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Nefrologia : Publicacion Oficial de La... 2011
Topics: Antigens, Viral; Colitis; Colonoscopy; Cytomegalovirus; Cytomegalovirus Infections; Diagnosis, Differential; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Mycophenolic Acid; Nocardia Infections; Opportunistic Infections; Pneumatosis Cystoides Intestinalis; Respiratory Tract Infections
PubMed: 21270929
DOI: 10.3265/Nefrologia.pre2010.Oct.10678 -
Current Opinion in Gastroenterology May 2011Autoimmune hepatitis (AIH) is a chronic, progressive hepatitis of uncertain cause which has fluctuating activity characterized by periods of flares and remissions.... (Review)
Review
PURPOSE OF REVIEW
Autoimmune hepatitis (AIH) is a chronic, progressive hepatitis of uncertain cause which has fluctuating activity characterized by periods of flares and remissions. Initial placebo-controlled trials carried out in the 1970s demonstrated that immunosuppression with steroids was extremely effective in reducing flares and progression of disease. The late 1980s-1990s could be described as the 'Dark Ages' of AIH treatment research. Very few clinical studies were performed during this time, although it became increasingly apparent that not all patients tolerated or responded to traditional immunosuppression, and that not all patients were easy to diagnose because of overlapping features with other autoimmune conditions. Fortunately, clinical research in the treatment of AIH has experienced a renaissance in the 21st century.
RECENT FINDINGS
This review highlights some of the more important recent discoveries, including the creation of the clinically useful short form of the autoimmune hepatitis diagnostic scoring system; accumulation of data supporting the use of mycophenolate and tacrolimus as second-line treatment; and the recent completion of the largest, double-blind, placebo-controlled trial of AIH treatment to date, comparing budesonide to prednisone.
SUMMARY
These new findings are pertinent to the everyday clinical management of patients with AIH.
Topics: Azathioprine; Budesonide; Drug Hypersensitivity; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Purine-Pyrimidine Metabolism, Inborn Errors; Tacrolimus
PubMed: 21451411
DOI: 10.1097/MOG.0b013e3283457ce0 -
The Cochrane Database of Systematic... Feb 2014Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system and a leading cause of disability in young and middle-aged adults. Mycophenolate... (Review)
Review
BACKGROUND
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system and a leading cause of disability in young and middle-aged adults. Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been used for the prevention of allograft rejection after renal, cardiac, or liver transplant and in patients with autoimmune diseases such as active relapsing-remitting (RRMS) and progressive MS.
OBJECTIVES
To assess the efficacy and safety of MMF for preventing disease activity in patients with RRMS.
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (January 14, 2013). We searched three Chinese databases (January 2013) and checked reference lists of identified trials. We contacted authors and pharmaceutical companies to ask for additional information. We applied no language restrictions.
SELECTION CRITERIA
We included randomized controlled trials with a follow-up of at least 12 months that compared MMF as monotherapy or in combination with other treatments versus placebo, another drug, or the same cointervention as the treated group.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the trials for inclusion, assessed trial quality, and extracted data.
MAIN RESULTS
One included study involving 26 participants with new-onset RRMS investigated the efficacy and safety of MMF (13 participants) versus placebo in interferon β-1a-treated participants. It was assessed to be at high risk of bias, and had a small numbers of participants receiving treatment with short-term duration. There was inadequate information provided by the study to determine the effect of MMF in reducing relapses, preventing disability progression, or developing new T2- or new gadolinium (Gd)-enhanced lesions on magnetic resonance imaging (MRI) after a 12-month follow-up period. No data were available at 24 months. No serious adverse effects were reported. All participants in the MMF-treated group suffered from gastrointestinal upset, but none of them discontinued therapy as a result.
AUTHORS' CONCLUSIONS
The evidence we found from one small study was insufficient to determine the effects of MMF as an add-on therapy for interferon β-1a in new-onset RRMS participants.
Topics: Adjuvants, Immunologic; Humans; Immunosuppressive Agents; Interferon beta-1a; Interferon-beta; Multiple Sclerosis, Relapsing-Remitting; Mycophenolic Acid; Randomized Controlled Trials as Topic
PubMed: 24505016
DOI: 10.1002/14651858.CD010242.pub2 -
The Cochrane Database of Systematic... Mar 2015Multifocal motor neuropathy (MMN) is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction... (Review)
Review
BACKGROUND
Multifocal motor neuropathy (MMN) is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin (IVIg) is beneficial but the role of immunosuppressive agents is uncertain. This is an update of a review first published in 2002 and previously updated in 2003, 2005, 2008 and 2011.
OBJECTIVES
To assess the effects of immunosuppressive agents for the treatment of multifocal motor neuropathy.
