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Iranian Journal of Kidney Diseases Mar 2012Chronic, progressive, and irreversible loss of a transplanted kidney function, previously named chronic allograft nephropathy, is the leading cause of chronic allograft... (Review)
Review
Chronic, progressive, and irreversible loss of a transplanted kidney function, previously named chronic allograft nephropathy, is the leading cause of chronic allograft failure among kidney transplant recipients. Chronic allograft dysfunction (CAD) is a multifactorial process associated with progressive interstitial fibrosis and tubular atrophy. Current Data confirms that an additive series of time-dependent immunological factors such as acute and chronic antibody- and/or cell-mediated rejection and nonimmunological factors are involved in development of interstitial fibrosis and tubular atrophy as the fundamental parts of CAD. The use of calcineurin inhibitors has produced a major impact on achieving successful organ transplantation; however, although this assumption has been doubted recently, calcineurin inhibitors are deemed to be associated with nephrotoxicity and subsequent interstitial fibrosis, tubular atrophy, and kidney dysfunction. The early fibrotic changes are due to implantation stress, T-cell-mediated rejection, and infection; however, usually they do not lead to progressive fibrosis and allograft dysfunction per se. In the setting of CAD, many factors occurring lately after 1 year, such as chronic antibody-mediated rejection, recurrent or de novo glomerulonephritis, and nonadherent adequately address the existence of ongoing injuries and progression to fibrosis. Identification of patients who are at risk, close clinical monitoring, and optimization and individualization of their maintenance immunosuppressive regimen are among the means that could help us to improve the long-term outcome of kidney transplantation.
Topics: Calcineurin Inhibitors; Chronic Disease; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Primary Graft Dysfunction; Tacrolimus; Transplantation, Homologous
PubMed: 22388603
DOI: No ID Found -
American Journal of Transplantation :... Jul 2009The concentration-effect relationship for mycophenolic acid (MPA), and the high variability in MPA concentrations in patients on standard dose mycophenolate mofetil... (Review)
Review
The concentration-effect relationship for mycophenolic acid (MPA), and the high variability in MPA concentrations in patients on standard dose mycophenolate mofetil (MMF) therapy, for some centers has provided enough evidence to implement therapeutic drug monitoring (TDM) for MMF in daily practice. Two randomized trials Adaption de Posologie du MMF en Greffe Renale (APOMYGRE) and fixed-dose versus concentration controlled (FDCC) investigated the added benefit of TDM for MMF in renal transplant recipients. The APOMYGRE study showed a significant reduction in the incidence of acute rejection in concentration-controlled patients, while the FDCC study had a negative outcome, despite a similar study design. Although it was expected that these prospective trials would give the final answer to the question of whether or not TDM for MMF would be of benefit, it seems that the studies have not had much impact on patient management. Several trials have shown the importance of early adequate exposure to MPA in the first week after transplantation. As it will be hard to improve MPA exposure with TDM, this early, ongoing study now investigates the use of an increased starting dose. The increased starting dose will avoid underexposure to MPA in higher proportions of patients shortly after transplantation but may result in more toxicity in patients with MPA exposures exceeding the upper threshold of the therapeutic window.
Topics: Drug Monitoring; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Mycophenolic Acid; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 19519824
DOI: 10.1111/j.1600-6143.2009.02678.x -
ACS Applied Bio Materials Oct 2023Exosomes are natural endogenous extracellular vesicles with phospholipid-based bilayer membrane structures. Due to their unique protein-decorated membrane properties,...
Exosomes are natural endogenous extracellular vesicles with phospholipid-based bilayer membrane structures. Due to their unique protein-decorated membrane properties, exosomes have been regarded as promising drug carriers to deliver small molecules and genes. A number of approaches have been developed for exosome-based drug loading. However, the drug loading capability of exosomes is inconsistent, and the effects of loading methods on the therapeutic efficacy have not been investigated in detail. Herein, we developed anti-inflammatory drug-loaded exosomes as an immunomodulatory nanoplatform. Naïve macrophage-derived exosomes (Mϕ-EVs) were loaded with the anti-inflammatory drug mycophenolic acid (MPA) by three major loading methods. Loading into exosomes significantly enhanced anti-inflammatory and antioxidation effects of MPA in vitro compared to free drugs. These findings provide a scientific basis for developing naïve macrophage-secreted exosomes as drug carriers for immunotherapy.
