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Sample records for mycophenolate mofetil treatment

  1. Mycophenolate mofetil as an alternative treatment for autoimmune hepatitis

    PubMed Central

    Park, Seung Woon; Um, Soon Ho; Lee, Han Ah; Kim, Sang Hyun; Sim, Yura; Yim, Sun Young; Seo, Yeon Seok; Ryu, Ho Sang

    2016-01-01

    Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease characterized by hepatocellular inflammation, necrosis, and fibrosis, which can progress to cirrhosis and fulminant hepatic failure. The standard treatment for AIH includes corticosteroids alone or in combination with azathioprine. Although most patients achieve remission using the standard regimen, some patients do not respond due to either drug intolerance or refractory disease; in such cases alternative immunosuppressive agents should be explored. The second-line therapies are cyclophilin inhibitors such as cyclosporine A or tacrolimus, and nowadays mycophenolate mofetil (MMF) is widely used if azathioprine-based therapies are not tolerated. Although these are recommended as an alternative to the first-line regimen, there is insufficient evidence for the efficacy of second-line therapies, with the evidence based mainly on expert opinion. Therefore, we report an AIH patient receiving the standard regimen in whom remission did not occur due to side effects to azathioprine, but was successfully treated with MMF in combination with corticosteroids as an alternative to the standard regimen. PMID:27246353

  2. Mycophenolate mofetil versus azathioprine for maintenance treatment of lupus nephritis.

    PubMed

    Kaballo, Babikir G; Ahmed, Ahmed Elias; Nur, Musa Mohammed; Khalid, Ismail Osman; Abu-Aisha, Hasan

    2016-01-01

    To compare the efficacy of mycophenolate mofetil (MMF) with that of azathioprine (AZA) drugs in the maintenance therapy of lupus nephritis (LN) patients, we studied 81 Sudanese patients with LN (32 in Class III, 34 in Class IV, and 15 in combined Class V + IV of the ISN/RPS 2003 Classification). All patients received induction therapy consisting of monthly intravenous pulse doses of cyclophosphamide (CYC) (500 mg/m 2 of body-surface area) for six months, plus three consecutive pulses of intravenous methylprednisolone 15 mg/kg/day of body weight (maximum 500 mg). Subsequently, 41 (50.6%) patients were randomized into a group that received oral MMF (22 mg/kg/day), and 40 (49.4%) patients randomized to a group that received oral AZA (2 mg/kg/day). All patients initially received oral prednisone (1 mg/kg of body weight daily) for four weeks. The baseline characteristics of the two groups were similar. Total remission rate was 75.3% (80.5% in MMF and 70% in AZA), complete remission rate of 54.3% (56.1% with MMF and 52.5% with AZA), and a partial remission rate of 21% (24.4% with MMF and 17.5% with AZA) over 29 months. During maintenance therapy, six patients died (four in the AZA group and two in the MMF group), and end-stage renal disease (ESRD) developed in five patients (three in the AZA group and two in the MMF group). During the 36-months of the study, both groups had comparable event-free survival rate for the composite end point of death or ESRD and rate of relapse-free survival. Furthermore, both groups had no significant differences in terms of frequency of hospitalization, amenorrhea, infection, nausea, and vomiting. We conclude that our study showed that short-term therapy with intravenous CYC followed by maintenance therapy with oral MMF or AZA had similar efficacy and safety for the treatment of patients with moderate to severe LN. PMID:27424688

  3. Severe Enteropathy From Mycophenolate Mofetil

    PubMed Central

    Shaikh, Bilal; Hunt, Jettie; Spiegel, Adam

    2016-01-01

    The adverse effects of mycophenolate mofetil on the colon are well known. However, isolated small intestinal involvement resulting in diarrhea and severe weight loss is infrequently reported in the literature. We present the case of a 45-year-old woman on mycophenolate mofetil following renal transplant, who presented with abdominal pain and weight loss. An esophagogastroduodenoscopy and colonoscopy with biopsies were normal. A small bowel capsule study revealed extensive enteropathy of jejunum and ileum that was confirmed on a push enteroscopy with biopsies. Her symptoms completely resolved after being switched to enteric-coated mycophenolic acid. PMID:26958559

  4. Idiopathic granulomatous interstitial nephritis responsive to mycophenolate mofetil therapy.

    PubMed

    Leeaphorn, Napat; Stokes, Michael B; Ungprasert, Patompong; Lecates, William

    2014-04-01

    Granulomatous interstitial nephritis (GIN) is a rare histologic disease. Various causes have been reported in the literature, including drugs, sarcoidosis, and infections. Other incidents have no discernible cause and are identified as idiopathic. We report a 68-year-old white man who presented with acute kidney injury and was given a diagnosis of idiopathic GIN. Mycophenolate mofetil treatment was elected because of steroid toxicity. He responded well to mycophenolate mofetil and has been in remission for more than 3 years. To our knowledge, this is the first report of successful treatment with mycophenolate mofetil of an adult patient with idiopathic GIN. PMID:24315767

  5. Paediatric use of mycophenolate mofetil

    PubMed Central

    Downing, Heather J; Pirmohamed, Munir; Beresford, Michael W; Smyth, Rosalind L

    2013-01-01

    A number of medications do not have a licence, or label, for use in the paediatric age group nor for the specific indication for which they are being used in children. Over recent years, mycophenolate mofetil has increasingly been used off-label (i.e. off-licence) in adults for a number of indications, including autoimmune conditions; progressively, this wider use has been extended to children. This review summarizes current use of mycophenolate mofetil (MMF) in children, looking at how MMF works, the pharmacokinetics, the clinical conditions for which it is used, the advantages it has when compared with other immunosuppressants and the unresolved issues remaining with use in children. The review aims to focus on off-label use in children so as to identify areas that require further research and investigation. The overall commercial value of MMF is limited because it has now come off patent in adults. Given the increasing knowledge of the pharmacodynamics, pharmacokinetics and pharmacogenomics demonstrating the clinical benefits of MMF, new, formal, investigator-led studies, including trials focusing on the use of MMF in children, would be of immense value. PMID:22519685

  6. Reproducible erythroid aplasia caused by mycophenolate mofetil.

    PubMed

    Arbeiter, K; Greenbaum, L; Balzar, E; Müller, T; Hofmeister, F; Bidmon, B; Aufricht, C

    2000-03-01

    Anemia secondary to mycophenolate mofetil (MMF) was recently described in experimental animals. A clinical association between MMF and anemia has been observed, but there are no proven reports. We describe a girl with chronic graft failure who developed erythroid aplasia under immunosuppression with MMF. She showed prompt resolution when MMF was discontinued and a recurrence of this clinical course when MMF was restarted. As re-challenge with a medication is the most definitive approach for showing a direct relationship between the drug and the side effect, this case clearly demonstrates that MMF can cause erythroid aplasia. PMID:10752755

  7. Long-term outcome of mycophenolate mofetil treatment for patients with microscopic polyangiitis: an observational study in Chinese patients.

    PubMed

    Chen, Yinghua; Gao, Erzhi; Yang, Liu; Liu, Xia; Li, Kang; Liu, Zhengzhao; Zeng, Caihong; Zhang, Haitao; Liu, Zhihong; Hu, Weixin

    2016-07-01

    This study aimed to retrospectively analyze the long-term outcome of mycophenolate mofetil (MMF) therapy for microscopic polyangiitis (MPA) with mild to moderate renal involvement in Chinese patients. Thirty-four MPA patients (24 females, 10 males, aged 44.7 ± 17 years, BVAS score 13.8 ± 3.2, SCr 2.2 ± 1.1 mg/dl) with SCr < 5 mg/dl and who received glucocorticoids plus MMF therapy for inducing and maintaining remission were included in this study. The remission and relapse rates, patient and renal survival rates and adverse events were retrospectively analyzed. We found that 31 (91.2 %) of 34 patients achieved remission and were continuously treated with glucocorticoids plus MMF for maintaining remission. The median duration of MMF treatment was 24 months (IQR 15-53 months) and follow-up time was 86 months (IQR 29-124 months). During the follow-up, 7 (22.6 %) patients relapsed, one patient died, and one patient progressed into end-stage renal disease. The 5-year patient and renal survival rates were 92.8 and 95.2 %, respectively. 11 (32.4 %) patients suffered 16 adverse events, 13 of which were pulmonary infection. In conclusion, glucocorticoids plus MMF regimen as induction and maintenance therapy could achieve high remission rate and good long-term renal survival in MPA patients with mild to moderate renal involvement. Prospective controlled trials with a large sample size are needed to confirm the efficacy of MMF in this population. PMID:27169414

  8. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats

    SciTech Connect

    Suzuki, Chihiro; Takahashi, Masafumi . E-mail: masafumi@sch.md.shinshu-u.ac.jp; Morimoto, Hajime; Izawa, Atsushi; Ise, Hirohiko; Hongo, Minoru; Hoshikawa, Yasushi; Ito, Takayuki; Miyashita, Hiroshi; Kobayashi, Eiji; Shimada, Kazuyuki; Ikeda, Uichi

    2006-10-20

    Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH.

  9. Effect of mycophenolate mofetil in heart transplantation

    PubMed Central

    Mathieu, Patrick; Carrier, Michel; White, Michel; Pellerin, Michel; Perrault, Louis; Pelletier, Guy; Robitaille, Danielle; Pelletier, L. Conrad

    2000-01-01

    Objective To study the effect of mycophenolate mofetil (MMF), a new immunosuppressive drug that acts by inhibiting de novo pathways of purine synthesis, and rabbit antithymocyte globulin (RATG) on the lymphocyte subpopulation after heart transplantation. Design A review of clinical and laboratory records. Setting The Montreal Heart Institute. Patients Thirty-one patients who underwent heart transplantation. In 9 patients, neoral cyclosporine, prednisone and azathioprine were administered (group 1). In 14 patients RATG was added during the first 3 postoperative days (group 2) and in 8 patients RATG and combination immunosuppression was given, but MMF was used instead of azathioprine (group 3). The demographic characteristics of donors and recipients were similar among the 3 groups. Main outcome measures The proportion of CD2, CD4 and CD8 receptor-positive lymphocytes, expressed as a mean (and standard deviation) percentage of the total lymphocyte population, measured at 7, 15 and 30 days and 6 months after transplantation. Results At 7 days after transplantation, CD2 lymphocytes averaged 55% (18%), 16% (15%) and 14% (11%) in groups 1, 2 and 3 respectively (p < 0.05), CD4 averaged 36% (11%), 9% (12%) and 7% (8%) in groups 1, 2 and 3 (p < 0.05), and CD8 averaged 14% (6%), 4% (3%) and 4% (3%) in groups 1, 2 and 3 (p < 0.05). At 15 days after transplantation CD2 averaged 69% (10%), 42% (16%) and 47% (20%) in groups 1, 2 and 3 respectively (p < 0.05), and CD8 averaged 16% (7%), 16% (6%) and 19% (7%) (p = NS). At 30 days after transplantion the percentages of CD2, CD4 and CD8 lymphocytes were similar among the groups. The freedom rate from acute rejection averaged 22% (14%), 9% (8%) and 50% (18%) (p < 0.05) in groups 1, 2 and 3 at 6 months after transplantation, and the freedom rate from infection averaged 56% (17%), 36% (13%) and 38% (17%) for the 3 groups at this time period (p = NS). Conclusions A short course of RATG causes severe, transitory depletion of CD2, CD4 and

  10. Mycophenolate Mofetil in Severe Atopic Dermatitis: A Review.

    PubMed

    Prussick, Lisa; Plotnikova, Natalia; Gottlieb, Alice

    2016-06-01

    Atopic Dermatitis (AD) is a chronic inflammatory skin disease that is a significant cause of morbidity, quality-of-life impairment and health-care costs. Although many patients can be treated satisfactorily with topical medications and phototherapy, a smaller subset requires more aggressive systemic therapies. Multiple studies have shown promise for the use of mycophenolate mofetil (MMF) to treat refractory AD. This report summarizes the evidence for use of MMF in the treatment of recalcitrant AD for both children and adults. Familiarity with these studies on the benefits and risks of MMF will enable the clinician and patient to select the most appropriate therapy.

    J Drugs Dermatol. 2016;15(6):715-718. PMID:27272078

  11. Successful treatment of pediatric IgG4 related systemic disease with mycophenolate mofetil: case report and a review of the pediatric autoimmune pancreatitis literature

    PubMed Central

    2011-01-01

    Autoimmune pancreatitis is frequently associated with elevated serum and tissue IgG4 levels in the adult population, but there are few reports of pediatric autoimmune pancreatitis, and even fewer reports of IgG4 related systemic disease in a pediatric population. The standard of care treatment in adults is systemic corticosteroids with resolution of symptoms in most cases; however, multiple courses of corticosteroids are occasionally required and some patients require long term corticosteroids. In these instances, steroid sparing disease modify treatments are in demand. We describe a 13-year-old girl with IgG4 related systemic disease who presented with chronic recurrent autoimmune pancreatitis resulting in surgical intervention for obstructive hyperbilirubinemia and chronic corticosteroid treatment. In addition, she developed fibrosing medianstinitis as part of her IgG4 related systemic disease. She was eventually successfully treated with mycophenolate mofetil allowing for discontinuation of corticosteroids. This is the first reported use of mycophenolate mofetil for IgG4 related pancreatitis. Although autoimmune pancreatitis as part of IgG4 related systemic disease is rarely reported in pediatrics, autoimmune pancreatitis is also characterized as idiopathic fibrosing pancreatitis. All pediatric autoimmune pancreatitis cases reported in the world medical literature were identified via a PUBMED search and are reviewed herein. Twelve reports of pediatric autoimmune pancreatitis were identified, most of which were treated with corticosteroids or surgical approaches. Most case reports failed to report IgG4 levels, so it remains unclear how commonly IgG4 related autoimmune pancreatitis occurs during childhood. Increased evaluation of IgG4 levels in patients with autoimmune pancreatitis may shed further light on the association of IgG4 with pancreatitis and the underlying pathophysiology. PMID:21205323

  12. Neonatal anemia and hydrops fetalis after maternal mycophenolate mofetil use.

    PubMed

    Tjeertes, I F A; Bastiaans, D E T; van Ganzewinkel, C J L M; Zegers, S H J

    2007-01-01

    After admitting a patient to our Neonatal Intensive Care with a severe anemia and an ear malformation, we ruled out any other cause than maternal medication use. Knowing she used mycophenolate mofetil during pregnancy, we looked for related articles. Two articles were found describing ear malformations, but no article was ever written about anemia caused by this medication. Consulting the international registers of drug effects through the National Institute for Public Health and the Environment, we found out that the anemia was never seen or reported before. PMID:17180133

  13. Steroid Refractory Autoimmune Haemolytic Anaemia Secondary to Sarcoidosis Successfully Treated with Rituximab and Mycophenolate Mofetil.

    PubMed

    Green, Sarah; Partridge, Erica; Idedevbo, Edore; Borg, Anton

    2016-01-01

    Autoimmune haemolytic anaemia is not a well-recognised complication of sarcoidosis. We describe the case of a 30-year-old female who presented with acute warm haemolytic anaemia and widespread lymphadenopathy. Sarcoidosis was diagnosed on lymph node biopsy and further investigation. The haemolytic anaemia responded only to a high dose of steroids. Evidence regarding treatment of steroid refractory autoimmune haemolysis secondary to sarcoidosis is lacking. Based on the emergent evidence that both disorders share common immunopathogenic mechanisms involving Th1 and Th17 lymphocytes, our patient was given rituximab and mycophenolate mofetil to successfully suppress the haemolysis and sarcoid activity. PMID:27563474

  14. Steroid Refractory Autoimmune Haemolytic Anaemia Secondary to Sarcoidosis Successfully Treated with Rituximab and Mycophenolate Mofetil

    PubMed Central

    Idedevbo, Edore; Borg, Anton

    2016-01-01

    Autoimmune haemolytic anaemia is not a well-recognised complication of sarcoidosis. We describe the case of a 30-year-old female who presented with acute warm haemolytic anaemia and widespread lymphadenopathy. Sarcoidosis was diagnosed on lymph node biopsy and further investigation. The haemolytic anaemia responded only to a high dose of steroids. Evidence regarding treatment of steroid refractory autoimmune haemolysis secondary to sarcoidosis is lacking. Based on the emergent evidence that both disorders share common immunopathogenic mechanisms involving Th1 and Th17 lymphocytes, our patient was given rituximab and mycophenolate mofetil to successfully suppress the haemolysis and sarcoid activity. PMID:27563474

  15. Determination of mycophenolic acid and mycophenolate mofetil by high-performance liquid chromatography using postcolumn derivatization.

    PubMed

    Renner, U D; Thiede, C; Bornhäuser, M; Ehninger, G; Thiede, H M

    2001-01-01

    An efficient method to lower the optical detection limit is described using the displacement of an absorption and emission band of an analyte after a polarity change in different solvents. This solvatochromic effect was used in a RP-HPLC assay for the fluorescence detection of mycophenolic acid (6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acid, MPA) and the prodrug mycophenolate mofetil (MMF), the N-(2-hydroxyethyl)morpholino ester of MPA. The rational to use fluorescence detection is based on the behavior of MMF and MPA, which fluoresce in a basic medium (pH >9.5). Following a simple protein precipitation, the analytes were separated in an isocratic RP-HPLC system. The postcolumn generation of the phenolate anions of MPA and MMF was achieved by addition of an aqueous sodium hydroxide solution regulated by a newly developed continuous-flow liquid control system. MPAG, not directly accessible for fluorescence detection, was analyzed after enzymatic deglucuronidation to MPA. Compared to published quantification limits for MPA and MMF by UV detection, this method is more than 100-fold more sensitive, with a lower limit of quantification of 45 fmol for both MPA and MMF. PMID:11195509

  16. Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

    PubMed

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  17. Intravenous Immunoglobulin and Mycophenolate Mofetil for Long-Standing Sensory Neuronopathy in Sjögren's Syndrome.