SEARCH METHODS
On 22 September 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE and LILACS for trials of MMN. We also searched two trials registers for ongoing studies.
SELECTION CRITERIA
We planned to include randomised controlled trials (RCTs) and quasi-RCTs. We considered prospective and retrospective case series and case reports in the Discussion.
DATA COLLECTION AND ANALYSIS
Two review authors searched the titles and abstracts of the articles identified and extracted the data independently.
MAIN RESULTS
Only one RCT of an immunosuppressive or immunomodulatory agent has been performed in MMN. This study randomised 28 participants and showed that mycophenolate mofetil, when used with IVIg, did not significantly improve strength, function or reduce the need for IVIg. No serious adverse events were observed. The study was deemed at low risk of bias. We summarised the results of retrospective and prospective case series in the discussion.
AUTHORS' CONCLUSIONS
According to moderate quality evidence, mycophenolate mofetil did not produce significant benefit in terms of reducing need for IVIg or improving muscle strength in MMN. Trials of other immunosuppressants should be undertaken.
Topics: Drug Therapy, Combination; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Motor Neuron Disease; Muscle Strength; Mycophenolic Acid; Polyneuropathies; Randomized Controlled Trials as Topic
PubMed: 25739040
DOI: 10.1002/14651858.CD003217.pub5 -
Clinical Pharmacokinetics May 2016Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and... (Review)
Review
Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.
Topics: Animals; Antilymphocyte Serum; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pharmacogenetics; Sirolimus
PubMed: 26620047
DOI: 10.1007/s40262-015-0340-9 -
American Journal of Transplantation :... Jun 2013The mycophenolic acid (MPA) preparations are one of the most commonly used immunosuppressants in the United States. However, these agents carry a black box warning... (Review)
Review
The mycophenolic acid (MPA) preparations are one of the most commonly used immunosuppressants in the United States. However, these agents carry a black box warning regarding their use during pregnancy due to an association with increased risk of miscarriage and congenital defects. To ensure that the benefits of MPA outweigh the risks, the Food and Drug Administration (FDA) required all manufacturers of MPA products to propose risk evaluation and mitigation strategies (REMS). Four years after initially calling for proposals, the FDA approved a single shared REMS system in September 2012. The elements of the MPA REMS include a medication guide and elements to assure safe use (ETASU). The medication guide, which was previously FDA-approved in 2008, should continue to be distributed to patients, and the ETASU requires physicians to complete training and obtain patient signatures on the "Patient-Prescriber Acknowledgement Form." A single, national, voluntary pregnancy registry is available, and pregnant patients should be encouraged to participate. Although the impact of the MPA REMS on clinical practice is not clear, it is a step toward increasing the understanding of fetal risks with MPA products among patients and possibly practitioners.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Female; Fetal Diseases; Fetus; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Mycophenolic Acid; Organ Transplantation; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Risk Management; United States
PubMed: 23617812
DOI: 10.1111/ajt.12238 -
Blood Reviews Dec 2000The increasing number of allogeneic stem cell transplants, particularly those involving donors other than HLA-identical siblings, has made the management of acute and... (Review)
Review
The increasing number of allogeneic stem cell transplants, particularly those involving donors other than HLA-identical siblings, has made the management of acute and chronic graft-versus-host disease (GVHD) a continuing problem for transplant experts. There have been improvements in the prevention of acute GVHD with cyclosporine- and FK506-based combination therapies, as well as lymphocyte depletion. However, fewer than 50% of patients have durable improvement after initial treatment. FK506 and mycophenolate mofetil (MMF) are promising salvage therapies in steroid-resistant GVHD, as are the anti-cytokine antibodies and the purine nucleoside analog, pentostatin. The incidence of chronic GVHD has unfortunately not decreased, despite advances in treatment of acute GVHD. Treatment of chronic GVHD involves treatment of the underlying immunologic process and supportive therapies. Initial therapy has tended to be cyclosporine and prednisone. Refractory patients have hope with combination MMF and FK506, etretinate, plaquenil, and nonpharmacologic approaches, such as PUVA. Supportive care is an integral part of chronic GVHD management with emphasis on infection control and symptom control. Death in chronic GVHD is still largely attributable to infection. The progress in therapies for GVHD has been encouraging, but the future of GVHD management lies in a better understanding of its pathogenesis.
Topics: Acute Disease; Chronic Disease; Drug Therapy, Combination; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous
PubMed: 11124107
DOI: 10.1054/blre.2000.0137 -
British Journal of Clinical Pharmacology Mar 2005The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of...
AIMS
The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients.
METHODS
Forty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin (n = 32) or tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant.
