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Clinical Journal of the American... Sep 2020
Topics: Humans; Immunosuppressive Agents; Kidney Diseases; Mycophenolic Acid
PubMed: 32841154
DOI: 10.2215/CJN.11740720 -
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 -
The European Respiratory Journal Jun 2023
Topics: Humans; Rituximab; Mycophenolic Acid; Double-Blind Method; Immunosuppressive Agents; Lung Diseases, Interstitial; Enzyme Inhibitors
PubMed: 37290812
DOI: 10.1183/13993003.00614-2023 -
Current Rheumatology Reports Jun 2020Treatment of scleroderma in children is challenging since little is known about its pathogenesis. Herein, we review the most recent evidence regarding the treatment of... (Review)
Review
PURPOSE OF REVIEW
Treatment of scleroderma in children is challenging since little is known about its pathogenesis. Herein, we review the most recent evidence regarding the treatment of juvenile scleroderma.
RECENT FINDINGS
According to the recent recommendations for Pediatric Rheumatology in Europe (SHARE), systemic treatment in localized scleroderma is needed when there is a risk for disability, such as in generalized or pansclerotic morphea and progressive linear scleroderma. In juvenile systemic sclerosis, the introduction of the severity score, J4S, has standardized the assessment of the patients in the daily practice and allowed a more tailored therapeutic approach. Since, to date, no clinical trial is available in JSSc, due to its rarity, the treatment is based on adults' experience. The recent recommendations for juvenile scleroderma represent an important instrument to standardize the treatment approach, confirm the role of methotrexate, and open new windows for effective experimental treatments, such as mycophenolate mofetil and biological agents, for severe or refractory cases.
Topics: Child; Humans; Methotrexate; Mycophenolic Acid; Scleroderma, Localized; Scleroderma, Systemic
PubMed: 32591919
DOI: 10.1007/s11926-020-00910-x -
Nephrology, Dialysis, Transplantation :... May 2020There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term...
BACKGROUND
There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance.
METHODS
We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated.
RESULTS
C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0-12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level.
CONCLUSION
MPA C12 correlates with the AUC0-12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.
Topics: Adult; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mycophenolic Acid; Organic Anion Transporters; Pharmacogenetics; Polymorphism, Single Nucleotide; Prospective Studies; Tissue Distribution
PubMed: 30215770
DOI: 10.1093/ndt/gfy284 -
European Journal of Medicinal Chemistry Mar 2020Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both...
Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA. Both amino acid and peptide derivatives of MPA acted as inosine-5'-monophosphate dehydrogenaze (IMPDH) inhibitors.
Topics: Amino Acids; Cell Proliferation; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Immunosuppressive Agents; Jurkat Cells; Leukocytes, Mononuclear; Molecular Structure; Mycophenolic Acid; Peptide Fragments; Structure-Activity Relationship
PubMed: 32007665
DOI: 10.1016/j.ejmech.2020.112091 -
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 -
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 -
Pharmacogenomics Oct 2021Mycophenolic acid (MPA) is a common immunosuppressive drug for kidney transplantation patients, and is characterized by a narrow therapeutic index and significant... (Review)
Review
Mycophenolic acid (MPA) is a common immunosuppressive drug for kidney transplantation patients, and is characterized by a narrow therapeutic index and significant individual variability. UGTs are the main enzymes responsible for the metabolism of MPA. Although, many studies have focused on the relationship between polymorphisms and pharmacokinetics and adverse reactions of MPA, the conclusion are controversial. We reviewed the relevant literature and summarized the significant influences of polymorphisms, such as (rs1042597, rs17863762), (rs72551330, rs6714486, rs17868320, rs2741045, rs2741045) and (rs7438135, rs7439366, rs7662029), on the pharmacokinetics of MPA and its metabolites and adverse reactions. The review provides a reference for guiding the individualized administration of MPA and reducing adverse reactions to MPA.
Topics: Glucuronosyltransferase; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Transplant Recipients
PubMed: 34581204
DOI: 10.2217/pgs-2021-0087 -
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