    PubMed

    Danieli, Maria Giovanna; Pettinari, Lucia; Morariu, Ramona; Monteforte, Fernando; Logullo, Francesco

    2012-01-01

    Sensory neuronopathy is described in association with the Sjögren's syndrome (SS). We studied a 55-year-old woman with a 4-year history of progressive asymmetric numbness, distal tingling, and burning sensation in upper and lower limbs. In a few months, she developed ataxia with increased hypoanaesthesia. Electrodiagnostic tests revealed undetectable distal and proximal sensory nerve action potential in upper and lower limbs. Cervical spine magnetic resonance showed a signal hyperintensity of posterior columns. Previous treatment with high-dose glucocorticoids and azathioprine was ineffective. A combined treatment with intravenous immunoglobulin and mycophenolate mofetil was followed by a progressive and persistent improvement. This case documented the efficacy and the safety of the coadministration of intravenous immunoglobulin and mycophenolate mofetil in sensory neuronopathy associated with SS refractory to conventional immunosuppressive therapy. PMID:25383230

  18. Intravenous Immunoglobulin and Mycophenolate Mofetil for Long-Standing Sensory Neuronopathy in Sjögren's Syndrome

    PubMed Central

    Danieli, Maria Giovanna; Pettinari, Lucia; Morariu, Ramona; Monteforte, Fernando; Logullo, Francesco

    2012-01-01

    Sensory neuronopathy is described in association with the Sjögren's syndrome (SS). We studied a 55-year-old woman with a 4-year history of progressive asymmetric numbness, distal tingling, and burning sensation in upper and lower limbs. In a few months, she developed ataxia with increased hypoanaesthesia. Electrodiagnostic tests revealed undetectable distal and proximal sensory nerve action potential in upper and lower limbs. Cervical spine magnetic resonance showed a signal hyperintensity of posterior columns. Previous treatment with high-dose glucocorticoids and azathioprine was ineffective. A combined treatment with intravenous immunoglobulin and mycophenolate mofetil was followed by a progressive and persistent improvement. This case documented the efficacy and the safety of the coadministration of intravenous immunoglobulin and mycophenolate mofetil in sensory neuronopathy associated with SS refractory to conventional immunosuppressive therapy. PMID:25383230

  19. Mycophenolate mofetil in erosive genital lichen planus: a case and review of the literature.

    PubMed

    Deen, Kristyn; McMeniman, Erin

    2015-03-01

    Erosive genital lichen planus is a disabling, inflammatory mucocutaneous condition that can cause significant patient morbidity and loss of function. Treatment initially involves topical corticosteroids but some patients can have severe treatment-resistant courses requiring systemic immunosuppression. With potentially unfavorable adverse effect profiles and subsequent intolerance of these agents by patients, erosive lichen planus can ultimately be a challenging condition to treat effectively. We present a case of a 66-year-old woman with treatment-resistant erosive genital lichen planus who was successfully managed with mycophenolate mofetil. Although there is only weak evidence for this agent in this condition, its role in dermatology is growing due to its efficacy and advantageous adverse effect profile and should therefore be considered in patients with treatment-resistant erosive genital lichen planus. PMID:25583369

  20. Use of Mycophenolate Mofetil in Patients with Severe Localized Scleroderma Resistant or Intolerant to Methotrexate.

    PubMed

    Mertens, Jorre S; Marsman, Diane; van de Kerkhof, Peter C M; Hoppenreijs, Esther P A H; Knaapen, Hanneke K A; Radstake, Timothy R D; de Jong, Elke M G J; Seyger, Marieke M B

    2016-04-12

    To assess the efficacy and safety of mycophenolate mofetil (MMF) in patients with localized scleroderma (LoS) resistant or intolerant to previous treatment with methotrexate (MTX). A case series of patients with LoS treated with MMF. Outcome was assessed through clinical examination. Adverse events were documented. Seven patients with LoS were treated with MMF. Median age at MMF initiation was 15 years (range 7-74 years). Three patients received MMF due to MTX ineffectiveness and 4 due to MTX intolerance. Disease remission was achieved in 4 patients and maintained in one patient. One patient showed a favourable response, but had to discontinue treatment due to elevated liver enzymes. The remaining patient experienced disease progression. MMF was shown to improve the clinical condition of patients with refractory LoS and may be a relatively safe alternative in patients who are intolerant to MTX. PMID:26582717

  1. Effect of mycophenolate mofetil on the white blood cell count and the frequency of infection in systemic lupus erythematosus.

    PubMed

    Subedi, Ananta; Magder, Laurence S; Petri, Michelle

    2015-10-01

    Leukopenia is a common manifestation of SLE. Addition of immunosuppressive therapy in a SLE patient who is already leukopenic is a clinical concern. It could worsen leukopenia, increase the risk of infection, or both. The aim of this study was to analyze the immediate effect of mycophenolate mofetil on the white blood cell count and the rate of infection in SLE patients. Two hundred and forty-four patients within the Hopkins Lupus Cohort who were newly started on mycophenolate mofetil were included in the study. The white blood cell count and interval infection history on the day mycophenolate mofetil was started were compared with the white blood cell count and interval infection history at the next visit. The study was based on 244 patients who began taking mycophenolate mofetil in the cohort. The study population included 47 % African Americans, 44 % Caucasians, and 9 % other ethnicities. There was a slight but not statistically significant increase in the white blood cell count (6.63 vs. 7.01), after starting mycophenolate mofetil. Patients with a baseline white blood cell count <3000/mm(3) did have a statistically significant increase in the white blood cell count after starting mycophenolate mofetil (2.57 vs. 5.13, P = 0.0047). We also found a statistically significant increase in the risk of bacterial infection (but not viral infection) after starting mycophenolate mofetil (4 vs. 9 %, P = 0.0036). Leukopenia does not worsen with mycophenolate mofetil. However, mycophenolate mofetil appears to slightly increase the rate of bacterial (but not viral) infection. PMID:25836768

  2. Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients

    PubMed Central

    Dalal, P; Shah, G; Chhabra, D; Gallon, Lorenzo

    2010-01-01

    Introduction: Several new medications are now available for immunosuppression in the kidney transplant field. Tacrolimus and mycophenolate mofetil were first introduced for immunosuppression in renal transplantation in the mid 1990s. Since then, the combination of tacrolimus and mycophenolate mofetil has been evaluated in numerous clinical trials. The outcomes of these trials have varied due to differences in induction and/or maintenance therapy, drug dosing and monitoring protocols, and study design. The aim of this review is to analyze the literature critically and to provide an overview of tacrolimus and mycophenolate mofetil combination therapy in renal transplantation. PMID:21694936

  3. Enhancement of Mycophenolate Mofetil Permeation for Topical Use by Eucalyptol and N-Methyl-2-pyrrolidone

    PubMed Central

    Songkram, Chalermkiat

    2016-01-01

    Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) which can be metabolized by esterase. MMF has been approved by the United States Food and Drug Administration (USFDA) for treatment of psoriasis patient with skin symptoms. However, it remains unclear whether MMF is efficiently effective to treat skin symptoms developed from psoriasis. The insufficient amount of MMF penetrating through the skin results in the treatment failure due to the difficulty in MMF penetration through the stratum corneum. Skin permeation enhancers such as eucalyptol (EUL) and N-methyl-2-pyrrolidone (NMP) potentially aid in increasing skin penetration. This study aimed to investigate the effects of a concentration ratio (% w/v) between two enhancers (EUL and NMP). The results showed that EUL enhanced MMF permeation with an enhancement ratio (ER) of 3.44 while NMP was not able to promote the penetration of MMF. Interestingly, the synergistic effect of the two enhancers was observed with a suitable ratio given that the ER was 8.21. EUL and NMP are promising enhancers for the development of MMF based skin product. PMID:27069715

  4. Enhancement of Mycophenolate Mofetil Permeation for Topical Use by Eucalyptol and N-Methyl-2-pyrrolidone.

    PubMed

    Amnuaikit, Thanaporn; Songkram, Chalermkiat; Pinsuwan, Sirirat

    2016-01-01

    Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) which can be metabolized by esterase. MMF has been approved by the United States Food and Drug Administration (USFDA) for treatment of psoriasis patient with skin symptoms. However, it remains unclear whether MMF is efficiently effective to treat skin symptoms developed from psoriasis. The insufficient amount of MMF penetrating through the skin results in the treatment failure due to the difficulty in MMF penetration through the stratum corneum. Skin permeation enhancers such as eucalyptol (EUL) and N-methyl-2-pyrrolidone (NMP) potentially aid in increasing skin penetration. This study aimed to investigate the effects of a concentration ratio (% w/v) between two enhancers (EUL and NMP). The results showed that EUL enhanced MMF permeation with an enhancement ratio (ER) of 3.44 while NMP was not able to promote the penetration of MMF. Interestingly, the synergistic effect of the two enhancers was observed with a suitable ratio given that the ER was 8.21. EUL and NMP are promising enhancers for the development of MMF based skin product. PMID:27069715

  5. Infundibuloneurohypophysitis Associated With Sjögren Syndrome Successfully Treated With Mycophenolate Mofetil

    PubMed Central

    Louvet, Camille; Maqdasy, Salwan; Tekath, Marielle; Grobost, Vincent; Rieu, Virginie; Ruivard, Marc; Le Guenno, Guillaume

    2016-01-01

    Abstract Hypophysitis is an inflammatory disorder of the pituitary gland and corticosteroids are usually recommended as the first-line treatment. Hypophysitis related to primary Sjögren syndrome (pSS) is uncommon. We describe the unusual case of a patient with infundibuloneurohypophysitis associated with pSS successfully treated with mycophenolate mofetil (MMF). We describe a case of a 60-year-old man with a medical history of pSS presented with central diabetes insipidus and panhypopituitarism. Magnetic resonance imaging (MRI) revealed a thickening of the pituitary stalk and intense enhancement of the posterior pituitary, pituitary stalk, and hypothalamus. We diagnosed infundibuloneurohypophysitis associated with pSS. Hormonal replacement was started immediately and MMF was introduced without corticosteroids. After 9 months of treatment, MRI of the pituitary revealed a complete regression of the nodular thickening of the pituitary stalk, with normal enhancement and appearance of the pituitary. The pituitary axes had completely recovered, whereas the diabetes insipidus was partially restored. Our findings suggest that MMF is an effective alternative to corticosteroids for the treatment of lymphocytic hypophysitis associated with an autoimmune disease. Furthermore, this report could contribute to extend the spectrum of the neurological and endocrinological manifestations of pSS. PMID:27043673

  6. A multicenter experience with generic mycophenolate mofetil conversion in stable liver transplant recipients

    PubMed Central

    Kim, Jong Man; Kwon, Choon Hyuck David; Yun, Ik Jin; Lee, Kwang-Woong; Yu, Hee Chul; Suh, Kyung-Suk; Cho, Baik Hwan

    2014-01-01

    Purpose Generic substitution of brand-name medications can lead to significant cost savings and is an accepted medical practice. This study evaluated clinical and safety outcomes among liver transplant recipients whose mycophenolate mofetil (MMF) was converted from the brand-name formulation (Cellcept) to a generic formulation (My-rept). Methods Clinical data from multiple centers were prospectively collected for determination of complications, safety, and quality of life after in 154 clinically stable, adult liver transplant recipients whose MMF was converted to a generic formulation between April 2010 and September 2012. This protocol was approved by Institutional Review Boards of all involved sites. Results In eight patients (5.19%), nine instances of drug-related complications occurred after medication conversion. Half of these complications were gastrointestinal disorders (n = 4), and most (7 of 9) were mild. No significant differences were noted in mean pre- and postconversion gastrointestinal symptoms via a rating system (8.9 vs. 10.4) or gastrointestinal quality-of-life index scores (125.6 vs. 123.1). More than 90% of patients reported a status of "about the same" when questioned about the brand-name and generic formulation using the Patient Overall Treatment Effect and Investigator Overall Treatment Effect measures. The incidence of serious adverse events was 5.8%. Acute rejection occurred in two patients, with no graft loss or death. Conclusion Clinical experience as well as research data showed that generic MMF was comparable in efficacy to the brand-name drug. Given the lack of adverse events and the safety findings, conversion from brand-name MMF to generic MMF should be encouraged. PMID:24783178

  7. The Effect of Mycophenolate Mofetil on Early Wound Healing in a Rodent Model

    PubMed Central

    Willems, Martine CM; Hendriks, Thijs; Lomme, Roger MLM; de Man, Ben M; van der Vliet, J Adam

    2016-01-01

    Background Immunosuppressant agents are inevitable for solid organ recipients, but may have a negative effect on wound healing that is difficult to measure because of clinical use of a polydrug regime. The evidence on mycophenolate mofetil (MMF) is scarce and contradictory. This study aims to investigate the effect of MMF administration on wound healing. Methods Ninety-six male Wistar rats divided into 4 groups underwent anastomotic construction in ileum and colon at day 0. Three groups received daily oral doses of 20 or 40 mg/kg MMF or saline (control group) from day 0 until the end of the experiment. Half of each group was analyzed after 3 days and half after 7 days. Another group started the medication 3 days after the laparotomy and was analyzed after 7 days, half of this group received 20 mg/kg and half 40 mg/kg MMF. Wound strength in anastomoses and in the abdominal wall was measured using bursting pressure, breaking strength, and histology. Trough levels were measured. Results Significant differences in wound strength were seen in ileum tissue after 3 days, which surprisingly showed a stronger anastomosis in the experimental groups. Bursting pressure as well as breaking strength was higher in the low-dose and high-dose MMF group compared with the control group. A negative effect was measured in abdominal wall tissue for the highest-dose group, which disappeared when the medication was delayed for 3 days. Histology showed poorer bridging of the submucosal layer and more polymorphonuclear cell infiltration in the ileum specimens of the control group compared with the treatment groups. Conclusions As a single agent in a preclinical wound healing model in the rat, MMF has no negative effect on healing of bowel anastomoses but might have a negative effect on the healing of abdominal wall. PMID:27500270

  8. Protective effect of mycophenolate mofetil against nephrotoxicity and hepatotoxicity induced by tacrolimus in Wistar rats.

    PubMed

    Ferjani, Hanen; El Arem, Amira; Bouraoui, Aicha; Achour, Abedellatif; Abid, Salwa; Bacha, Hassen; Boussema-Ayed, Imen

    2016-06-01

    Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co-administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF's possible protective effect. Our results showed that MMF (at 50 mg kg(-1) body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg(-1) b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process. PMID:26746208

  9. Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

    PubMed Central

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  10. Inosine monophosphate dehydrogenase variability in renal transplant patients on long-term mycophenolate mofetil therapy

    PubMed Central

    Chiarelli, Laurent R; Molinaro, Mariadelfina; Libetta, Carmelo; Tinelli, Carmine; Cosmai, Laura; Valentini, Giovanna; Canton, Antonio Dal; Regazzi, Mario

    2010-01-01

    AIMS Long-term mycophenolate mofetil (MMF) therapy may induce inosine 5′-monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells (PBMCs), thus decreasing MMF immunosuppressive properties. Pharmacodynamic monitoring was used to investigate whether biological activity is altered after long-term therapy. METHODS IMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t0) and 2 h after (t2) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations. RESULTS During the 15 months' monitoring, t0 IMPDH activity in transplant recipients increased from 5.9 ± 3.7 nmol h−1 mg−1[95% confidence interval (CI) 4.9, 6.9] to 9.0 ± 3.9 nmol h−1 mg−1 (95% CI 7.2, 10.8), with an intra- and interpatient variability of 28% and 42%. Five patients experienced acute rejection during the follow-up: t0 IMPDH activity was increased during rejection vs. nonrejection, and the trend was significantly higher in rejecting than in nonrejecting subjects for the whole monitoring period. CONCLUSIONS Even though a correlation has been found between IMPDH activity and rejection, its efficacy as a predictive tool in long-term transplant outcomes may be affected by high interpatient variability; on the other hand, continuous monitoring of the IMPDH trend could make an effective prognostic parameter of rejection. Other trials also including pre-transplant data on both IMPDH expression and activity are warranted to better assess their role as biomarkers for MPA effect in clinical practice. PMID:20078611

  11. Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients.