Topics: Mycophenolic Acid; Myoblasts, Cardiac; Extracellular Vesicles; Drug Carriers; Macrophages; Anti-Inflammatory Agents
PubMed: 37774367
DOI: 10.1021/acsabm.3c00475 -
Anais Da Academia Brasileira de Ciencias 2013The chemical reactions carried out by microorganisms have been used as a tool in modern chemistry. This paper reports the production of mycophenolic acid and a new...
The chemical reactions carried out by microorganisms have been used as a tool in modern chemistry. This paper reports the production of mycophenolic acid and a new phthalide by the endophytic fungus Penicillium crustosum obtained from coffee seeds. The fungus was cultivated in a liquid medium for a period of seven days and after that the culture medium was divided into four treatments: A, B, C and D, to which different organic substances were added. Treatment A was maintained as the control to evaluate the occurrence of biotransformation. Organic acids were added to the culture media of treatments B (ferulic and quinic acids) and C [cinnamic and 3,4-(methylenedioxy) cinnamic acids], and caffeine was added in the treatment D. All these organic compounds were dissolved in DMSO, and the fermentation was maintained for more 13 days, totalizing 20 days. Mycophenolic acid was isolated from the culture with no added acids (treatment A). Mycophenolic acid and a new phthalide, 5-hydroxy-7-methoxy-4-methylphthalide were isolated from treatments B and C, and mycophenolic acid and caffeine (added to the culture medium) were isolated from treatment D. The structures were determined by NMR techniques and confirmed by MS and MS/MS techniques.
Topics: Benzofurans; Biotransformation; Coffee; Culture Media; Magnetic Resonance Spectroscopy; Mycophenolic Acid; Penicillium; Tandem Mass Spectrometry; Time Factors
PubMed: 23780307
DOI: 10.1590/S0001-37652013005000024 -
Journal of the American Academy of... Sep 1997Oral mycophenolic acid (MPA) therapy has been investigated in the treatment of moderate to severe psoriasis since the early 1970s and has been found to be both safe and... (Review)
Review
Oral mycophenolic acid (MPA) therapy has been investigated in the treatment of moderate to severe psoriasis since the early 1970s and has been found to be both safe and effective. By inhibiting de novo purine biosynthesis, it functions as an antifungal, antibacterial, antiviral, and immunosuppressive agent. The recent availability of mycophenolate mofetil (MMF), a morpholinoester of MPA, has created renewed interest in the antipsoriatic properties of MPA. MMF is currently indicated for the prevention of organ rejection in transplant recipients and is used concomitantly with cyclosporine and corticosteroids. This review focuses on the pharmacology of MPA and MMF, studies of MPA in the treatment of psoriasis, and therapy with MMF. There is a potential application of MMF in the treatment of severe psoriasis and other inflammatory dermatoses, as well as topical MPA for the treatment of psoriasis.
Topics: Humans; Immunosuppressive Agents; Mycophenolic Acid; Psoriasis; Skin Diseases
PubMed: 9308561
DOI: 10.1016/s0190-9622(97)70147-6 -
Biomedical Chromatography : BMC Sep 2015Monitoring of pharmacodynamics in addition to pharmacokinetics is one of strategies to individualize mycophenolate mofetil therapy. The purpose of this study was to...
Monitoring of pharmacodynamics in addition to pharmacokinetics is one of strategies to individualize mycophenolate mofetil therapy. The purpose of this study was to develop sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for evaluation of the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA). Concentrations of mycophenolic acid glucuronide (MPAG), mycophenolic acid acyl-glucuronide, as well as unbound MPA and MPAG, were determined, and inosine-5'-monophosphate dehydrogenase activity was calculated by measuring concentrations of produced xanthosine-5'-monophosphate (XMP) and intracellular adenosine-5'-monophosphate after incubation of peripheral blood mononuclear cell (PBMC) lysates. A metal-free Mastro(TM) column and two gradient patterns were used to improve the quantification limit of XMP to 0.1 μM. In the clinical MPA concentration range, the linearity of the calibration curve, inter- and intra-day precision and accuracy satisfied the relevant US Food and Drug Administration guidelines. The MPA concentrations in hematopoietic stem cell transplant (HSCT) patients determined by the enzyme assay and the present LC-MS/MS method showed a good correlation (r(2) = 0.95, p < 0.001). In this study, we report sensitive and validated LC-MS/MS methods to evaluate the pharmacokinetics and pharmacodynamics of MPA, which are sufficiently sensitive to assess small quantities of PBMC lysates collected shortly after HSCT.