RESULTS
Kinetic variability of free and total mycophenolic acid and its glucuronide was greater in patients on cyclosporin (12- to 18-fold variation) than on tacrolimus (four- to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC0-6 (r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively (r > 0.46), whilst albumin correlated negatively (r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower albumin and 4 +/- 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4).
CONCLUSIONS
The marked variability in mycophenolic acid/glucuronide pharmacokinetics occurring early post-transplant during the current study was greater in cyclosporin (12-18-fold) than in tacrolimus (four- to fivefold) treated patients. Concomitant cyclosporin was associated with total mycophenolic acid concentrations approximately half that of tacrolimus. Patients with marked renal impairment had the highest free fractions reported to date. The exposure to unbound mycophenolic acid was significantly related to infections and haematological toxicity.
Topics: Adult; Aged; Antibiotics, Antineoplastic; Area Under Curve; Chromatography, High Pressure Liquid; Cyclosporine; Female; Glucuronates; Glucuronides; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Period; Protein Binding; Tacrolimus
PubMed: 15752372
DOI: 10.1111/j.1365-2125.2004.02235.x -
The Journal of Biological Chemistry Oct 2022Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies...
Adipocyte browning is one of the potential strategies for the prevention of obesity-related metabolic syndromes, but it is a complex process. Although previous studies make it increasingly clear that several transcription factors and enzymes are essential to induce browning, it is unclear what dynamic and metabolic changes occur in induction of browning. Here, we analyzed the effect of a beta-adrenergic receptor agonist (CL316243, accelerator of browning) on metabolic change in mice adipose tissue and plasma using metabolome analysis and speculated that browning is regulated partly by inosine 5'-monophosphate (IMP) metabolism. To test this hypothesis, we investigated whether Ucp-1, a functional marker of browning, mRNA expression is influenced by IMP metabolism using immortalized adipocytes. Our study showed that mycophenolic acid, an IMP dehydrogenase inhibitor, increases the mRNA expression of Ucp-1 in immortalized adipocytes. Furthermore, we performed a single administration of mycophenolate mofetil, a prodrug of mycophenolic acid, to mice and demonstrated that mycophenolate mofetil induces adipocyte browning and miniaturization of adipocyte size, leading to adipose tissue weight loss. These findings showed that IMP metabolism has a significant effect on adipocyte browning, suggesting that the regulator of IMP metabolism has the potential to prevent obesity.
Topics: Animals; Mice; Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Inosine Monophosphate; Metabolomics; Mice, Inbred C57BL; Mycophenolic Acid; Obesity; RNA, Messenger
PubMed: 36063990
DOI: 10.1016/j.jbc.2022.102456 -
American Journal of Veterinary Research Oct 2018OBJECTIVE To evaluate the plasma disposition of mycophenolic acid (MPA) and its derivatives MPA glucuronide and MPA glucoside after twice-daily infusions of...
OBJECTIVE To evaluate the plasma disposition of mycophenolic acid (MPA) and its derivatives MPA glucuronide and MPA glucoside after twice-daily infusions of mycophenolate mofetil (MMF) in healthy cats for 3 days and to assess the effect of MMF administration on peripheral blood mononuclear cell (PBMC) counts and CD4-to-CD8 ratios. ANIMALS 5 healthy adult cats. PROCEDURES MMF was administered to each cat (10 mg/kg, IV, q 12 h for 3 days). Each dose of MMF was diluted with 5% dextrose in water and then administered over a 2-hour period with a syringe pump. Blood samples were collected for analysis. A chromatographic method was used to quantitate concentrations of MPA and its metabolites. Effects of MMF on PBMC counts and CD4-to-CD8 ratios were assessed by use of flow cytometry. RESULTS All cats biotransformed MMF into MPA. The MPA area under the plasma concentration-time curve from 0 to 14 hours ranged from 14.6 to 37.6 mg·h/L and from 14.4 to 22.3 mg·h/L after the first and last infusion, respectively. Total number of PBMCs was reduced in 4 of 5 cats (mean ± SD reduction, 25.9 ± 15.8% and 26.7 ± 19.3%) at 24 and 48 hours after the end of the first infusion of MMF, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Plasma disposition of MPA after twice-daily IV infusions for 3 days was variable in all cats. There were no remarkable changes in PBMC counts and CD4-to-CD8 ratios.
Topics: Animals; Area Under Curve; Cats; Drug Administration Schedule; Female; Flow Cytometry; Glucuronides; Immunosuppressive Agents; Infusions, Intravenous; Leukocytes, Mononuclear; Male; Mycophenolic Acid
PubMed: 30256137
DOI: 10.2460/ajvr.79.10.1093