    PubMed

    Barau, Caroline; Barrail-Tran, Aurélie; Hemerziu, Bogdan; Habes, Dalila; Taburet, Anne-Marie; Debray, Dominique; Furlan, Valérie

    2011-10-01

    Mycophenolate mofetil (MMF) is now commonly used in pediatric liver transplant recipients, but no clear recommendations about the dosing regimen have been made for this population. The aim of this study was to determine the MMF dosage required for pediatric liver transplant recipients to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12) ) for mycophenolic acid (MPA) greater than 30 mg hour/L. A pharmacokinetic study of 15 children (median age = 8.3 years, range = 1.1-15.2 years) was performed at a median of 11.0 months (range = 0.5-88.0 months) after liver transplantation. MMF was initially introduced at a median starting dose of 300 mg/m(2) twice a day (range = 186-554 mg/m(2) twice a day). Thirteen of the 15 patients had an MPA AUC(0-12) value less than 30 mg hour/L. The MMF dosage had to be increased in all patients except 1. The MMF dosage required to reach an MPA AUC(0-12) value greater than the defined target of 30 mg hour/L ranged from 371 to 1014 mg/m(2) /day. For 2 patients who received rifampin in addition to MMF, the MPA AUC(0-12) value remained low despite a 2-fold increase in the MMF dosage. In conclusion, an initial MMF dose of 600 mg/m(2) twice a day led to MPA AUC(0-12) values greater than the 30 mg hour/L threshold except when rifampin was coadministered. Because of the important interindividual variability of MPA pharmacokinetics, therapeutic drug monitoring is recommended for optimizing the daily MMF dosage. Furthermore, these results suggest that the coadministration of MPA with rifampin should be avoided. PMID:21695772

  12. Synthetic lethality for linking the mycophenolate mofetil mode of action with molecular disease and drug profiles.

    PubMed

    Söllner, Johannes; Mayer, Paul; Heinzel, Andreas; Fechete, Raul; Siehs, Christian; Oberbauer, Rainer; Mayer, Bernd

    2012-10-30

    Systematic study of the effect of mycophenolate mofetil (MMF) on the molecular level in the context of other drugs and molecular disease profiles became possible due to the availability of large scale molecular profiles on both disease characterization and drug mode of action. Such analysis is of particular value in elucidating alternative drug use for addressing clinically unmet needs, and the concept of synthetic lethality provides an alternative tool for such repositioning strategies. Resting on consolidation of transcriptomics data and literature mining, a MMF molecular footprint became available including a set of 170 genes specifically affected by the drug. Analysis of this profile on a molecular pathway level reveals a set of 14 pathways as affected. Next to assignment of molecular pathways and associated diseases synergistic drug combinations are proposed by utilizing the synthetic lethal interaction network. Of particular interest is the combination of MMF with adenosine deaminase inhibitors, sulfasalazine, and other selected drugs interfering with calcium-based regulatory pathways and metabolism. Indeed analysis of drugs in clinical trials positively identifies combinations with MMF in the context of synthetic lethality and affected pathways, particularly in diseases such as multiple sclerosis, vasculitis, GVHD and lupus nephritis. Importantly, the synthetic lethal interaction of the drug mode of action is an interesting basis for rational repositioning strategies by suggesting combinations which exhibit a synergistic rather than a mere additive effect, as for example is evident for the combination of tacrolimus and MMF. Inherent is also the assessment of possible adverse effects of drug combinations. PMID:23014771

  13. Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases

    PubMed Central

    Streicher, Caroline; Djabarouti, Sarah; Xuereb, Fabien; Lazaro, Estibaliz; Legeron, Rachel; Bouchet, Stéphane; Greib, Carine; Breilh, Dominique; Pellegrin, Jean-Luc; Viallard, Jean-François

    2014-01-01

    Aim To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis. Methods MPA areas under the concentration–time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C0) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed. Results In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l–1 (IQR 0.9–2.1 mg l–1) vs. 2.95 mg l–1 (IQR 1.38–3.73 mg l–1) for SLE (P = 0.048) and 1.55 mg l–1 (IQR 0.98–2.18 mg l–1) vs. 3 mg l–1 (IQR 2.2–4.4 mg l–1) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5–3 mg l–1 was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5–3 mg l–1 at inclusion had better clinical outcomes during the 12 months following PK assessment. Conclusion Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post-dose. PMID:25041114

  14. Fructooligosaccharide raftilose reduces the mycophenolate mofetil-induced complications: Hematological and biochemical alterations

    PubMed Central

    Cheraghi, Hadi; Khaki, Zohreh; Malekinejad, Hassan; Sasani, Farhang

    2015-01-01

    Mycophenolate mofetil (MMF) is a selective inhibitor of Inosine-5′-monophosphate dehydrogenase. Gastrointestinal (GI) disturbances in immature ones are reported for MMF-induced compilations, which in the case of occurrence dose reduction is required. Thus, in the present study, the fructooligosaccharide raftilose® (RFT) was co-administrated with MMF to estimate the protective effect of RFT against MMF-induced GI complications. Thirty six immature male Wistar rats were divided into six groups including: Control (normal saline), RFT-treated (100 mg kg-1), MMF-treated (20 mg kg-1), MMF + LRFT (50 mg kg-1), MMF + MRFT (100 mg kg-1) and MMF + HRFT (200 mg kg-1) groups. The hematocrit (Hct), lymphocyte/total WBC, feces water content and pH were analyzed. Moreover, the hepatic functional tests, kidney-related biomarkers, lipid and protein profiles, total antioxidant capacity (TAC), malondialdehyde (MDA) and nitric oxide (NO) contents were assessed. Co-administration of RFT stabilized the MMF-reduced body weight. The MMF significantly diminished Hct and lymph/total WBC (p < 0.05). Only MRFT enhanced the lymphocyte/total WBC. Increased water content, no changes in feces pH, increased serum ALT and AST, no alteration in urea and mild enhancement in creatinine were demonstrated in MMF-received animals. However, RFT at low dose ameliorated the feces parameters and reduced ALT. No significant changes were demonstrated for serum lipid and protein profiles in MMF- and RFT + MMF-treated groups. The RFT enhanced the serum TAC, reduced MDA and NO contents. In conclusion, our data suggested that RFT could be considered as an effective agent to subsidize the MMF-induced clinical, hematological and biochemical disorders. PMID:26973768

  15. Endoscopic and histological features of mycophenolate mofetil colitis in patients after solid organ transplantation

    PubMed Central

    Calmet, Fernando H.; Yarur, Andres J.; Pukazhendhi, Geetha; Ahmad, Jawad; Bhamidimarri, Kalyan R.

    2015-01-01

    Background Mycophenolate mofetil (MMF) is an immunosuppressive agent commonly used after organ transplantation. Gastrointestinal side effects occur in approximately 45% of patients. The spectrum of histologic features associated with MMF colitis has been well described, but data on the endoscopic features is lacking. The aim of the study was to describe the endoscopic features of MMF colitis in solid organ transplant recipients (SOTRs) as well as the frequency of histologic features and identify associated risk factors. Methods A retrospective review of all SOTRs taking MMF and who underwent colonoscopy between 2000 and 2010 was performed. 36 cases of MMF colitis were identified and 361 patients served as controls. Descriptive statistics and data analysis looking for associated risk factors were performed. Results Among SOTRs taking MMF who underwent colonoscopy, MMF colitis was diagnosed in 9%. Endoscopic findings ranged from erythema (33%) to erosions/ulcers (19%). 47% of patients had a normal colonoscopy and everyone had rectal sparing. Histological findings included acute colitis-like findings (50%), inflammatory bowel disease-like characteristics (36%), ischemia-like findings (5.6%), and graft-versus-host disease-like features (8.3%). Diarrhea occurred in 83%. Kidney transplantation was associated with a higher risk of MMF colitis (OR 5.8 [2.86-11.86], P<0.0001) whereas liver transplantation was associated with a lower risk (OR 0.06 [0.03-0.16], P<0.0001). Conclusion MMF colitis is fairly prevalent in SOTRs taking MMF who undergo colonoscopy. Diarrhea is the most common reason for colonoscopy referral (83%) and up to 47% of patients have normal colonoscopy, suggesting the need for routine biopsies to help confirm the diagnosis. PMID:26126799

  16. Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression.

    PubMed

    Kim, Su-Mi; Lee, Sang-Ho; Lee, Arah; Kim, Dong-Jin; Kim, Yang-Gyun; Kim, Se-Yun; Jeong, Kyung-Hwan; Lee, Tae-Won; Ihm, Chun-Gyoo; Lim, Sung-Jig; Moon, Ju-Young

    2015-10-01

    Proinflammatory T helper 1 (Th1) and T helper 17 (Th17) cell subsets have been reported to have an immunopathogenic role in metabolic disease. We previously demonstrated that CD4(+) T cells are increased in kidneys in type 2 diabetic patients. However, the role of Th1 and Th17 cells in the development and progression of diabetic nephropathy is unclear. In this study, we examined the hypothesis that mycophenolate mofetil (MMF) attenuates diabetic kidney injury by the suppression of renal T-cell proliferation and related cytokines. Four groups of male C57/BL6 mice (8-weeks-old) were studied: (1) untreated controls, (2) MMF-treated controls (30 mg/kg of body weight per day), (3) streptozotocin (STZ)-induced diabetes, and (4) MMF-treated STZ-induced diabetes. The interferon gamma (IFN-γ) and interleukin 17 (IL-17) from renal CD4(+) T cells were analyzed in kidney mononuclear cells by flow cytometry. We found proliferating CD4(+) T cells were significantly increased in the kidney compared with the spleen. There were increases in IFN-γ(+) CD4(+) and IL-17A(+) CD4(+) T cells from the initiation of albuminuria in the kidneys of diabetic mice. We found MMF suppresses only the intrarenal IL-17A(+) CD4(+) T cells from early diabetic nephropathy and improves albuminuria, tubulointerstitial fibrosis independent of glycemic control. Our study results suggest that Th17 may play an independent role in the progression of diabetic nephropathy and modulation of IL-17 has potential as an immunologic therapeutic target. PMID:26001596

  17. A prospective multicentre study of mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis.

    PubMed

    F, Lu; Y, Tu; X, Peng; L, Wang; H, Wang; Z, Sun; H, Zheng; Z, Hu

    2008-07-01

    Mycophenolate mofetil (MMF) with prednisolone has been associated with high remission rates when used as induction treatment for lupus nephritis. This prospective, multicentre, cohort study investigates the efficacy and safety of this regimen over 24 weeks in 213 Chinese patients with active lupus nephritis (Classes III, IV, V or combination). Baseline activity index (AI) was 6.91+/-3.33 and chronicity index (CI) was 1.9+/-1.2. The remission rate was 82.6% at 24 weeks (complete remission, 34.3%; partial remission, 48.4%). There were significant (P<0.01) improvements in kidney function shown by reductions in proteinuria, serum albumin, serum creatinine and creatinine clearance, as well as in systemic lupus erythematosus disease activity index (SLEDAI) scores. Independent risk factors influencing remission were pathological classification (including Class V and III or Class V and IV nephritis) and elevated serum creatinine at baseline (OR 2.967, 95% CI: 1.479-6.332, P=0.001 and OR 1.007, 95% CI: 1.002-1.011, P=0.001, respectively). Patients with concomitant membranous features on biopsy had a lower remission rate than those with Class III and IV nephritis (66.7% vs 87.3%, P=0.002). Renal biopsy was repeated in 25 patients following treatment. There was a transition to less severe pathological morphologies in majority of subjects. Infections were monitored throughout treatment: eight patients (3.8%) experienced bacterial infections, whereas herpes zoster occurred in seven patients. Nine patients (4.2%) suffered from gastrointestinal upset, which resolved without discontinuation of MMF. One patient became leucopenic, whereas another died from active disease unrelated to kidney symptoms. MMF combined with prednisolone is an effective and well-tolerated induction treatment for patients with active lupus nephritis and for controlling SLE systemic activity. PMID:18625634

  18. Development and Validation of a Novel Dual Wavelength UV-Spectrophotometric Method for the Simultaneous Estimation of Mycophenolate Mofetil and Prednisolone

    NASA Astrophysics Data System (ADS)

    Kaur, J.; Sharma, P. Kumar; Namdev, K. Kumar; Bala, I.; Verma, S.

    2014-07-01

    A dual wavelength UV-spectrophotometric method has been developed for the simultaneous estimation of mycophenolate mofetil and prednisolone. In this method two wavelengths were selected for the estimation of each drug in such a way that the difference in the absorbance was zero for the second drug on the respective wavelength for the first drug. This method was selected because of the overlapping of the absorbance maxima of the drugs. Prednisolone has equal absorbance value at wavelengths 235.11 and 261.33 nm; therefore, these two wavelengths were used to determine the concentration of mycophenolate mofetil in the combination. Similarly, 270.3 and 277.4 nm wavelengths were selected to determine the concentrations of prednisolone, where mycophenolate mofetil was observed with equal absorbance values. Regression analysis for the method shows good correlation in the concentration ranges 10-50 μg/ml for mycophenolate mofetil and 2-10 μg/ml for prednisolone. The method was validated using parameters provided as per ICH guidelines.

  19. Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.

    PubMed

    Li, Hong; Mager, Donald E; Sandmaier, Brenda M; Storer, Barry E; Boeckh, Michael J; Bemer, Meagan J; Phillips, Brian R; Risler, Linda J; McCune, Jeannine S

    2014-08-01

    A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker. PMID:24727337

  20. Intensified Mycophenolate Mofetil Dosing and Higher Mycophenolic Acid Trough Levels Reduce Severe Acute Graft-versus-Host Disease After Double-Unit Cord Blood Transplantation

    PubMed Central

    Harnicar, S.; Ponce, D.M.; Hilden, P.; Zheng, J.; Devlin, S.M.; Lubin, M.; Pozotrigo, M.; Mathew, S.; Adel, N.; Kernan, N.A.; O'Reilly, R.; Prockop, S.; Scaradavou, A.; Hanash, A.; Jenq, R.; van den Brink, M.; Giralt, S.; Perales, M.A.; Young, J.W.; Barker, J.N.

    2015-01-01

    While mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit CBT (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 double-unit CBT recipients (median age 39 years, range 1–71) transplanted for hematologic malignancies. Recipients of a MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III-IV acute GVHD (aGVHD) incidence compared with patients who received > 36 mg/kg/day (24% versus 8%, p = 0.008). Recipients of ≤ the median dose who had highly HLA-allele (1-3/6) mismatched dominant units had the highest day 100 grade III-IV aGVHD incidence of 37% (p = 0.009). This finding was confirmed in multivariate analysis (p = 0.053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1-2 trough < 0.5 mcg/mL had an increased day 100 grade III-IV aGVHD of 26% versus 9% (p = 0.063), and those who received a low total daily MMF dose and had a low week 1-2 MPA trough had a 40% incidence (p = 0.008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in mg/kg/day and MPA trough level monitoring early post-transplant in dCBT recipients. PMID:25687796

  1. Natural Killer Cell Activating Receptor NKG2D Is Involved in the Immunosuppressive Effects of Mycophenolate Mofetil and Hepatitis B Virus Infection.

    PubMed

    Dong, Shuai; Geng, Lei; Shen, Miao-Da; Zheng, Shu-Sen

    2015-05-01

    The purpose of this study is to investigate whether mycophenolate mofetil (MMF), a new immunosuppressant, and its metabolite mycophenolic acid (MPA) affect the activity of liver resident natural killer (NK) cells, resulting in increased susceptibility to hepatitis B virus (HBV) infection. Hepatic NK cells were isolated from C57BL/6 and C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice treated with MMF in the presence or absence of IL-15. After incubation of isolated hepatic NK cells in the presence or absence of MPA, reverse transcription polymerase chain reaction and immunolabeling were used to assess the expression of NK receptors Ly49A, NKG2A and NKG2D. In addition, cytokine enzyme-linked immunosorbent assay and [H]-TdR-release assay were carried out to assess NK cell activation and cytotoxic capacity. After treatment with MMF in the presence or absence of IL-15, HBsAg titers were measured in C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice. Treatment with either MPA or MMF resulted in reduced NK cell cytotoxicity, downregulated NKG2D and Ly49A expression and upregulated NKG2A. Interestingly, NKG2D downregulation was ameliorated by IL-15. In HBV-transgenic mice, MMF treatment impaired NK cell activity but did not affect virus replication, whereas IL-15 treatment reduced HBsAg titers. MPA and MMF mediate NKG2D downregulation both in vitro and in vivo, reducing the cytotoxic capacity of NK cells. These findings indicate that NKG2D regulation may be important in the immunosuppressive effect NK cells and involved in HBV infection. PMID:25828197

  2. Natural Killer Cell Activating Receptor NKG2D Is Involved in the Immunosuppressant Effect of Mycophenolate Mofetil and Infection of Hepatitis B Virus.

    PubMed

    Dong, S; Geng, L; Shen, M-D; Zheng, S-S

    2015-01-01

    In this study we investigated whether mycophenolate mofetil (MMF), a new immunosuppressant, and its metabolite mycophenolic acid (MPA) influence the activity of liver resident natural killer (NK) cells, resulting in increased susceptibility to hepatitis B virus (HBV) infection. We isolated the hepatic NK cells of C57BL/6 and C57BL/6JTgN (A1b1HBV) 44Bri) transgenic mice administered MMF in the presence or absence of interleukin (IL)-15, or incubated isolated hepatic NK cells in the presence or absence of MPA and used RT-PCR, immunolabeling to assess the expression of NK receptors Ly49A, NKG2A and NKG2D, and cytokine ELISA and [(3)H]-TdR-release assay to assess the activation and cytotoxic capacity of NK cells. After treatment of MMF in the presence or absence of IL-15, HBsAg titer was also measured in C57BL/6JTgN (A1b1HBV) 44Bri) transgenic mice. After both MPA and MMF treatments, NK cytotoxicity was reduced, NKG2D and Ly49A expression was down-regulated, but NKG2A was up-regulated. Down-regulation of NKG2D could be ameliorated by IL-15, and in HBV-transgenic mice, MMF treatment impaired NK cell activity, but did not influence virus replication, whereas IL-15 treatment depressed HBsAg titer. MPA and MMF mediate down-regulation of NKG2D in vitro and vivo, restricting the cytotoxic capacity of NK cells. Regulation of NKG2D may be important in the effect of immunosuppressant on NK cell activity and involved in HBV infection. PMID:26293053

  3. A four-drug combination therapy consisting of low-dose tacrolimus, low-dose mycophenolate mofetil, corticosteroids, and mizoribine in living donor renal transplantation: A randomized study

    PubMed Central

    Yan, Tian-zhong; Wu, Xiao-qiang; Rong, Lu

    2016-01-01

    Objective: We compared a three-drug combination therapy (control group) consisting of tacrolimus, mycophenolate mofetil, and corticosteroids in living donor renal transplantation with a four-drug combination therapy (study group), in which the doses of tacrolimus and mycophenolate mofetil were halved and the immunosuppressive drug mizoribine was added, in order to determine whether the incidence rates of acute rejection after transplantation between the study group and the control group are similar, whether the study group regimen prevents the occurrence of calcineurin inhibitor–induced renal damage, and whether the study group regimen prevents adverse effects such as diarrhea caused by mycophenolate mofetil. Methods: We investigated the incidence of acute rejection, serum creatinine levels, and estimated glomerular filtration rate and the incidence of adverse effects such as diarrhea. Results: There was no significant difference between the two groups in the incidence of acute rejection. Renal function (estimated glomerular filtration rate and serum creatinine) was maintained in the control group whereas in the study group renal function gradually improved, with a statistical difference observed at 12 months. The incidence of gastrointestinal symptoms including diarrhea was significantly higher in the control group than in the study group. There was no significant difference in the incidence of cytomegalovirus infection and other adverse effects. Conclusion: These results suggest the study group therapy is an effective regimen in preventing acute rejection and the deterioration of renal function. These results also show this therapy can reduce the incidence of adverse effects such as gastrointestinal symptoms. PMID:27231549

  4. The Effect of Mycophenolate Mofetil on Disease Development in the gld.apoE−/− Mouse Model of Accelerated Atherosclerosis and Systemic Lupus Erythematosus

    PubMed Central

    Richez, Christophe; Richards, Rocco J.; Duffau, Pierre; Weitzner, Zachary; Andry, Christopher D.; Rifkin, Ian R.; Aprahamian, Tamar

    2013-01-01

    Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by autoantibody production and inflammatory disease involving multiple organs. Premature atherosclerosis is a common complication of SLE and results in substantial morbidity and mortality from cardiovascular disease (CVD). The reasons for the premature atherosclerosis in SLE are incompletely understood, although chronic inflammation is thought to play an important role. There is currently no known preventative treatment of premature atherosclerosis in SLE. Mycophenolate mofetil (MMF) is an immunosuppressive agent that is commonly used for treatment of patients with SLE. In order to study the impact of this drug on murine lupus disease including premature atherosclerosis development, we treated gld.apoE−/− mice, a model of SLE and accelerated atherosclerosis, with MMF. We maintained seven-week old gld.apoE−/− mice on a high cholesterol Western diet with or without MMF. After 12 weeks on diet, mice receiving MMF showed decreased atherosclerotic lesion area compared to the control group. MMF treatment also improved the lupus phenotype, indicated by a significant decrease circulating autoantibody levels and ameliorating lupus nephritis associated with this model. This data suggests that the effects of MMF on the immune system may not only be beneficial for lupus, but also for inflammation driving lupus-associated atherosclerosis. PMID:23577189

  5. Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus.