Topics: Chromatography, High Pressure Liquid; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Sensitivity and Specificity; Tandem Mass Spectrometry
PubMed: 25624121
DOI: 10.1002/bmc.3423 -
Acta Pharmacologica Sinica Nov 2017Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester...
Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group). Population pharmacokinetic data analysis was performed using the NONMEM software. The pharmacokinetics of MPA was best described by a two-compartment model with a first-order absorption rate with no lag time. Body weight and serum creatinine level were positively correlated with apparent clearance (CL/F). The polymorphism in uridine diphosphate glucuronosyltransferase gene, UGT2B7, significantly explained the interindividual variability in the initial volume of distribution (V/F). The estimated population parameters (and interindividual variability) were CL/F 18.3 L/h (34.2%) and V/F 27.9 L (21.3%). The interoccasion variability was 13.7%. These population pharmacokinetic data have significant clinical value for the individualization of MMF therapy in Chinese adult renal transplant patients.
Topics: Administration, Oral; Adolescent; Adult; Aged; Asian People; Bayes Theorem; China; Female; Glucuronosyltransferase; Humans; Immunosuppressive Agents; Intestinal Absorption; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Mycophenolic Acid; Pharmacogenomic Variants; Retrospective Studies; Young Adult
PubMed: 28836585
DOI: 10.1038/aps.2017.115 -
American Journal of Transplantation :... Jun 2004Sirolimus (SRL) is a macrolide immunosuppressant that has gained widespread use in organ transplantation. Its full spectrum of side-effects is yet to be defined. We...
Sirolimus (SRL) is a macrolide immunosuppressant that has gained widespread use in organ transplantation. Its full spectrum of side-effects is yet to be defined. We describe herein three cases of SRL-induced angioedema (AE) in African-American (AA) primary renal allograft recipients who received SRL in combination with mycophenolate mofetil and steroids. In two cases, AE manifested after SRL was restarted after a period of discontinuation. The third case presented upon initial exposure to the drug. None of the patients was receiving any drug that has been previously associated with AE. Complete resolution occurred only after SRL was withdrawn. AE has not recurred in any of the patients during a follow-up period of up to 21 months. We conclude that AE is a previously unrecognized adverse event associated with SRL use. Close monitoring for this side-effect, especially in AA patients, is warranted.
Topics: Black or African American; Angioedema; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Retreatment; Sirolimus; Transplantation, Homologous
PubMed: 15147436
DOI: 10.1111/j.1600-6143.2004.00429.x -
Therapeutic Drug Monitoring Dec 2012Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic...
BACKGROUND
Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy.
METHODS
MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C.
RESULTS
Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05).
CONCLUSION
Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.
Topics: Adolescent; Biotransformation; Child; Child, Preschool; Cohort Studies; Drug Resistance; Female; Genetic Association Studies; Glucuronosyltransferase; Heterozygote; Humans; Kidney Transplantation; Male; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mycophenolic Acid; Polymorphism, Single Nucleotide; Prodrugs; Prospective Studies; UDP-Glucuronosyltransferase 1A9; United States; Young Adult
PubMed: 23131697
DOI: 10.1097/FTD.0b013e3182708f84 -
Antimicrobial Agents and Chemotherapy Sep 1975The final step in the biosynthesis of mycophenolic acid involves the transfer of a methyl group from S-adenosylmethionine to demethylmycophenolic acid. The enzyme,...
The final step in the biosynthesis of mycophenolic acid involves the transfer of a methyl group from S-adenosylmethionine to demethylmycophenolic acid. The enzyme, S-adenosylmethionine:demethylmycophenolic acid O-methyltransferase, was isolated from Penicillium stoloniferum and purified 2,700-fold by ammonium sulfate fractionation and diethylaminoethyl-cellulose and Sephadex G-200 chromatography. Maximum enzyme activity was achieved at pH 7.5 and a temperature of 27 to 28 C. The apparent K(m) for demethylmycophenolic acid was 3.1 x 10(-6) M. The enzyme preparation was 50% inactivated when exposed to 33 C for 15 min. Mycophenolic acid, homocystine, S-adenosyl-homocysteine, ethanol, and Mg(2+) inhibited the methyltransferase. This enzyme appears to be subject to end product inhibition which may regulate the synthesis of mycophenolic acid. The methyltransferase activity was highest during the early phases of the fermentation.
Topics: Ammonium Sulfate; Hydrogen-Ion Concentration; Kinetics; Methyltransferases; Mycophenolic Acid; Penicillium; S-Adenosylmethionine; Temperature
PubMed: 241289
DOI: 10.1128/AAC.8.3.321