustered terms related to actin and inflammation-related cell death. Indeed, quantification of the actin cytoskeleton of BSA treated podocytes revealed a significant increase of thickness and number of actin filaments after treatment with MPA. Further, MPA significantly reduced TNFα and cycloheximide induced cell death. MPA has a substantial effect on the transcriptome of podocytes in vitro, particularly including functional clusters related to non-immune cell dependent mechanisms. This may provide a molecular basis for direct beneficial effects of MPA on the structural integrity and survival of podocytes under pro-inflammatory conditions.
Topics: Animals; Mice; Actin Cytoskeleton; Cell Survival; Cycloheximide; Mycophenolic Acid; Podocytes
PubMed: 36922538
DOI: 10.1038/s41598-023-31326-z -
American Journal of Transplantation :... Oct 2021Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment...
Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment tracheal transplantation. Narrow-band imaging and bronchoscopic biopsies demonstrate allograft vascularization and viable epithelial lining. The recipient was immunosuppressed with Tacrolimus, Mycophenolate mofetil, and corticosteroids. Six months after transplantation, the trachea is both functional and the patient is breathing without the need of a tracheostomy or stent.
Topics: Humans; Mycophenolic Acid; Plastic Surgery Procedures; Trachea; Transplantation, Heterotopic; Transplantation, Homologous
PubMed: 34236746
DOI: 10.1111/ajt.16752 -
Journal of Enzyme Inhibition and... Dec 2022The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as...
The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5'-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue () revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.
Topics: Amides; Amines; Anhydrides; Benzoxazoles; Enzyme Inhibitors; IMP Dehydrogenase; Immunosuppressive Agents; Inosine; Mycophenolic Acid; Solvents
PubMed: 36189734
DOI: 10.1080/14756366.2022.2127701 -
Clinical Journal of the American... Jul 2019
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Humans; Mycophenolic Acid; Recurrence; Remission Induction
PubMed: 31278112
DOI: 10.2215/CJN.06250519 -
Basic & Clinical Pharmacology &... Jul 2022Clinical and genetic influencing factors on free fraction of mycophenolic acid (MPA) have rarely been discussed. The present study investigated whether the clinical and...
Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants.
Clinical and genetic influencing factors on free fraction of mycophenolic acid (MPA) have rarely been discussed. The present study investigated whether the clinical and genetic factors could explain the variability in the pharmacokinetics of free MPA (fMPA) and total MPA (tMPA) in Chinese paediatric and adult renal transplant recipients. Twenty-eight paediatric and 31 adult patients were enrolled, and the concentrations of tMPA and fMPA were determined at 0 h (predose) and 0.5, 1, 1.5, 2, 4, 5, 8, 9, 10 and 12 h after mycophenolate mofetil administration. Genetic polymorphisms of UGTs (rs671448, rs1042597, rs2741049, rs62298861, rs7439366, rs12233719) and ABCC2 (rs717620) were simultaneously determined. The clinical and genetic data were analysed and reported. tMPA and fMPA concentrations adjusted for dose per body weight were consistently higher in adults than in paediatric patients. In the paediatric group, only albumin and time after transplantation correlated significantly with the MPA-free fraction variation, which could explain 32.4% of the variability. Besides, ABCC2 polymorphism, albumin and time after transplantation correlated significantly with the MPA-free fraction variation in adults, which could explain 56.9% of the variability. The influencing factors in the paediatric group are different from those in adults, which may be due to age-related transporter expression.
Topics: Adult; Albumins; Area Under Curve; Child; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Multidrug Resistance-Associated Protein 2; Mycophenolic Acid
PubMed: 35567285
DOI: 10.1111/bcpt.13743 -
Kidney International Dec 2021The most frequently used immunosuppressive treatment in kidney transplant recipients is the combination therapy of a calcineurin inhibitor (CNI) and mycophenolate... (Review)
Review
The most frequently used immunosuppressive treatment in kidney transplant recipients is the combination therapy of a calcineurin inhibitor (CNI) and mycophenolate mofetil, with or without corticosteroids. Cyclosporine and tacrolimus are the 2 CNIs registered for this indication. Also, in the treatment of glomerular diseases, CNIs and mycophenolate are being used on a worldwide scale, either alone or as combined treatment. In January 2021, the US Food and Drug Administration approved voclosporin, a novel CNI, for the treatment of adult patients with active lupus nephritis. There is a clinically relevant drug-drug interaction between cyclosporine and mycophenolate. As a result of cyclosporine-induced inhibition of the enterohepatic recirculation of mycophenolate, the mycophenolic acid area under the curve is significantly lower (40%) in case of cyclosporine coadministration compared with cotreatment with either tacrolimus or voclosporin (or no CNI cotreatment). The aim of this mini review is to summarize this potential drug-drug interaction and explain how cyclosporine affects the pharmacokinetics of mycophenolate. The optimal dose of mycophenolate mofetil is likely to depend on the CNI with which it is coadministered. Furthermore, clinical implications are discussed, including the potential emergence of mycophenolic acid-related adverse effects after discontinuation of cyclosporine cotreatment.
Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Tacrolimus
PubMed: 34284043
DOI: 10.1016/j.kint.2021.06.036 -
Journal of Neurology Jun 2023A variety of novel monoclonal antibodies and immunosuppressant have been proved effective in treating Neuromyelitis Optica Spectrum Disorder (NMOSD). This network... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A variety of novel monoclonal antibodies and immunosuppressant have been proved effective in treating Neuromyelitis Optica Spectrum Disorder (NMOSD). This network meta-analysis compared and ranked the efficacy and tolerability of currently used monoclonal antibodies and immunosuppressive agents in NMOSD.
METHODS
Electronic database including PubMed, Embase and Cochrane Library were searched for relevant studies evaluating monoclonal antibodies and immunosuppressants in patients with NMOSD. The primary outcome measures were annualized relapse rate (ARR), relapse rate, the Expanded Disability Status Scale (EDSS) score, and total adverse events (AEs).
RESULTS
We identified 25 studies with 2919 patients in our meta-analysis. For the primary outcome, rituximab (RTX) (SUCRA: 0.02) ranked first in reduction ARR with a significant difference compared with azathioprine (AZA) (MD - 0.34, 95% CrI - 0.55 to - 0.12) and mycophenolate mofetil (MMF) (MD -0.38, 95% CrI - 0.63 to - 0.14). Tocilizumab (SUCRA: 0.05) ranked first in relapse rate, which was superior to satralizumab (lnOR - 25.4, 95% CrI - 74.4 to - 2.49) and inebilizumab (lnOR - 24.86, 95% CrI - 73.75 to - 1.93). MMF (SUCRA: 0.27) had the fewest AEs followed by RTX (SUCRA: 0.35), both of which showed a significant difference compared with AZA and corticosteroids (MMF vs AZA: lnOR - 1.58, 95% CrI - 2.48 to - 0.68; MMF vs corticosteroids: lnOR - 1.34, 95% CrI - 2.3 to - 0.37) (RTX vs AZA: lnOR - 1.34, 95% CrI - 0.37 to - 2.3; RTX vs corticosteroids: lnOR - 2.52, 95% CrI - 0.32 to - 4.86). In EDSS score, no statistical difference was found between different interventions.
CONCLUSION
RTX and tocilizumab showed better efficacy than traditional immunosuppressants in reducing relapse. For safety, MMF and RTX had fewer AEs. However, studies with larger sample size on newly developed monoclonal antibodies are warranted in the future.
Topics: Humans; Immunosuppressive Agents; Antibodies, Monoclonal; Neuromyelitis Optica; Network Meta-Analysis; Bayes Theorem; Treatment Outcome; Azathioprine; Mycophenolic Acid; Rituximab; Recurrence; Adrenal Cortex Hormones
PubMed: 36884069
DOI: 10.1007/s00415-023-11641-1 -
Clinical Transplantation Jul 2021Diarrhea is a well-known side effect of mycophenolic acid (MPA) use in kidney transplant recipients (KTRs). It is unknown whether self-reported diarrhea using the...
BACKGROUND
Diarrhea is a well-known side effect of mycophenolic acid (MPA) use in kidney transplant recipients (KTRs). It is unknown whether self-reported diarrhea using the Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) corresponds to stool water content and how both relate to MPA usage.
METHODS
MTSOSD-59R questionnaires filled out by 700 KTRs from the TransplantLines Biobank and Cohort Study (NCT03272841) were analyzed and compared with stool water content. Stool samples (N = 345) were freeze-dried, and a water content ≥80% was considered diarrhea.
RESULTS
Self-perceived diarrhea was reported by 46%, while stool water content ≥80% was present in 23% of KTRs. MPA use was not associated with self-perceived diarrhea (odds ratio(OR) 1.32; 95% confidence interval(CI), 0.87-1.99, p = .2), while it was associated with stool water content ≥80% (OR 2.88; 95%CI, 1.41-5.89, p = .004), independent of potential confounders. Adjustment for prior MPA discontinuation because of severe diarrhea, uncovered an association between MPA use and self-perceived diarrhea (OR 1.80; 95%CI, 1.13-2.89, p = .01).
CONCLUSIONS
These results suggest that reporting bias could add to the discrepancy between both methods for diarrhea assessment. We recommend use of objective biomarkers or more extensive questionnaires which assess information on stool frequency and stool consistency, to investigate post-transplantation diarrhea.
Topics: Cohort Studies; Diarrhea; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 33882147
DOI: 10.1111/ctr.14321