    PubMed

    Miles, Clifford D; Skorupa, Jill Y; Sandoz, John P; Rigley, Theodore H; Nielsen, Kathleen J; Stevens, R Brian

    2011-01-01

    Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications. PMID:21077952

  6. Cost-Utility Analysis of Mycophenolate Mofetil versus Azathioprine Based Regimens for Maintenance Therapy of Proliferative Lupus Nephritis

    PubMed Central

    Nee, Robert; Rivera, Ian; Little, Dustin J.; Yuan, Christina M.; Abbott, Kevin C.

    2015-01-01

    Background/Aims. We aimed to examine the cost-effectiveness of mycophenolate mofetil (MMF) and azathioprine (AZA) as maintenance therapy for patients with Class III and Class IV lupus nephritis (LN), from a United States (US) perspective. Methods. Using a Markov model, we conducted a cost-utility analysis from a societal perspective over a lifetime horizon. The modeled population comprised patients with proliferative LN who received maintenance therapy with MMF (2 gm/day) versus AZA (150 mg/day) for 3 years. Risk estimates of clinical events were based on a Cochrane meta-analysis while costs and utilities were retrieved from other published sources. Outcome measures included costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratios (ICER), and net monetary benefit. Results. The base-case model showed that, compared with AZA strategy, the ICER for MMF was $2,630,592/QALY at 3 years. Over the patients' lifetime, however, the ICER of MMF compared to AZA was $6,454/QALY. Overall, the ICER results from various sensitivity and subgroup analyses did not alter the conclusions of the model simulation. Conclusions. In the short term, an AZA-based regimen confers greater value than MMF for the maintenance therapy of proliferative LN. From a lifelong perspective, however, MMF is cost-effective compared to AZA. PMID:26600951

  7. Cost-Utility Analysis of Mycophenolate Mofetil versus Azathioprine Based Regimens for Maintenance Therapy of Proliferative Lupus Nephritis.

    PubMed

    Nee, Robert; Rivera, Ian; Little, Dustin J; Yuan, Christina M; Abbott, Kevin C

    2015-01-01

    Background/Aims. We aimed to examine the cost-effectiveness of mycophenolate mofetil (MMF) and azathioprine (AZA) as maintenance therapy for patients with Class III and Class IV lupus nephritis (LN), from a United States (US) perspective. Methods. Using a Markov model, we conducted a cost-utility analysis from a societal perspective over a lifetime horizon. The modeled population comprised patients with proliferative LN who received maintenance therapy with MMF (2 gm/day) versus AZA (150 mg/day) for 3 years. Risk estimates of clinical events were based on a Cochrane meta-analysis while costs and utilities were retrieved from other published sources. Outcome measures included costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratios (ICER), and net monetary benefit. Results. The base-case model showed that, compared with AZA strategy, the ICER for MMF was $2,630,592/QALY at 3 years. Over the patients' lifetime, however, the ICER of MMF compared to AZA was $6,454/QALY. Overall, the ICER results from various sensitivity and subgroup analyses did not alter the conclusions of the model simulation. Conclusions. In the short term, an AZA-based regimen confers greater value than MMF for the maintenance therapy of proliferative LN. From a lifelong perspective, however, MMF is cost-effective compared to AZA. PMID:26600951

  8. A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients.

    PubMed

    Windreich, Randy M; Goyal, Rakesh K; Joshi, Rujuta; Kenkre, Tanya S; Howrie, Denise; Venkataramanan, Raman

    2016-04-01

    Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 μg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 μg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 μg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 μg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in

  9. Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients

    PubMed Central

    Brunkhorst, Lena Caroline; Fichtner, Alexander; Höcker, Britta; Burmeister, Greta; Ahlenstiel-Grunow, Thurid; Krupka, Kai; Bald, Martin; Zapf, Antonia

    2015-01-01

    Introduction Data on the efficacy and safety of everolimus in pediatric renal transplantation compared to other immunosuppressive regimens are scarce. Patients/Methods We therefore performed a multicenter, observational, matched cohort study over 4 years post-transplant in 35 patients on everolimus plus low-dose cyclosporine, who were matched (1:2) with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen. Results Corticosteroids were withdrawn in 83% in the everolimus vs. 39% in the control group (p<0.001). Patient and graft survival were comparable. The rate of biopsy-proven acute rejection episodes Banff score ≥ IA during the first year post-transplant was 6% in the everolimus vs. 13% in the control group (p = 0.23). The rate of de novo donor-specific HLA antibodies (11% in everolimus, 18% in controls) was comparable (p = 0.55). At 4 years post-transplant, mean eGFR in the everolimus group was 56±33 ml/min per 1.73 m² vs. 63±22 ml/min per 1.73 m² in the control group (p = 0.14). Everolimus therapy was associated with less BK polyomavirus replication (3% vs. 17% in controls; p = 0.04), but with a higher percentage of arterial hypertension and more hyperlipidemia (p<0.001). Conclusion In pediatric renal transplantation, an everolimus-based regimen with low-dose cyclosporine yields comparable four year results as a standard regimen, but with a different side effect profile. PMID:26407177

  10. Impact of switching from mycophenolate mofetil to enteric-coated mycophenolate sodium on gastrointestinal side effects in patients with autoimmune disease: a Phase III, open-label, single-arm, multicenter study

    PubMed Central

    Manger, Bernhard; Hiepe, Falk; Schneider, Matthias; Worm, Margitta; Wimmer, Peter; Paulus, Eva-Maria; Schwarting, Andreas

    2015-01-01

    Background The purpose of this study was to assess changes in gastrointestinal symptom severity in patients with autoimmune disease who were switched from mycophenolate mofetil to enteric-coated mycophenolate sodium (EC-MPS). Methods In this national, explorative, single-arm study, 111 patients were enrolled and switched to equimolar EC-MPS at baseline. The primary endpoint was change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6–8 weeks of treatment (Visit 2). The optional follow-up visit was 6–12 weeks after completion of the study (Visit 2). Secondary endpoints were changes in GSRS subscale score; changes in gastrointestinal-related quality of life measured by the Gastrointestinal Quality of Life Index (GIQLI); and general health-related quality of life (HRQoL) measured by Psychological General Well-Being Index and assessment of overall treatment effect (OTE). Change was evaluated by paired t-tests. Results At Visit 2, the mean ± standard deviation GSRS total score improved from 2.28±1.13 to 2.02±0.93 points. The change (−0.28±0.92 points, P=0.002) was statistically significant. The change at the follow-up visit (−0.36±0.94 points, P=0.001) was statistically significant and more than the minimal clinical important difference. GSRS subscores showed statistically significant and clinically relevant improvement for abdominal pain (−0.51±1.2 points, P<0.001) and indigestion (−0.42±1.33 points, P=0.002). Overall GIQLI score showed significant improvement from baseline to Visit 2 (−5.8±18.6 points, P=0.002). Per OTE, improvement was reported in 44.1% and 34.2% patients as rated by physicians and patients, respectively. The majority of patients (55%) reported OTE-HRQoL as unchanged. Diarrhea and nausea were the commonly reported adverse events. Conclusion Patients switched to EC-MPS experienced less gastrointestinal symptom burden and showed improvement in HRQoL. PMID:26229499

  11. Mycophenolate mofetil and curcumin provide comparable therapeutic benefit in experimental chronic kidney disease: role of Nrf2-Keap1 and renal dopamine pathways.

    PubMed

    Tapia, Edilia; García-Arroyo, Fernando; Silverio, Octaviano; Rodríguez-Alcocer, Alma N; Jiménez-Flores, Ana B; Cristobal, Magdalena; Arellano, Abraham S; Soto, Virgilia; Osorio-Alonso, Horacio; Molina-Jijón, Eduardo; Pedraza-Chaverri, José; Sanchez-Lozada, Laura G

    2016-07-01

    Increased oxidative stress and inflammation have an important role in the pathophysiology of chronic kidney disease (CKD). On the other hand, more affordable therapeutic alternatives for treating this disease are urgently needed. Therefore, we compared the therapeutic efficacy of curcumin and mycophenolate mofetil (MMF) in 5/6 nephrectomy (5/6 Nx) model of CKD. Also, we evaluated whether both compounds provide benefit through the preservation of similar antioxidant mechanisms. Four groups of male Wistar were studied over a period of 4 wk. Control sham group (n= 12), 5/6 Nx (n = 12), 5/6 Nx + MMF (30 mg/k BW/day, n = 11) and 5/6 Nx + Curcumin (120 mg/k BW/day, n = 12). Renal function and markers of oxidative stress and inflammation were evaluated. Also Nrf2-Keap1 and renal dopamine, antioxidant pathways were assessed. 5/6 Nx induced an altered renal autoregulation response, proteinuria, and hypertension; these effects were in association with increased oxidative stress, endothelial dysfunction and renal inflammation. The mechanisms associated with these alterations included a reduced nuclear translocation of Nrf2 and hyperphosphorylation of dopamine D1 receptor with a concurrent overactivation of renal NADPH oxidase. Treatments with MMF and curcumin provided equivalent therapeutic efficacy as both prevented functional renal alterations as well as preserved antioxidant capacity and avoided renal inflammatory infiltration. Moreover, both treatments preserved Nrf2-Keap1 and renal dopamine antioxidant pathways. In summary, therapeutic strategies aimed to preserve renal antioxidant pathways can help to retard the progression of CKD. PMID:27050624

  12. Efficacy and safety of a conversion from the original tacrolimus and mycophenolate mofetil to the generics Tacpan® and Mowel® after liver transplantation

    PubMed Central

    Vollmar, Johanna; Bellmann, Maren Christina; Darstein, Felix; Hoppe-Lotichius, Maria; Mittler, Jens; Heise, Michael; Rüttger, Bernd; Weyer, Veronika; Zimmermann, Anca; Lang, Hauke; Galle, Peter R; Zimmermann, Tim

    2015-01-01

    Background Expensive pharmaceuticals are a major reason for cost intensive health care systems. Long-term immunosuppressive therapy plays a relevant role after organ transplantation. Patents of original drugs have expired and cheaper products are available. Little data are available regarding efficacy and safety of generic immunosuppressive agents. Methods In this prospective study, 25 patients, who were clinically stable for a minimum of 2 years after liver transplantation, were converted from the original formulations of tacrolimus (TAC) and mycophenolate mofetil to the generics Tacpan® (TAP) and Mowel® (MOW). Patients were followed-up for 6 months. Results were compared retrospectively to 25 age- and sex-matched controls treated with the original brands. Results In the matched-pair analysis of TAC trough level/dose ratio, no significant difference was found between TAP/MOW and TAC/mycophenolate mofetil groups. No acute rejection occurred in either group. In total, 17 patients reported mild side effects in the TAP/MOW group. The most common side effects were gastrointestinal symptoms. Intra-individual analysis of costs revealed a considerable cost reduction in the TAP/MOW group (in median 25.03%; P<0.001). Conclusion In summary, the use of the generics TAP/MOW is effective and seems to be safe and cost-efficient in stable liver-transplantation patients. PMID:26604701

  13. Mycophenolate revisited.

    PubMed

    van Gelder, Teun; Hesselink, Dennis A

    2015-05-01

    The patent of mycophenolate mofetil (MMF) has expired, and for enteric-coated mycophenolate sodium (EC-MPS), this will happen in 2017. In the twenty years these drugs have been used, they have become extremely popular. In this review, the reasons for the popularity of mycophenolate are discussed, including the benefits compared to azathioprine. MMF and EC-MPS are therapeutically equivalent. Although neither is considered to be a narrow therapeutic index drug, this should not lead to careless switching between the innovator drug and generic formulations, or between one generic formulation and another. The pipeline of new immunosuppressive drugs is dry, and it is very likely that we will be using mycophenolate for many more years to come as a first-line immunosuppressive drug in our transplant population. Whether or not the development of donor-specific anti-HLA antibodies is related to drug exposure (mycophenolic acid concentrations) remains to be investigated. PMID:25758949

  14. Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients.

    PubMed

    Prémaud, A; Rousseau, A; Le Meur, Y; Venisse, N; Loichot, C; Turcant, A; Hoizey, G; Compagnon, P; Hary, L; Debruyne, D; Saivin, S; Jacqz-Aigrain, E; Marquet, P

    2010-02-01

    The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians' compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians' compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1+/-14.6mgh/L versus 36.7+/-16.3mgh/L, p=0.0035) and to more AUCs in the target range (69% versus 56%, p=0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses. PMID:19800973

  15. Graft-versus-Host Disease Prophylaxis in Unrelated Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil.

    PubMed

    Moiseev, Ivan S; Pirogova, Olga V; Alyanski, Alexandr L; Babenko, Elena V; Gindina, Tatyana L; Darskaya, Elena I; Slesarchuk, Olga A; Bondarenko, Sergey N; Afanasyev, Boris V

    2016-06-01

    Clinical efficacy of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has been demonstrated in haploidentical and HLA-matched bone marrow but not in unrelated peripheral blood stem cell (PBSC) transplantations. Also, no direct comparisons have been published with current standard of care, combination of antithymocyte globulin (ATG), calcineurin inhibitors, and either methotrexate or mycophenolate mofetil (MMF). Eighty-six adult patients (median age 34 years; range, 18 to 59) with acute myeloblastic and lymphoblastic leukemia underwent unrelated PBSC transplantation with PTCy, tacrolimus, and MMF as GVHD prophylaxis in the single-center trial (clinicaltrial.govNCT02294552). The control group comprised 125 consecutive historical control patients who received ATG, tacrolimus, and methotrexate or MMF. Cumulative incidences of grades II to IV acute (19% versus 45%, P = .0003), grades III to IV acute (4% versus 27%, P < .0001), and chronic GVHD (16% versus 65%, P < .0001) were significantly lower in the PTCy compared with the ATG group. PTCy-based prophylaxis was associated with reduced incidence of nonrelapse mortality (16% versus 36%, P = .005; HR, .55; 95% CI, .34 to .89) and improved overall survival (69% versus 40%, P = .0007; HR, .43; 95% CI, .26 to .70), event-free survival (65% versus 38%, P = .0006; HR, .49; 95% CI, .31 to .78), and GVHD relapse-free survival (52% versus 12%, P < .0001). PTCy-based prophylaxis also had a better safety profile compared with ATG with reduced incidence of veno-occlusive disease, cytomegalovirus reactivation, invasive mycosis, and reduced severity of mucositis. In this study we demonstrated that PTCy in combination with tacrolimus and MMF is a safe and effective GVHD prophylaxis for unrelated PBSC transplantation. Although there are several limitations of the historical control approach, this study suggests the superiority of a PTCy-based approach over an ATG

  16. A Retrospective Comparison of Mycophenolate Mofetil with Low-Exposure Cyclosporine Versus Standard Cyclosporine Therapy in De Novo Liver Transplant Patients.

    PubMed

    Senft, Jonas D; Gotthardt, Daniel N; Frischbier, Lina; Bruns, Helge; Schemmer, Peter

    2015-01-01

    BACKGROUND Data on low-exposure calcineurin inhibitor therapy with mycophenolate mofetil (MMF) in de novo liver transplant patients are limited and restricted to tacrolimus. MATERIAL AND METHODS Twenty-eight patients receiving cyclosporine and MMF at a single center were identified retrospectively and categorized as low-exposure or standard-exposure CsA (median concentration <80 ng/mL [n=16] or ≥80 ng/mL [n=12] during days 1-7) and analyzed to 12 weeks post-transplant. RESULTS Biopsy-proven acute rejection (Banff ≥4) occurred in 3 low-CsA patients and no standard-CsA patients (p=0.238); graft failure occurred in 4 and zero patients, respectively (p=0.113); no graft loss was attributable to rejection. Mean (SD) estimated GFR at baseline and week 12 was 79.5 (45.3) and 79.3 (24.5) mL/min/1.73 m2 in the low-CsA group (p=0.508), and 106.0 (66.9) and 86.7 (23.2) mL/min/1.73 m2 in the standard-CsA group (p=0.093). Estimated GFR decreased significantly in patients with good baseline renal function (≥80 mL/min/1.73 m2) in the standard-CsA (p=0.028) and increased markedly in patients with poor function (≤60 mL/min/1.73 m2) given low-CsA (p=0.043). There was no significant between-group difference regarding incidence of infections. CONCLUSIONS These preliminary findings suggest that immunosuppressive efficacy is maintained with low-exposure CsA and MMF in de novo liver transplant patients and good baseline renal function may be better preserved, but no benefit for infections was observed. PMID:26364728

  17. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients.

    PubMed

    Vítko, Stefan; Margreiter, Raimund; Weimar, Willem; Dantal, Jacques; Kuypers, Dirk; Winkler, Michael; Øyen, Ole; Viljoen, Hendrik G; Filiptsev, Pavel; Sadek, Sami; Li, Yulan; Cretin, Nathalie; Budde, Klemens

    2005-10-01

    Everolimus 1.5 or 3 mg/day was compared with mycophenolate mofetil (MMF) 2 g/day in a randomized, multicenter 36-month trial in de novo renal allograft recipients (n = 588) receiving cyclosporine microemulsion (CsA) and corticosteroids. The study was double-blind until all patients had completed 12 months, then open-label. By 36 months, graft loss occurred in 7.2, 16.7 and 10.7% of patients in the everolimus 1.5, 3 mg/day, and MMF groups, respectively (p = 0.0048 for everolimus 1.5 mg/day vs. 3 mg/day); efficacy failure (biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up) occurred in 33.0, 38.9 and 37.2% of patients (p = 0.455 overall), respectively. Mortality and incidence of BPAR were comparable in all groups. Creatinine values were higher in everolimus groups, requiring a protocol amendment that recommended lower CsA exposure. Diarrhea, lymphocele, peripheral edema and hyperlipidemia were more common among everolimus-treated patients, whereas viral infections, particularly cytomegalovirus infection, increased in the MMF group. Overall safety and tolerability were better with MMF and everolimus 1.5 mg/day than with everolimus 3 mg/day. In conclusion, at 36 months, an immunosuppressive regimen containing everolimus 1.5 mg/day had equivalent patient, and graft survival and rejection rates compared with MMF in de novo renal transplant recipients, whereas everolimus 3 mg/day had inferior graft survival. Renal dysfunction in everolimus cohorts necessitates close monitoring. PMID:16162203

  18. Advantage of tacrolimus/mycophenolate mofetil regimen for cytotoxic T cell-mediated defence and its inhibition by additive steroid administration in high-risk liver transplant recipients.

    PubMed

    Uemoto, S; Ozawa, K; Kaido, T; Mori, A; Fujimoto, Y

    2016-04-01

    Our previous work revealed that the recipients with the highest pre-existing numbers of CD8(+) effector T cells (TE ) [hyperparathyroidism (HPT)E recipients] occupied approximately 30% of adult transplant recipients performed in our hospital. HPTE recipients demonstrated very poor clinical outcome compared with the remaining 70% of recipients with the lowest pre-existing TE (LPTE recipient). This study aimed to clarify the best combined immunosuppressive regimen related to function of cytotoxic T lymphocytes (CTLs) for HPTE recipients. Eighty-one HPTE recipients were classified into three types, according to the immunosuppressive regimens: type 1, tacrolimus (Tac)/glucocorticoid (GC); type 2, Tac/mycophenolate mofetil (MMF)/GC; and type 3, Tac/MMF. Frequencies of severe infection, rejection and hospital death were the highest in types 1 and 2, whereas the lowest occurred in type 3. The survival rate in type 3 was the highest (100%) during follow-up until post-operative day 2000. Regarding the immunological mechanism, in type 1 TE perforin and interferon (IFN)-γ were generated through the self-renewal of CD8(+) central memory T cells (TCM ), but decreased in the early post-transplant period due to marked down-regulation of interleukin (IL)-12 receptor beta-1 of TCM. In type 2, the self-renewal TCM did not develop, and the effector function could not be increased. In type 3, in contrast, the effectors and cytotoxicity were correlated inversely with IL-12Rβ1(+) TCM levels, and increased at the highest level around the pre-transplant levels of IL-12Rβ1(+) TCM . However, the immunological advantage of Tac/MMF therapy was inhibited strongly by additive steroid administration. PMID:26560892

  19. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis

    PubMed Central

    Tamirou, Farah; D'Cruz, David; Sangle, Shirish; Remy, Philippe; Vasconcelos, Carlos; Fiehn, Christoph; Ayala Guttierez, Maria del Mar; Gilboe, Inge-Magrethe; Tektonidou, Maria; Blockmans, Daniel; Ravelingien, Isabelle; le Guern, Véronique; Depresseux, Geneviève; Guillevin, Loïc; Cervera, Ricard; Houssiau, Frédéric A

    2016-01-01

    Objective To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome. Methods In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up. Results Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker. Conclusions The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome. Trial registration number NCT00204022. PMID:25757867

  20. Cyclosporine Plus Methotrexate or Cyclosporine Plus Mycophenolate Mofetil as Graft Versus Host Disease Prophylaxis in Acute Leukemia Transplant: Comparison of Toxicity, Engraftment Kinetics and Transplant Outcome.

    PubMed

    Gupta, Alok; Punatar, Sachin; Mathew, Libin; Kannan, Sadhana; Khattry, Navin

    2016-09-01

    We sought to compare two graft-versus-host disease (GVHD) prophylaxis regimen, cyclosporine and methotrexate (CsA+MTX) with CsA+mycophenolate mofetil (MMF) in 77 acute leukemia patients who underwent hematopoietic stem cell transplant (HSCT) between January 2008 and March 2013. Fifty-three patients received CsA+MTX while 24 received CsA+MMF. The incidence of grade 3-4 mucositis and grade 3-4 diarrhea was 74 and 6 % with CsA+MTX compared to 33 % and 21 % with CsA+MMF (P = 0.001 and 0.09 respectively). Forty-two (79 %) patients in CsA+MTX group required total parenteral nutrition compared to 14 (58 %) in CsA+MMF group (P = 0.09). The incidence of engraftment fever was 17 % with CsA+MTX and 41 % with CsA+MMF (P = 0.02). The median time to neutrophil and platelet engraftment was 14 days and 13 days with CsA+MTX compared to 12 days and 10 days with CsA+MMF (P = 0.003 and 0.08 respectively). The incidence of any grade and grade II-IV acute GVHD was 45 and 13 % with CsA+MTX compared to 42 and 29 % with CsA+MMF (P = NS). Incidence of overall and extensive chronic GVHD was 57 and 38 % with CsA+MTX compared to 42 and 17 % with CsA+MMF (P = NS). Incidence of relapse was 38 % with CsA+MTX compared to 33 % with CsA+MMF (P = NS). TRM was 6 % with CsA+MTX and 21 % with CsA+MMF (P = NS). At 2 years, overall survival (OS) was 64 % in CsA+MTX group compared to 46 % in CsA+MMF group (P = NS). We conclude that CsA+MMF is associated with lesser toxicity, faster myeloid engraftment and similar rates of acute and chronic GVHD, TRM, relapse and OS compared to CsA+MTX in acute leukemia transplant. PMID:27429515

  1. Everolimus in combination with mycophenolate mofetil as pre- and post-transplantation immunosuppression after nonmyeloablative hematopoietic stem cell transplantation in canine littermates.

    PubMed

    Machka, Christoph; Lange, Sandra; Werner, Juliane; Wacke, Rainer; Killian, Doreen; Knueppel, Anne; Knuebel, Gudrun; Vogel, Heike; Lindner, Iris; Roolf, Catrin; Murua Escobar, Hugo; Junghanss, Christian

    2014-09-01

    The mammalian target of rapamycin inhibitor everolimus (RAD001) is a successfully used immunosuppressant in solid-organ transplantation. Several studies have already used RAD001 in combination with calcineurin inhibitors after hematopoietic stem cell transplantation (HSCT). We investigated calcineurin inhibitor-free pre- and post-transplantation immunosuppression of RAD001 combined with mycophenolate mofetil (MMF) in a nonmyeloablative HSCT setting. After nonmyeloablative conditioning with 2 Gy total body irradiation, 8 dogs received HSCT from dog leukocyte antigen-identical siblings. Immunosuppressives were given at doses of 1.5 mg RAD001 twice daily from day -1 to +49, then tapered until day +56, and 20 mg/kg MMF from day 0 to +28, then tapered until day +42. An historical cyclosporin A (CsA)/MMF regimen was used in the control group. All dogs engrafted. Median platelet nadir amounted in all dogs to 0 × 10(9)/L (median, day +10; duration <50 × 10(9)/L, 22 days) and median leukocyte nadir was 1.0 × 10(9)/L (range, .1 to 2.5 × 10(9)/L; median, day +13). Eventually, 5 of 8 (63%) animals rejected their grafts. Two dogs died of infections on day +19 and +25. Pharmacokinetics of RAD001 and MMF showed median trough levels of 19.1 (range, 10.5 to 43.2) μg/L and .3 (.1 to 1.3) mg/L, respectively. The median area under the curve was 325 (range, 178 to 593) μg/L × hour for RAD001 and 29.6 (range, 7.9 to 40.5) ng/L × hour for MMF. All dogs developed clinically mucosal viral infections during the clinical course. Compared with the control group, the level of toxicities for RAD001/MMF increased in all qualities. Combined immunosuppression of RAD001 and MMF after nonmyeloablative HSCT is associated with significant toxicities, including a prolonged platelet recovery time as well as increased infections compared to the CsA/MMF regimen. PMID:24923538

  2. A randomized, blinded, parallel-group, pilot trial of mycophenolate mofetil (CellCept) compared with interferon beta-1a (Avonex) in patients with relapsing–remitting multiple sclerosis

    PubMed Central

    Frohman, Elliot M.; Cutter, Gary; Remington, Gina; Gao, Hongjiang; Rossman, Howard; Weinstock-Guttman, Bianca; Durfee, Jacqueline E.; Conger, Amy; Carl, Ellen; Treadaway, Katherine; Lindzen, Eric; Salter, Amber; Frohman, Teresa C.; Shah, Anjali; Bates, Angela; Cox, Jennifer L.; Dwyer, Michael G.; Stüve, Olaf; Greenberg, Benjamin M.; Racke, Michael K.; Zivadinov, Robert

    2010-01-01

    Background: Mycophenolate mofetil (MMF, CellCept®) has been utilized as an antirejection agent in transplant recipients and in patients with myriad autoimmune disorders including multiple sclerosis (MS). Objective: To investigate radiographic and clinical safety involving monotherapy use of daily oral MMF (1 g b.i.d.) versus weekly intramuscular interferon beta 1a (Avonex® at 30 mcg) in relapsing–remitting MS (RRMS). Methods: We organized a randomized, serial, 6-monthly, MRI-blinded, parallel-group multicenter pilot study to determine the safety of MMF versus interferon beta monotherapy in 35 untreated patients with RRMS, all of whom exhibited evidence of gadolinium (Gd) enhancement on a screening MRI of the brain. The primary outcome was the reduction in the cumulative mean number of combined active lesions (CAL), new Gd-enhancing lesions, and new T2 lesions on MRI analyses. Results: Both interferon beta and MMF appeared safe and well tolerated in the majority of patients. There was no difference between MMF therapy and the standard regimen of interferon beta therapy on the primary safety MRI endpoints of the study. However, the MMF group showed a trend toward a lower accumulation of combined active lesions, CAL, Gd and T2 lesions when compared with interferon beta treated patients. Conclusions: The results from this pilot study suggest that the application of MMF monotherapy in MS deserves further exploration. PMID:21180633

  3. Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation.

    PubMed

    Offer, Katharine; Kolb, Michelle; Jin, Zhezhen; Bhatia, Monica; Kung, Andrew L; George, Diane; Garvin, James H; Robinson, Chalitha; Sosna, Jean; Karamehmet, Esra; Satwani, Prakash

    2015-03-01

    Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL. PMID:25536217

  4. Fludarabine and Total-Body Irradiation Followed By Donor Stem Cell Transplant and Cyclosporine and Mycophenolate Mofetil in Treating HIV-Positive Patients With or Without Cancer

    ClinicalTrials.gov

    2015-08-28

    Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV Infection; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Central Nervous System Lymphoma; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma

  5. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease.

    PubMed

    Abd Rahman, Azrin N; Tett, Susan E; Staatz, Christine E

    2013-05-01

    polymorphisms in genes encoding uridine diphosphate glucuronosyltransferase were identified in some studies as having a significant influence on the pharmacokinetics of mycophenolate. Typical MPA CL/F values in autoimmune disease patients were generally slightly lower than values published previously in population pharmacokinetic studies involving renal allograft recipients, possibly because of usage of ciclosporin, poorer renal function or lower serum albumin levels in the renal transplant cohort. In a single crossover study involving ten subjects only, significantly higher MPA AUC12 and maximum MPA concentration (C max) and lower MPA CL/F were reported following EC-MPS administration compared to mycophenolate mofetil administration. MPA exposure correlated well with treatment efficacy in patients with autoimmune disease (response to treatment, active disease and disease markers); however the relationship between MPA exposure and adverse events (infectious episodes, haematological toxicity and gastrointestinal symptoms) was unclear. Further investigation is required in autoimmune diseases such as chronic plaque psoriasis and rheumatoid arthritis and following EC-MPS administration. The extent of within-subject variability in the pharmacokinetics of mycophenolate is largely unknown and potential covariate influences need to be confirmed in studies with large subject numbers. A relationship between MPA and MPA metabolite exposure and toxicity needs to be established. The contribution of pharmacogenetics to the pharmacokinetics and pharmacodynamics of mycophenolate warrants further investigation, as does the utility of therapeutic drug monitoring. Dosing to achieve a target MPA AUC12 >35 mg·h/L is likely to lead to better efficacy outcomes in patients with autoimmune disease (rather than just giving standard doses, which lead to a wide range of exposures). However, the relationship between mycophenolate exposure and toxicity requires further investigation to determine the upper

  6. Treatment of Idiopathic Membranous Nephropathy

    PubMed Central

    Austin, Howard A.

    2012-01-01

    Exciting progress recently has been made in our understanding of idiopathic membranous nephropathy, as well as treatment of this disease. Here, we review important advances regarding the pathogenesis of membranous nephropathy. We will also review the current approach to treatment and its limitations and will highlight new therapies that are currently being explored for this disease including Rituximab, mycophenolate mofetil, and adrenocorticotropic hormone, with an emphasis on results of the most recent clinical trials. PMID:22859855

  7. [Clinical guideline for the treatment of lupus nephritis and single-centre results of mycofenolate mofetil among patients with lupus nephritis in the National Institute of Rheumatology and Physiotherapy, Budapest].

    PubMed

    Szabó, Melinda Zsuzsanna; Kiss, Emese

    2016-08-01

    The authors present the latest guideline for the treatment of lupus nephritis and their own single-centre results with mycofenolate mofetil treated lupus nephritis. Lupus nephritis and mainly its proliferative form is a frequent and potentially life-threatening manifestation of systemic lupus erythematosus that can lead to end-stage renal disease. The treatment of lupus nephritis greatly improved in the last decades; mycofenolate mofetil has become an alternative of cyclophosphamide both in remission induction and as a maintenance regimen as well in the treatment of Class III and IV glomerulonephritis. The authors ordered mycofenolate mofetil for 25 patients with lupus nephritis so far. Histologically most of them had Class III (A/C) or IV (A) glomerulonephritis (30-30%), and only 16% of the patients had renal impairment at that time. Mycofenolate mofetil given after glucocorticoid and cyclophosphamide induction therapy reduced the daily proteinuria from 3.18 grs to 1.06 grs. Complete remission could be achieved in 24% and partial remission in 48% of the patients. The authors conclude that mycofenolate mofetil is effective in the therapy of lupus nephritis. Orv. Hetil., 2016, 157(35), 1385-1393. PMID:27569461

  8. Hematologic toxicity of immunosuppressive treatment.

    PubMed

    Danesi, R; Del Tacca, M

    2004-04-01

    The administration of immunosuppressive agents may be associated with the occurrence of hematologic toxicity, such as anemia, due to bone marrow suppression or hemolysis, leukopenia, and thrombocytopenia. The administration of azathioprine and mycophenolate mofetil is more frequently associated with bone marrow suppression, while hemolytic-uremic syndrome may occur after administration of cyclosporine, tacrolimus, or muromonab (OKT3) and may be associated with the loss of the allograft. Moreover, microangiopathic hemolytic anemia and thrombocytopenia are rare, but potentially severe, complications of immunosuppressive treatment with tacrolimus and cyclosporine; they are characterized by intravascular hemolysis due to mechanical destruction of red cells as a result of pathological changes in small blood vessels. Viral infections (cytomegalovirus), administration of antiviral agents (gancyclovir), inhibitors of angiotensin-converting enzyme and angiotensin II receptor antagonists, antibacterial agents (sulfamethoxazole and trimethoprim), and allopurinol may aggravate bone marrow suppression, particularly when administered with agents that interfere with purine biosynthesis, including azathioprine and mycophenolate mofetil. PMID:15110637

  9. Mycophenolic Acid Inhibits Migration and Invasion of Gastric Cancer Cells via Multiple Molecular Pathways

    PubMed Central

    Dun, Boying; Sharma, Ashok; Teng, Yong; Liu, Haitao; Purohit, Sharad; Xu, Heng; Zeng, Lingwen; She, Jin-Xiong

    2013-01-01

    Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA’s antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA’s overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment. PMID:24260584

  10. In Vitro Influence of Mycophenolic Acid on Selected Parameters of Stimulated Peripheral Canine Lymphocytes

    PubMed Central

    Guzera, Maciej; Szulc-Dąbrowska, Lidia; Cywińska, Anna; Archer, Joy; Winnicka, Anna

    2016-01-01

    Mycophenolic acid (MPA) is an active metabolite of mycophenolate mofetil, a new immunosuppressive drug effective in the treatment of canine autoimmune diseases. The impact of MPA on immunity is ambiguous and its influence on the canine immune system is unknown. The aim of the study was to determine markers of changes in stimulated peripheral canine lymphocytes after treatment with MPA in vitro. Twenty nine healthy dogs were studied. Phenotypic and functional analysis of lymphocytes was performed on peripheral blood mononuclear cells cultured with mitogens and different MPA concentrations– 1 μM (10−3 mol/m3), 10 μM or 100 μM. Apoptotic cells were detected by Annexin V and 7-aminoactinomycin D (7-AAD). The expression of antigens (CD3, CD4, CD8, CD21, CD25, forkhead box P3 [FoxP3] and proliferating cell nuclear antigen [PCNA]) was assessed with monoclonal antibodies. The proliferation indices were analyzed in carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled cells. All analyses were performed using flow cytometry. The influence of MPA on apoptosis was dependent on the mechanism of cell activation and MPA concentration. MPA caused a decrease in the expression of lymphocyte surface antigens, CD3, CD8 and CD25. Its impact on the expression of CD4 and CD21 was negligible. Its negative influence on the expression of FoxP3 was dependent on cell stimulation. MPA inhibited lymphocyte proliferation. In conclusion, MPA inhibited the activity of stimulated canine lymphocytes by blocking lymphocyte activation and proliferation. The influence of MPA on the development of immune tolerance–expansion of Treg cells and lymphocyte apoptosis–was ambiguous and was dependent on the mechanism of cellular activation. The concentration that MPA reaches in the blood may lead to inhibition of the functions of the canine immune system. The applied panel of markers can be used for evaluation of the effects of immunosuppressive compounds in the dog. PMID:27138877

  11. A multicentre, randomised controlled study of enteric-coated mycophenolate sodium for the treatment of relapsed or resistant proliferative lupus nephritis: an Asian experience

    PubMed Central

    Anutrakulchai, Sirirat; Panaput, Thanachai; Wongchinsri, Jeerapat; Chaishayanon, Somchai; Satirapoj, Bancha; Traitanon, Opas; Pima, Warabhorn; Rukrung, Chutima; Thinkhamrop, Bandit; Avihingsanon, Yingyos

    2016-01-01

    Objective The optimal treatment of relapse or resistant lupus nephritis (LN) is still unclear. Mycophenolate might be an alternative therapy to avoid toxicities of cyclophosphamide (CYC). This study was aimed to compare enteric-coated mycophenolate sodium (EC-MPS) versus intravenous CYC as an induction therapy. Methods The study was a 12-month period of multicentre, open-labelled randomised controlled trial. Fifty-nine patients who had relapsed (36%) or who were resistant to previous CYC treatment (64%) and all who were biopsy-proven class III/IV, were randomised into CYC (n=32) and EC-MPS groups (n=27). The CYC group received intravenous CYC 0.5–1 g/m2 monthly and the EC-MPS group was treated with EC-MPS 1440 mg/day for first 6 months. After induction therapy, both groups received EC-MPS 720 mg/day until the end of study at 12 months. Results The study was prematurely terminated due to high rate of serious adverse events in CYC arm. Death and serious infections were observed more in the CYC group (15.6% in CYC and 3.5% in EC-MPS; p=0.04). The early discontinuation rates, mainly from serious infections, were significantly higher in CYC group (percentage differences of 16.9; 95% CI 1.3 to 32.4). At the 12th month, both arms were comparable in terms of complete and partial remission rates (68% CYC and 71% EC-MPS) and times to remission (96 days CYC and 97 days EC-MPS). Composites of unfavourable outcomes (death, doubling of serum creatinine, non-remission and intolerance to treatment) were 46.9% and 37% in CYC and EC-MPS (risk difference=9.84; p=0.44). Conclusions EC-MPS may have comparable efficacy, but was better tolerated than CYC. EC-MPS should be an alternative choice of treatment for difficult-to-treat LN, particularly in CYC-experienced LN patients. Due to an early termination of the study, further clinical implementation could be cautiously used. Trial registration number Clinicaltrials.gov ID#NCT01015456. PMID:26835147

  12. [Neurosarcoidosis - clinical characteristics, diagnosis and treatment].

    PubMed

    Horyniecki, Maciej; Konieczna, Marta; Torbus, Magdalena; Pierzchała, Krystyna; Wawrzyńczyk, Maciej; Łabuz-Roszak, Beata

    2016-01-01

    Neurosarcoidosis (NS) manifests itself clinically in approximately 8-13% of patients with sarcoidosis. Granulomas are localized in both the central and peripheral nervous system, mainly within the meninges and cranial nerves. Changes may spread interstitially, occupying different structures of the brain and spinal cord. Diagnosis of NS is made by characteristic clinical symptoms and the exclusion of other diseases, with the presence of specific changes in the magnetic resonance and cerebrospinal fluid, and it is mainly based on histopathological examination. The first choice treatment are corticosteroids. In case of failure or adverse events, methotrexate, azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil and infliximab could be used. PMID:27164284

  13. Treatment of inflammatory myopathy: emerging therapies and therapeutic targets

    PubMed Central

    Moghadam-Kia, Siamak; Aggarwal, Rohit; Oddis, Chester V

    2016-01-01

    Despite the lack of placebo-controlled trials, glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy and myositis-associated interstitial lung disease. Glucocorticoid-sparing agents are often given concomitantly with other immunosuppressive agents, particularly in patients with moderate or severe disease. First-line conventional immunosuppressive drugs include either methotrexate or azathioprine, and when they fail, more aggressive therapy includes mycophenolate mofetil, tacrolimus or cyclosporine, intravenous immunoglobulin, rituximab, or cyclophosphamide, used alone or in various combinations. Further investigations are required to assess the role of more novel therapies in the treatment of myositis and myositis-associated interstitial lung disease. PMID:26313852

  14. Changes in the Immune System of Female Wistar Rats After Exposure to Immunosuppressive Treatment During Pregnancy.

    PubMed

    Kabat-Koperska, J; Kolasa-Wołosiuk, A; Wojciuk, B; Wojciechowska-Koszko, I; Roszkowska, P; Krasnodębska-Szponder, B; Paczkowska, E; Safranow, K; Gołembiewska, E; Machaliński, B; Ciechanowski, K

    2016-06-01

    This experimental study assessed the impact of medications frequently used after kidney transplantation on the immune system of pregnant female Wistar rats. The study evaluates medications, both approved and contraindicated during pregnancy in common therapeutic combinations. The study was conducted on 32 female Wistar rats, subjected to immunosuppressive regimens most commonly used in therapy of human kidney transplant recipients (cyclosporine A, mycophenolate mofetil and prednisone; tacrolimus, mycophenolate mofetil and prednisone; and cyclosporine A, everolimus and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and at 3 weeks of pregnancy. We found drug regimen-dependent differences in cytometry from spleen. Many subpopulations of lymphocytes were suppressed in rats treated with cyclosporine A, mycophenolate mofetil and prednisone and tacrolimus, mycophenolate mofetil and prednisone; the number of NK cells was increased in group of rats treated with cyclosporine A, everolimus and prednisone. We also found changes in histological examination of thymus and spleen of all treated dams. In cytokine assay, we noticed increasing levels of IL-17 with increasing doses of concanavalin A in control group and in group of dams treated with cyclosporine A, mycophenolate mofetil and prednisone. This increase was blocked in rats treated with tacrolimus, mycophenolate mofetil and prednisone and cyclosporine A, everolimus and prednisone. Qualitative, quantitative and morphological changes of immune system in pharmacologically immunosuppressed females have been observed. Thymus structure, spleen composition and splenocytes IL-17 production were mostly affected in drug regimen-dependent manner. PMID:27007325

  15. Immunosuppressive Treatment for Retinal Degeneration in Juvenile Neuronal Ceroid Lipofuscinosis (Juvenile Batten Disease).

    PubMed

    Drack, Arlene V; Mullins, Robert F; Pfeifer, Wanda L; Augustine, Erika F; Stasheff, Steven F; Hong, Sandy D

    2015-01-01

    Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) presents with progressive vision loss at 4-7 years of age. Blindness results within 2 years, followed by inexorable neurologic decline and death. There is no treatment or cure. Neuroinflammation is postulated to play a role in the neurodegeneration. The JNCL mouse model demonstrated decreased neuroinflammation and improved motor skills with immunosuppression. Based on this work, a short-term human clinical trial of mycophenolate mofetil has begun, however longer term effects, and whether immunosuppression modulates vision loss, have not been studied. We report a JNCL patient treated with immunosuppressive therapy in whom visual function was comprehensively characterized over 2 years. PMID:24547931

  16. Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT

    ClinicalTrials.gov

    2016-06-14

    Adult Hodgkin Lymphoma; Adult Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Hodgkin Lymphoma; Childhood Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelofibrosis; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Non-Hodgkin Lymphoma

  17. How accurate and precise are limited sampling strategies in estimating exposure to mycophenolic acid in people with autoimmune disease?

    PubMed

    Abd Rahman, Azrin N; Tett, Susan E; Staatz, Christine E

    2014-03-01

    Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h post-dose (AUC12) is likely to lead to better treatment outcomes in patients with autoimmune disease than a standard fixed-dose strategy. This review summarizes the available published data around concentration monitoring strategies for MPA in patients with autoimmune disease and examines the accuracy and precision of methods reported to date using limited concentration-time points to estimate MPA AUC12. A total of 13 studies were identified that assessed the correlation between single time points and MPA AUC12 and/or examined the predictive performance of limited sampling strategies in estimating MPA AUC12. The majority of studies investigated mycophenolate mofetil (MMF) rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation of MPA. Correlations between MPA trough concentrations and MPA AUC12 estimated by full concentration-time profiling ranged from 0.13 to 0.94 across ten studies, with the highest associations (r (2) = 0.90-0.94) observed in lupus nephritis patients. Correlations were generally higher in autoimmune disease patients compared with renal allograft recipients and higher after MMF compared with EC-MPS intake. Four studies investigated use of a limited sampling strategy to predict MPA AUC12 determined by full concentration-time profiling. Three studies used a limited sampling strategy consisting of a maximum combination of three sampling time points with the latest sample drawn 3-6 h after MMF intake, whereas the remaining study tested all combinations of sampling times. MPA AUC12 was best predicted when three samples were taken at pre-dose and at 1 and 3 h post-dose with a mean bias and imprecision of 0.8 and 22.6 % for multiple linear regression analysis and of -5.5 and 23.0 % for

  18. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage

    PubMed Central

    Crane, Genevieve M.; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E.; Burger, Peter C.; Ambinder, Richard F.; Swinnen, Lode J.; Borowitz, Michael J.; Duffield, Amy S.

    2015-01-01

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011–2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  19. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage.

    PubMed

    Crane, Genevieve M; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E; Burger, Peter C; Ambinder, Richard F; Swinnen, Lode J; Borowitz, Michael J; Duffield, Amy S

    2015-10-20

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  20. [Systemic treatment of cutaneous lupus erythematosus].

    PubMed

    Wenzel, Joerg; Bieber, Thomas; Uerlich, Manfred; Tüting, Thomas

    2003-09-01

    The treatment of cutaneous lupus erythematosus (CLE) remains a therapeutic challenge. In many cases, systemic treatment of the disease is necessary, especially in cases resistant to topical treatment or with internal organ involvement. Even though many different agents can be employed in this situation, most are not approved in Germany for the treatment of CLE. We give an overview of the agents used in the systemic treatment of CLE and review their mechanisms of action, indications and their practical use in cutaneous LE based on literature results and our own experience. We discuss corticosteroids, antimalarials, dapsone, azathioprine, cyclophosphamide, methotrexate, retinoids, cyclosporine A, mycophenolate mofetil, sulfasalazine, thalidomide, clofazimine, tacrolimus, immunoglobulins, monoclonal antibodies, plasmapheresis, etanercept, infliximab, feflunomid, gold and interferon-alpha. PMID:16285276

  1. Mycophenolate

    MedlinePlus

    ... attack of the transplanted organ by the immune system of the person receiving the organ) in people ... agents. It works by weakening the body's immune system so it will not attack and reject the ...

  2. Mycophenolate

    MedlinePlus

    ... Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for ...

  3. Current treatment strategies in autoimmune hemolytic disorders.

    PubMed

    Barcellini, Wilma

    2015-10-01

    Autoimmune hemolytic anemia (AIHA) is a heterogeneous disease usually classified according to the thermal range of the autoantibody in warm, cold and mixed forms. The treatment of AIHA is still not evidence-based. Corticosteroids are the first-line therapy for warm AIHA. For refractory/relapsed cases, the choice is between splenectomy (effective in ∼70% cases but with a presumed cure rate of 20%) and rituximab (effective in ∼70-80% of cases), which is becoming the preferred second-line treatment, and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins and danazol. For severe or refractory cases, last option treatments are plasma-exchange, high-dose cyclophosphamide and alemtuzumab. As regards cold agglutinin disease, rituximab is now recommended as first-line treatment. PMID:26343892

  4. Non-relapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation

    PubMed Central

    McDermott, Cara L.; Sandmaier, Brenda M.; Storer, Barry; Li, Hong; Mager, Donald E.; Boeckh, Michael J.; Bemer, Meagan J.; Knutson, Jennifer; McCune, Jeannine S.

    2013-01-01

    We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplant. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (N=132) or unrelated (N=176) donors, and received post-grafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in nine patients, eight of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades 3–4 acute graft versus host disease (aGVHD) and increased non-relapse mortality, but not with day 28 T-cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades 3–4 aGVHD and non-relapse mortality in patients receiving an unrelated donor graft. PMID:23660171

  5. Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation.

    PubMed

    McDermott, Cara L; Sandmaier, Brenda M; Storer, Barry; Li, Hong; Mager, Donald E; Boeckh, Michael J; Bemer, Meagan J; Knutson, Jennifer; McCune, Jeannine S

    2013-08-01

    We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft. PMID:23660171

  6. Frailty, Mycophenolate Reduction, and Graft Loss in Kidney Transplant Recipients

    PubMed Central

    McAdams-DeMarco, Mara A.; Law, Andrew; Tan, Jingwen; Delp, Cassandra; King, Elizabeth A.; Orandi, Babak; Salter, Megan; Alachkar, Nada; Desai, Niraj; Grams, Morgan; Walston, Jeremy; Segev, Dorry L.

    2014-01-01

    Background: Mycophenolate mofetil (MMF) side effects often prompt dose reduction or discontinuation, and this MMF dose reduction (MDR) can lead to rejection and possibly graft loss. Unfortunately, little is known about what factors might cause or contribute to MDR. Frailty, a measure of physiologic reserve, is emerging as an important, novel domain of risk in kidney transplantation (KT) recipients. We hypothesized that frailty, an inflammatory phenotype, might be associated with MDR. Methods: We measured frailty (shrinking, weakness, exhaustion, low activity, and slowed walking speed), other patient and donor characteristics, longitudinal MMF doses, and graft loss in 525 KT recipients. Time-to-MDR was quantified using an adjusted Cox proportional hazards model. Results: By 2 years post-transplant, 54% of frail recipients and 45% of non-frail recipients experienced MDR; by 4 years, incidence was 67% and 51%. Frail recipients were 1.29-times (95%CI:1.01-1.66; P=0.04) more likely to experience MDR, as were deceased donor recipients (aHR=1.92, 95%CI:1.44-2.54, P<0.001) and older adults (age≥65 vs. <65; aHR=1.47, 95%CI:1.10-1.96, P=0.01). MDR was independently associated with a substantially increased risk of death-censored graft loss (aHR=5.24, 95%CI:1.97-13.98, P=0.001). Conclusion: A better understanding of risk factors for MMF intolerance might help in planning alternate strategies to maintain adequate immunosuppression and prolong allograft survival. PMID:25393156

  7. Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages.

    PubMed

    Jonsson, Charlotte A; Carlsten, Hans

    2002-01-01

    Mycophenolic acid (MPA) inhibits reversibly inosine 5(')-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. Previously, mycophenolate mofetil (MMF), the pro-drug of MPA, was shown to exert beneficial effects on the systemic lupus erythematosus (SLE)-like disease in MRLlpr/lpr mice. In this study MPA's immunomodulating effects in vitro on the murine macrophage cell line IC-21 were investigated. The cells were exposed to MPA together with lipopolysaccharide and IFN-gamma. Cytokine, NO(2)(-), and lactate dehydrogenase levels in supernatants and cell lysates were analysed as well as the proliferation of IC-21 cells. MPA exposure reduced the total levels of all molecules investigated and suppressed the proliferation. All MPA-induced effects were reversed by the addition of guanosine to the cultures. Since macrophages play a role in lupus nephritis, our results indicate that modulation of macrophages may be involved in the ameliorating effects of MMF in SLE. PMID:12381354

  8. Immunosuppressive treatment for kidney transplantation.

    PubMed

    Zivčić-Ćosić, S; Trobonjača, Z; Rački, S

    2011-01-01

    Immunosuppressive treatment minimizes unwanted immune reactivity, but it also leads to complications such as metabolic disorders, cardiovascular diseases and malignant tumours. In this paper we summarise the recent developments in action mechanisms of available immunosuppressive drugs and their usage for renal transplantation. These drugs act at various levels of lymphocytic activation and proliferation, and they may have additive or synergic effects when combined. In the majority of patients, the immunosuppressive protocol includes a calcineurin inhibitor (tacrolimus or cyclosporin), an antimetabolite (mycophenolate mofetil or mycophenolic acid) and a corticosteroid. Most patients also receive induction with monoclonal or polyclonal antilymphocytic antibodies. These immunosuppressive drugs allow a one-year survival of renal allografts in over 90% of cases and an incidence of acute rejection episodes below 15%. In most cases, acute cell-mediated rejection can be reversed with pulse doses of methylprednisolone; less often antilymphocytic antibodies must be applied. Acute humoral rejection can be suppressed with high doses of intravenous immunoglobulines or low doses of cytomegalovirus hyperimmune globuline, in combination with plasmapheresis, to obtain a satisfactory reduction of anti-donor antibodies. This treatment also allows renal transplantation for sensitised recipients, or transplantation against a positive cross match or AB0 incompatibility. Less often, immunoadsorption, alemtuzumab, rituximab or splenectomy are applied. New immunosuppressive drugs and protocols are currently under investigation. Immunosuppressive agents and methods targeting the induction of immune tolerance to the donor organ are especially promising. PMID:22286615

  9. RECENT CLINICAL TRIALS IN LUPUS NEPHRITIS

    PubMed Central

    Ward, Michael M.

    2014-01-01

    SYNOPSIS Recent clinical trials have provided evidence for the efficacy of low-dose intravenous cyclophosphamide and mycophenolate mofetil as induction treatment for patients with proliferative lupus nephritis in comparative trials with standard-dose intravenous cyclophosphamide. Trials of maintenance treatments have had more variable results, but suggest that mycophenolate mofetil may be similar to quarterly standard-dose intravenous cyclophosphamide and somewhat more efficacious than azathioprine. Differential responses to mycophenolate mofetil based on ethnicity suggest that it may be more effective in black and Hispanic patients. Rituximab was not efficacious as an adjunct to induction treatment with mycophenolate mofetil. PMID:25034160

  10. Treatment of progressive IgA nephropathy: an update.

    PubMed

    Wang, Weiming; Chen, Nan

    2013-01-01

    IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. About 25-30% of IgAN patients will progress to end-stage kidney disease in 20-25 years. Early-onset symptoms that are highly suggestive of progressive IgAN include massive proteinuria, hypertension, renal damage, glomerular sclerosis, crescent formation, and tubulointerstitial fibrosis. Progressive IgAN may progress to renal failure in a short time. Optimized supportive therapy is the fundamental treatment for progressive IgAN patients, and includes renin-angiotensin system blockers, blood pressure control, antiplatelet and anticoagulant drugs, statins, and allopurinol. In progressive IgAN patients whose clinical and pathological manifestations are more severe, active therapy may be considered including glucocorticoid therapy, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, and other immunosuppressants. However, there are currently controversies on the definition and treatment of progressive IgAN. PMID:23689569

  11. Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab.

    PubMed

    Unal, Sule; Sag, Erdal; Kuskonmaz, Baris; Kesici, Selman; Bayrakci, Benan; Ayvaz, Deniz C; Tezcan, Ilhan; Yalnızoglu, Dilek; Uckan, Duygu

    2014-05-01

    Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up. PMID:24307660

  12. Population pharmacokinetics of mycophenolic acid and dose optimization with limited sampling strategy in liver transplant children

    PubMed Central

    Barau, Caroline; Furlan, Valérie; Debray, Dominique; Taburet, Anne-Marie; Barrail-Tran, Aurélie

    2012-01-01

    AIMS The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h). METHODS Twenty-eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model-building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (ka), the apparent volume of distribution (V/F) and apparent clearance (CL/F). RESULTS Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. ka, estimated at 1.7 h−1 at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h−1. To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II® software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did not differ from reference values. CONCLUSIONS This study allowed the estimation of the population pharmacokinetic MPA parameters. A simple sampling procedure is suggested to help to optimize pediatric patient care. PMID:22329639

  13. Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients.

    PubMed

    Colom, Helena; Lloberas, Núria; Andreu, Franc; Caldés, Ana; Torras, Joan; Oppenheimer, Federico; Sanchez-Plumed, Jaime; Gentil, Miguel A; Kuypers, Dirk R; Brunet, Mercè; Ekberg, Henrik; Grinyó, Josep M

    2014-06-01

    Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure. PMID:24402086

  14. A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients.

    PubMed

    Li, Hong; Mager, Donald E; Bemer, Meagan J; Salinger, David H; Vicini, Paolo; Sandmaier, Brenda M; Nash, Richard; McCune, Jeannine S

    2012-11-01

    Mycophenolate mofetil (MMF) is a key component of postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5-sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC(0-12 h) for Q12-hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC(0-8) (h) for Q8-hour dosing. PMID:22174435

  15. A Limited Sampling Schedule to Estimate Mycophenolic Acid Area Under the Concentration-Time Curve in Hematopoietic Cell Transplantation Recipients

    PubMed Central

    Li, Hong; Mager, Donald E.; Bemer, Meagan J.; Salinger, David H.; Vicini, Paolo; Sandmaier, Brenda M.; Nash, Richard; McCune, Jeannine S.

    2011-01-01

    Mycophenolate mofetil (MMF) is a key component of post-grafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSS) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2 hr MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of one and two compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSS were derived using a simulation approach based on the scaled mean squared error. A five-sample schedule of 2, 2.5, 3, 5, and 6 hr from the start of the infusion precisely estimated MPA AUC0–12 hr for Q12 hr IV MMF. A comparable schedule (2, 2.5, 3, 4 and 6 hr) similarly estimated MPA AUC0–8hr for Q8 hr dosing. PMID:22174435

  16. A Protocol for the Pharmacokinetics of Enteric Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN): an open-label, randomised controlled trial

    PubMed Central

    Ranganathan, Dwarakanathan; John, George T; Healy, Helen; Roberts, Matthew J; Fassett, Robert G; Lipman, Jeffrey; Kubler, Paul; Ungerer, Jacobus; McWhinney, Brett C; Lim, Aaron; Purvey, Megan; Reyaldeen, Reza; Roberts, Jason A

    2013-01-01

    Introduction Mycophenolate sodium, an enteric-coated tablet (EC-MPS), is as effective and safe as mycophenolate mofetil (MMF) in preventing transplant rejection. EC-MPS and MMF improve the outcome of severe lupus nephritis (LN) and have fewer side effects than pulsed intravenous cyclophosphamide. Blood concentrations of mycophenolic acid (MPA), the active metabolite of EC-MPS, vary between participants despite fixed dosing. Interpatient variability has been studied in transplantation, but not well documented in LN. The relationship between MPA concentration and its clinical effect on LN has not been described. Methods and analysis This is a prospective, open-label, randomised controlled trial. –32 participants with LN who meet the inclusion and exclusion criteria will be randomised into two groups: one receiving a fixed dose of EC-MPS and the second, a dosing regimen that is titrated with therapeutic drug monitoring. Included participants will have blood sampled over a period of 8–12 h on three different occasions. Pharmacokinetic parameters will be calculated using non-compartmental methods. Ethics and dissemination The Human Research and Ethics Committee of the Royal Brisbane Women's Hospital have approved this study. The study is registered with Australian and New Zealand Clinical Trials Registry—ACTRN12611000798965 We planned to present the de-identified information at conferences and publish the results in medical journals. Trial Registration ACTRN12611000798965 PMID:23929919

  17. Immunosuppressive treatment protects against angiotensin II-induced renal damage.

    PubMed

    Muller, Dominik N; Shagdarsuren, Erdenechimeg; Park, Joon-Keun; Dechend, Ralf; Mervaala, Eero; Hampich, Franziska; Fiebeler, Anette; Ju, Xinsheng; Finckenberg, Piet; Theuer, Jürgen; Viedt, Christiane; Kreuzer, Joerg; Heidecke, Harald; Haller, Hermann; Zenke, Martin; Luft, Friedrich C

    2002-11-01

    Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response. PMID:12414515

  18. Immunosuppressive Treatment Protects Against Angiotensin II-Induced Renal Damage

    PubMed Central

    Muller, Dominik N.; Shagdarsuren, Erdenechimeg; Park, Joon-Keun; Dechend, Ralf; Mervaala, Eero; Hampich, Franziska; Fiebeler, Anette; Ju, Xinsheng; Finckenberg, Piet; Theuer, Jürgen; Viedt, Christiane; Kreuzer, Joerg; Heidecke, Harald; Haller, Hermann; Zenke, Martin; Luft, Friedrich C.

    2002-01-01

    Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-α on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-α receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-κB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-α is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response. PMID:12414515

  19. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents.

    PubMed

    Menter, Alan; Korman, Neil J; Elmets, Craig A; Feldman, Steven R; Gelfand, Joel M; Gordon, Kenneth B; Gottlieb, Alice B; Koo, John Y M; Lebwohl, Mark; Lim, Henry W; Van Voorhees, Abby S; Beutner, Karl R; Bhushan, Reva

    2009-09-01

    Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guidelines of care for psoriasis, we discuss the use of traditional systemic medications for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety, and offer recommendations for the use of the 3 most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin. We will also briefly discuss the available data for the use of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, and 6-thioguanine in psoriasis. PMID:19493586

  20. Sjögren Sensory Neuronopathy (Sjögren Ganglionopathy): Long-Term Outcome and Treatment Response in a Series of 13 Cases.

    PubMed

    Pereira, P Ricardo; Viala, Karine; Maisonobe, Thierry; Haroche, Julien; Mathian, Alexis; Hié, Miguel; Amoura, Zahir; Cohen Aubart, Fleur

    2016-05-01

    Primary Sjögren syndrome (SS) is an autoimmune disease mainly affecting the exocrine glands causing a sicca syndrome. Neurological manifestations are rarely seen in SS although they are debilitating. Peripheral neuropathies namely sensory axonal neuropathy and painful small fiber neuropathy are the most frequent neurological manifestations. Sensory neuronopathy (SN) is less frequently seen although leading to more severe handicap.The aim of the study was to analyze the clinical presentation and treatment efficacy in a series of SS-related SN.We retrospectively studied patients with SS fulfilling the American-European Classification Criteria and SN according to recent criteria. Studied variables were neurological findings, associated autoimmune diseases, biological profiles, nerve conduction and sensory/motor amplitudes study, treatments received, and outcomes. Handicap scores were studied at beginning and end of each treatment using the modified Rankin Scale (mRS).Thirteen patients were included (12 women, 1 man; median age 55 years at SN diagnosis) presenting with SN with a median follow-up of 3 years (range 2-17). In 11 patients, SN preceded or coincided with SS diagnosis. Most common neurological findings were ataxia and areflexia followed by paresthesia and pain. Lower limbs were more affected than upper limbs, neurological deficits were often symmetric and cranial nerves were affected in 3 patients. Seven patients were treated with corticosteroids, 7 with mycophenolate mofetil, 6 with hydroxychloroquine, 5 with intravenous immunoglobulins, 4 with cyclophosphamide, and 2 patients received other immunosuppressive drugs. At the beginning and at the end of follow-up, average mRS was 2.15 (median 2) and 2.38 (median 2), respectively.SS-related SN progression is heterogeneous but tends to be chronic, insidious, and debilitating despite treatment. From these data concerning a small number of patients, treatment strategies with corticosteroids in association with

  1. Changes in referral, treatment and outcomes in patients with systemic lupus erythematosus in Germany in the 1990s and the 2000s

    PubMed Central

    Albrecht, Katinka; Huscher, Dörte; Richter, Jutta; Backhaus, Marina; Bischoff, Sascha; Kötter, Ina; Thiele, Katja; Zink, Angela

    2014-01-01

    Objective To evaluate trends in the referral, treatment and outcome of patients with systemic lupus erythematosus (SLE) in Germany over two decades. Methods From 1993 to 2012, ∼1200 patients with SLE were recorded annually in the national database of the German Collaborative Arthritis Centres. Treatment patterns, healthcare use and outcomes, such as disease activity, function and work participation, were evaluated over time. Furthermore, two distinct cohorts of patients (enrolment 1994–1998, n=467; and 2004–2008, n=376) observed over 5 years were assessed for changes in outcomes. Results The mean disease duration at the first visit to a rheumatologist decreased from 2.6 (1994) to 1.5 (2012) years. Glucocorticoids (69%), antimalarials (56%), azathioprine (22%), non-steroidal anti-inflammatory drugs (23%) and mycophenolate mofetil (15%) were the most frequently used treatments in 2012. A significant increase was observed in the use of antimalarials and mycophenolate mofetil. The use of glucocorticoids at >7.5 mg/day decreased from 27% (1994) to 10% (2012). The average length of sick leave taken due to SLE declined from 9 weeks (1997) to 6 weeks (2012). When comparing the two longitudinal cohorts, in the cohort from the 2000s, the intraindividual decline of disease activity was significantly stronger (p<0.001), and fewer patients retired early (36% vs 46%). Conclusions The disease activity and resource use declined considerably over the observation period, and more patients remained in the labour force. Earlier treatment onset, faster modification of the treatment regimen and more intensive use of anti-inflammatory therapy may account for the improved outcomes in patients with SLE across the years. PMID:25553251

  2. Mycophenolate-Induced Posterior Reversible Encephalopathy Syndrome.

    PubMed

    Khajuria, Bhavik; Khajuria, Mansi; Agrawal, Yashwant

    2016-01-01

    A 29-year-old woman presented with diffuse anasarca and shortness of breath. Workup revealed a creatinine of 3.3 and a glomerular filtration rate of 17. The patient was also found to be pancytopenic with evidence of hemolytic anemia. A renal biopsy showed evidence of stage IV lupus nephritis with rapidly progressive glomerulonephritis. Her lupus was further classified as ANA negative and anti-dsDNA positive. Mycophenolate and triweekly hemodialysis were started along with a steroid burst of methylprednisolone 1 g for 3 days followed by prednisone 60 mg daily. Four days after discharge, the patient represented with a witnessed 3-minute seizure involving bowel incontinence, altered mental status, and tongue biting. She was given 2 mg intravenous lorazepam and loaded with 1000 mg levetiracetam for seizure prophylaxis. Magnetic resonance imaging of the head revealed bilateral posterior hemispheric subcortical edema, and the diagnosis of posterior reversible encephalopathy syndrome was made. Mycophenolate was immediately discontinued and replaced with cyclophosphamide. Strict blood pressure control below 140/90 mm Hg was maintained initially with intravenous nicardipine drip and then transitioned to oral nifedipine, clonidine, losartan, and minoxidil. A repeat head magnetic resonance imaging 8 days later showed resolved subcortical edema consistent with the patient's improved mental status. No permanent neurologic sequelae were recorded as a result of this hospital episode. PMID:25933141

  3. Treatment of chronic urticaria.

    PubMed

    Jurakić Toncić, Ruzica; Lipozencić, Jasna; Marinović, Branka

    2009-01-01

    Urticaria is a disorder characterized by rapid onset of localized swelling of the skin or mucosa, called wheals or urtica. According to frequency and duration, urticaria can be divided into acute and chronic type. Chronic urticaria is any type of urticaria occurring every day or twice per week, lasting longer than 6 weeks. Chronic urticaria is a common disorder and estimated prevalence is 1% of the population. Also, it is not rare in childhood. The pathogenesis of chronic urticaria has not yet been completely understood. Chronic urticaria is a heterogeneous group of disorders, and according to the etiology and cause, several groups of chronic urticaria are distinguished, i.e. autoimmune, pseudoallergic, infection-related, physical urticaria, vasculitis urticaria and idiopathic urticaria. Treatment and management of chronic urticaria can be non-pharmacological and pharmacological, and sometimes it is not possible to control the disease with antihistamines only, which are considered to be the mainstay of treatment. In severe cases of chronic urticaria, especially if autoimmunity has been proven, several authors describe different modules of immunomodulation: cyclosporine, cyclophosphamide, mycophenolate-mofetil, omalizumab, plasmapheresis, systemic corticosteroids, and immunoglobulin therapy. This article primarily addresses the treatment of chronic idiopathic and autoimmune urticaria. PMID:20021986

  4. Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation.

    PubMed

    Naito, Takafumi; Shinno, Kazuko; Maeda, Toshio; Kagawa, Yoshiyuki; Hashimoto, Hisakuni; Otsuka, Atsushi; Takayama, Tatsuya; Ushiyama, Tomomi; Suzuki, Kazuo; Ozono, Seiichiro

    2006-02-01

    Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) has been introduced into renal transplant immunosuppressant protocols in combination with calcineurin inhibitors (CNIs) and steroids. This study compared the pharmacokinetic profiles of MPA and its major metabolite MPA glucuronide (MPAG) in combination with tacrolimus (TAC) or cyclosporine (CyA) during the maintenance period (>6 months) following renal transplantation. There was no difference between TAC and CyA-treated groups in MPA plasma concentration before drug administration (C(0)). MPA C(0) in TAC and CyA-treated patients did not differ from that in patients who were not treated with a CNI. In patients treated with a CNI, MPAG C(0) was significantly greater in those treated with CyA compared with TAC. The MPAG/MPA ratio in CyA-treated patients was significantly greater than that in the TAC-treated group. We observed that C(0) of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C(0), MPAG C(0) and serum creatinine was stronger in patients treated with CyA compared with TAC. Our study suggests that CyA, but not TAC, inhibits enterohepatic circulation of MPAG as a secondary excretion pathway, and that renal function makes a major contribution to elimination of MPA and MPAG. We indicate that it may be necessary to estimate biliary excretion of MPAG to avoid the risk of intestinal injury in patients receiving combination therapy with TAC during the maintenance period. PMID:16462031

  5. Treatment of autoimmune hemolytic anemias

    PubMed Central

    Zanella, Alberto; Barcellini, Wilma

    2014-01-01

    Autoimmune hemolytic anemia (AIHA) is a relatively uncommon disorder caused by autoantibodies directed against self red blood cells. It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody. AIHA may develop gradually, or have a fulminant onset with life-threatening anemia. The treatment of AIHA is still not evidence-based. The first-line therapy for warm AIHA are corticosteroids, which are effective in 70–85% of patients and should be slowly tapered over a time period of 6–12 months. For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%), rituximab (effective in approx. 80–90% of cases), and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins, danazol, plasma-exchange, and alemtuzumab and high-dose cyclophosphamide as last resort option. As the experience with rituximab evolves, it is likely that this drug will be located at an earlier point in therapy of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In CAD, rituximab is now recommended as first-line treatment. PMID:25271314

  6. Lichen planopilaris: update on pathogenesis and treatment.

    PubMed

    Baibergenova, Akerke; Donovan, Jeff

    2013-01-01

    Lichen planopilaris (LPP) is considered to be a follicular variant of lichen planus. Clinical variants include classic LPP, frontal fibrosing alopecia, and the Graham-Little-Piccardi-Lassueur syndrome. The pathogenesis of LPP remains to be fully elucidated, but like other cicatricial alopecias involves the irreversible destruction of hair follicle stem cells and loss of a hair follicle's capacity to regenerate itself In the early stages of LPP, patients may have scalp pruritus, burning, tenderness, and increased hair shedding. A scalp biopsy shows a lymphocytic infiltrate involving the isthmus and infundibulum. Apoptotic cells present in the external root sheath and concentric fibrosis surrounds the hair follicle. Treatment is prescribed with the goal to alleviate patient symptoms and to halt the progression of hair loss. Treatment involves use of potent topical corticosteroids and/or intralesional corticosteroids. Options for systemic treatment include anti-inflammatory agents such as hydroxychloroquine, tetracyclines, pioglitazones, and immunosuppressive medications such as cyclosporine, mycophenolate mofetil, or systemic corticosteroids. Hair transplantation may also be an option if the disease has been in clinical remission. The management of LPP can sometimes be challenging and additional research is needed to improve outcomes for patients. PMID:23930355

  7. Immune Hemolysis: Diagnosis and Treatment Recommendations.

    PubMed

    Barcellini, Wilma

    2015-10-01

    Autoimmune hemolytic anemia (AIHA) is a heterogeneous disease usually classified as warm, cold [cold agglutinin disease (CAD)] or mixed, according to the thermal range of the autoantibody. Diagnosis is based on the direct antiglobulin test (DAT), typically positive with anti-IgG antisera in warm AIHA and anti-C3d in CAD. Diagnostic pitfalls are due to IgA autoantibodies, warm IgM, low-affinity IgG, or IgG below the threshold of sensitivity, and about 5% of AIHA remains DAT-negative. The treatment of AIHA is still not evidence-based. Corticosteroids are the first-line therapy for warm AIHA. For refractory/relapsed cases, the choice is between splenectomy (effective in ~70% cases but with a presumed cure rate of 20%) and rituximab (effective in ~70%-80% of cases), which is becoming the preferred second-line treatment, and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil). Rituximab is now recommended as first-line treatment for CAD. Additional therapies are intravenous immunoglobulins, danazol, and plasma exchange, with alemtuzumab and high-dose cyclophosphamide as the last options. PMID:26404442

  8. Treatment challenges and investigational opportunities in autoimmune hepatitis.

    PubMed

    Czaja, Albert J; Bianchi, Francesco B; Carpenter, Herschel A; Krawitt, Edward L; Lohse, Ansgar W; Manns, Michael P; McFarlane, Ian G; Mieli-Vergani, Giorgina; Toda, Gotaro; Vergani, Diego; Vierling, John; Zeniya, Mikio

    2005-01-01

    New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The assessment of new front-line and salvage therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic criteria and treatment regimens for children required codification, and pharmacokinetic studies were encouraged to develop optimal dosing schedules based on therapeutic ranges. Collaborative efforts were proposed to help understand racial, geographical, and genetic factors affecting outcome and to establish definitions and therapies for variant syndromes and graft dysfunction after transplantation. The development of experimental animal models was deemed essential for the study of site-specific molecular interventions, and gene therapy was endorsed as a means of bolstering reparative processes. In conclusion, evolving pharmacological and technical advances promise to improve the treatment of autoimmune hepatitis, and investigations of these advances are timely, feasible, and necessary. PMID:15690485

  9. Transcriptomic changes induced by mycophenolic acid in gastric cancer cells

    PubMed Central

    Dun, Boying; Sharma, Ashok; Xu, Heng; Liu, Haitao; Bai, Shan; Zeng, Lingwen; She, Jin-Xiong

    2014-01-01

    Background: Inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA) can inhibit proliferation and induce apoptosis in cancer cells. This study investigated the underlying molecular mechanisms of MPA’s anticancer activity. Methods: A gastric cancer cell line (AGS) was treated with MPA and gene expression at different time points was analyzed using Illumina whole genome microarrays and selected genes were confirmed by real-time RT-PCR. Results: Transcriptomic profiling identified 1070 genes with ≥2 fold changes and 85 genes with >4 fold alterations. The most significantly altered biological processes by MPA treatment include cell cycle, apoptosis, cell proliferation and migration. MPA treatment altered at least ten KEGG pathways, of which eight (p53 signaling, cell cycle, pathways in cancer, PPAR signaling, bladder cancer, protein processing in ER, small cell lung cancer and MAPK signaling) are cancer-related. Among the earliest cellular events induced by MPA is cell cycle arrest which may be caused by six molecular pathways: 1) up-regulation of cyclins (CCND1 and CCNE2) and down-regulation of CCNA2 and CCNB1, 2) down-regulation of cyclin-dependent kinases (CDK4 and CDK5); 3) inhibition of cell division related genes (CDC20, CDC25B and CDC25C) and other cell cycle related genes (MCM2, CENPE and PSRC1), 4) activation of p53, which activates the cyclin-dependent kinase inhibitors (CDKN1A), 5) impaired spindle checkpoint function and chromosome segregation (BUB1, BUB1B, BOP1, AURKA, AURKB, and FOXM1); and 6) reduction of availability of deoxyribonucleotides and therefore DNA synthesis through down-regulation of the RRM1 enzyme. Cell cycle arrest is followed by inhibition of cell proliferation, which is mainly attributable to the inhibition of the PI3K/AKT/mTOR pathway, and caspase-dependent apoptosis due to up-regulation of the p53 and FAS pathways. Conclusions: These results suggest that MPA has beneficial anticancer activity through

  10. Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver.

    PubMed

    Iwamura, Atsushi; Fukami, Tatsuki; Higuchi, Ryota; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-03-16

    Mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil (MMF), is primarily metabolized by glucuronidation to a phenolic glucuronide (MPAG) and an acyl glucuronide (AcMPAG). It is known that AcMPAG, which may be an immunotoxic metabolite, is deglucuronidated in human liver. However, it has been reported that recombinant β-glucuronidase does not catalyze this reaction. AcMPAG deglucuronidation activity was detected in both human liver cytosol (HLC) and microsomes (HLM). In this study, the enzyme responsible for AcMPAG deglucuronidation was identified by purification from HLC with column chromatographic purification steps. The purified enzyme was identified as α/β hydrolase domain containing 10 (ABHD10) by amino acid sequence analysis. Recombinant ABHD10 expressed in Sf9 cells efficiently deglucuronidated AcMPAG with a K(m) value of 100.7 ± 10.2 μM, which was similar to those in HLM, HLC, and human liver homogenates (HLH). Immunoblot analysis revealed ABHD10 protein expression in both HLC and HLM. The AcMPAG deglucuronidation by recombinant ABHD10, HLC, and HLH were potently inhibited by AgNO(3), CdCl(2), CuCl(2), PMSF, bis-p-nitrophenylphosphate, and DTNB. The CL(int) value of AcMPAG formation from MPA, which was catalyzed by human UGT2B7, in HLH was increased by 1.8-fold in the presence of PMSF. Thus, human ABHD10 would affect the formation of AcMPAG, the immunotoxic metabolite. PMID:22294686

  11. Do cytostatic drugs reach drinking water? The case of mycophenolic acid.

    PubMed

    Franquet-Griell, Helena; Ventura, Francesc; Boleda, M Rosa; Lacorte, Silvia

    2016-01-01

    Mycophenolic acid (MPA) has been identified as a new river contaminant according to its wide use and high predicted concentration. The aim of this study was to monitor the impact of MPA in a drinking water treatment plant (DWTP) that collects water downstream Llobregat River (NE Spain) in a highly densified urban area. During a one week survey MPA was recurrently detected in the DWTP intake (17-56.2 ng L(-1)). The presence of this compound in river water was associated to its widespread consumption (>2 tons in 2012 in Catalonia), high excretion rates and low degradability. The fate of MPA in waters at each treatment step of the DWTP was analyzed and complete removal was observed after pretreatment with chlorine dioxide. So far, MPA has not been described as water contaminant and its presence associated with its consumption in anticancer treatments is of relevance to highlight the importance of monitoring this compound. PMID:26552545

  12. Current and emerging treatment options in the management of lupus.

    PubMed

    Jordan, Natasha; D'Cruz, David

    2016-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease with variable clinical manifestations. While the clearest guidelines for the treatment of SLE exist in the context of lupus nephritis, patients with other lupus manifestations such as neuropsychiatric, hematologic, musculoskeletal, and severe cutaneous lupus frequently require immunosuppression and/or biologic therapy. Conventional immunosuppressive agents such as mycophenolate mofetil, azathioprine, and cyclophosphamide are widely used in the management of SLE with current more rationalized treatment regimens optimizing the use of these agents while minimizing potential toxicity. The advent of biologic therapies has advanced the treatment of SLE particularly in patients with refractory disease. The CD20 monoclonal antibody rituximab and the anti-BLyS agent belimumab are now widely in use in clinical practice. Several other biologic agents are in ongoing clinical trials. While immunosuppressive and biologic agents are the foundation of inflammatory disease control in SLE, the importance of managing comorbidities such as cardiovascular risk factors, bone health, and minimizing susceptibility to infection should not be neglected. PMID:27529058

  13. Update on the pharmacological treatment of adult myositis.

    PubMed

    Oddis, C V

    2016-07-01

    The management of patients with idiopathic inflammatory myopathy (IIM) remains a challenge given the systemic features beyond active myositis. That is, recognizing the inflammatory arthropathy, varying dermatomyositis rashes, and overt and occult features of interstitial lung disease in addition to myositis adds to the complexity of diagnosis and treatment of IIM. However, clinicians now have available many more immunosuppressive drugs as well as biologic agents for use in patients with myositis and other autoimmune diseases. Here, the use of these agents is reviewed and support based on available published literature is provided even though many studies have been small and results somewhat anecdotal. Glucocorticoids remain the initial treatment of choice in most instances and methotrexate and azathioprine are often used early in the treatment course. These agents are followed by other immunosuppressive drugs, for example mycophenolate mofetil, tacrolimus, cyclosporine and cyclophosphamide, some of which are used alone while combinations of these agents also provide an effective option. There is more rationale for the use of biologic agents such as rituximab from a mechanistic perspective and, given the incorporation of validated core set measures in assessing myositis patients, we can look forward to better designed clinical trials in the future. PMID:27098592

  14. Current and emerging treatment options in the management of lupus

    PubMed Central

    Jordan, Natasha; D’Cruz, David

    2016-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disease with variable clinical manifestations. While the clearest guidelines for the treatment of SLE exist in the context of lupus nephritis, patients with other lupus manifestations such as neuropsychiatric, hematologic, musculoskeletal, and severe cutaneous lupus frequently require immunosuppression and/or biologic therapy. Conventional immunosuppressive agents such as mycophenolate mofetil, azathioprine, and cyclophosphamide are widely used in the management of SLE with current more rationalized treatment regimens optimizing the use of these agents while minimizing potential toxicity. The advent of biologic therapies has advanced the treatment of SLE particularly in patients with refractory disease. The CD20 monoclonal antibody rituximab and the anti-BLyS agent belimumab are now widely in use in clinical practice. Several other biologic agents are in ongoing clinical trials. While immunosuppressive and biologic agents are the foundation of inflammatory disease control in SLE, the importance of managing comorbidities such as cardiovascular risk factors, bone health, and minimizing susceptibility to infection should not be neglected. PMID:27529058

  15. Treatment Strategies of Adult Primary Focal Segmental Glomerulosclerosis: A Systematic Review Focusing on the Last Two Decades

    PubMed Central

    Beer, Arno; Mayer, Gert

    2016-01-01

    Adult primary focal segmental glomerulosclerosis (FSGS) remains a therapeutic challenge for the treating physician. With the advent of novel immunosuppressive measures, our arsenal of therapeutic options increased considerably. The aim of this review was to summarize reports published over the last two decades which reported on treatment outcome. Most reports included patients with a steroid-resistant (SR) disease course, yet the cohort with the highest unmet need, since persistent nephrotic range proteinuria is associated with a poor renal prognosis and portends a high risk of developing end-stage renal disease. While in first-line treatment, steroid treatment remains the recommended standard with an overall remission rate of 50% and higher, optimal treatment strategies for steroid-dependent/multirelapsing (SD/MR) and SR patients have to be defined. In both entities, calcineurin inhibitors showed good efficacy, while mycophenolate mofetil was less effective in SR cases compared to those with SD/MR. The same was true for rituximab, a monoclonal antibody targeting B-cells. In resistant cases, addition of extracorporeal treatment options or treatment with alkylating agents may be considered. To shape the future for treatment of FSGS, international collaborations to conduct larger clinical trials are needed to identify potential novel efficacious immunosuppressive or immunomodulatory therapies. PMID:27144166

  16. Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

    ClinicalTrials.gov

    2016-06-13

    Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  17. Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine, Mycophenolate Mofetil, Donor Lymphocyte Infusion in Treating Patients With Hematopoietic Cancer

    ClinicalTrials.gov

    2016-08-01

    Acute Undifferentiated Leukemia; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Systemic Amyloidosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Renal Cell Cancer; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  18. Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-03-01

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Renal Cell Carcinoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Renal Cell Cancer; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Small Noncleaved Cell Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage II Adult T-cell Leukemia/Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Small Noncleaved Cell Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Childhood Lymphoblastic Lymphoma; Stage III Childhood Small Noncleaved Cell Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Childhood Lymphoblastic Lymphoma; Stage IV Childhood Small Noncleaved Cell Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Renal Cell Cancer; T-cell Large Granular Lymphocyte Leukemia; Type 1 Papillary Renal Cell Carcinoma; Type 2 Papillary Renal Cell Carcinoma; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Waldenström Macroglobulinemia

  19. Tacrolimus and Mycophenolate Mofetil With or Without Sirolimus in Preventing Acute Graft-Versus-Host Disease in Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

    ClinicalTrials.gov

    2015-10-14

    Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Refractory Chronic Lymphocytic Leukemia; Refractory Plasma Cell Myeloma; Waldenstrom Macroglobulinemia; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Lymphoma; Childhood Myelodysplastic Syndrome; Stage II Contiguous Adult Burkitt Lymphoma; Stage II Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Contiguous Immunoblastic Lymphoma; Stage II Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Contiguous Follicular Lymphoma; Stage II Grade 2 Contiguous Follicular Lymphoma; Stage II Grade 3 Contiguous Follicular Lymphoma; Stage II Contiguous Mantle Cell Lymphoma; Stage II Non-Contiguous Adult Burkitt Lymphoma; Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Mixed Cell Lymphoma; Stage II Non-Contiguous Adult Diffuse Small Cleaved Cell Lymphoma; Stage II Adult Non-Contiguous Immunoblastic Lymphoma; Stage II Non-Contiguous Adult Lymphoblastic Lymphoma; Stage II Grade 1 Non-Contiguous Follicular Lymphoma; Stage II Grade 2 Non-Contiguous Follicular Lymphoma; Stage II Grade 3 Non-Contiguous Follicular Lymphoma; Stage II Non-Contiguous Mantle Cell Lymphoma; Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Burkitt Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Myelodysplastic Syndrome; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Childhood Lymphoblastic Lymphoma; Stage I Childhood Burkitt Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Grade 3 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Lymphoblastic Lymphoma; Stage II Childhood Burkitt Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage II

  20. Fludarabine Phosphate, Cyclophosphamide, Tacrolimus, Mycophenolate Mofetil, Total-Body Irradiation, and Donor Bone Marrow Transplant in Treating Patients With High-Risk Hematologic Cancer

    ClinicalTrials.gov

    2014-02-27

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hematopoietic/Lymphoid Cancer; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Childhood Hodgkin Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Stage IV Childhood Hodgkin Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  1. Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Hematologic Malignancies Undergoing Donor Peripheral Blood Stem Cell Transplant

    ClinicalTrials.gov

    2016-09-06

    Adult Acute Lymphoblastic Leukemia; Adult Acute Myeloid Leukemia; Adult Diffuse Large B-Cell Lymphoma; Adult Myelodysplastic Syndrome; Adult Non-Hodgkin Lymphoma; Aggressive Non-Hodgkin Lymphoma; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Myeloid Leukemia; Childhood Diffuse Large B -Cell Lymphoma; Childhood Myelodysplastic Syndrome; Childhood Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Hematopoietic and Lymphoid Cell Neoplasm; Mantle Cell Lymphoma; Plasma Cell Myeloma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  2. Case report: successful treatment of membranous lupus nephritis with belimumab in an African female immigrant.

    PubMed

    De Scheerder, Marie-Angélique; Boey, O; Mahieu, E; Vanuytsel, J; Bogaert, Anne-Marie

    2016-06-01

    We describe the case of a 26-year-old African female who was treated successfully with belimumab in a case of severe membranous lupus nephritis and retinal vasculitis, resistant to first line therapy. She presented initially with chronic dacryoadenitis and screening showed nephrotic-range proteinuria. Biopsy of the kidney confirmed the diagnosis of membranous lupus nephritis. Clinical features (joint pain, dacryoadenitis, retinal vasculitis and lupus nephritis) in combination with serology (positive anti-double-stranded DNA (ds-DNA) antibodies, hypocomplementemia) confirmed the diagnosis of systemic lupus erythematosus (SLE). Treatment was immediately initiated with glucocorticosteroids (GCS), mycophenolate mofetil (MMF) and hydroxychloroquine sulphate (Plaquenil®). Tacrolimus was associated but no effect was observed with the proteinuria remaining in the nephrotic range and secondary effects of the glucocorticosteroids becoming a real concern. The patient was started on add-on belimumab with quasi-immediate effect on the proteinuria, making it possible to decrease the dosage of the other immunosuppressants and gradually stop them, even the GCS. The patient is currently in complete remission after 3 years of treatment with belimumab. We were able to stop immunosuppressive treatment but will keep her on antimalarial treatment as the most recent guidelines in treatment of SLE recommend. PMID:26712500

  3. Treatment of Refractory Chronic Urticaria

    PubMed Central

    Mehta, Aayushi; Godse, Kiran; Patil, Sharmila; Nadkarni, Nitin; Gautam, Manjyot

    2015-01-01

    Chronic spontaneous urticaria is a distressing disease encountered frequently in clinical practice. The current mainstay of therapy is the use of second-generation, non-sedating antihistamines. However, in patients who do not respond satisfactorily to these agents, a variety of other drugs are used. This article examines the available literature for frequently used agents including systemic corticosteroids, leukotriene receptor antagonists, dapsone, sulfasalazine, hydroxychloroquine, H2 antagonists, methotrexate, cyclosporine A, omalizumab, autologous serum therapy, and mycophenolate mofetil, with an additional focus on publications in Indian literature. PMID:26120147

  4. Developments in the Classification and Treatment of the Juvenile Idiopathic Inflammatory Myopathies

    PubMed Central

    Rider, Lisa G.; Katz, James D.; Jones, Olcay Y.

    2013-01-01

    The juvenile idiopathic inflammatory myopathies (JIIM) are rare, heterogeneous autoimmune diseases that share chronic muscle inflammation and weakness. JIIM broadly includes three major clinicopathologic groups: juvenile dermatomyositis, juvenile polymyositis, and overlap myositis. A growing spectrum of clinicopathologic groups and serologic phenotypes defined by the presence of myositis-specific or myositis-associated autoantibodies are now recognized, each with differing demographics, clinical manifestations, laboratory findings, and prognoses. With the first multi-center collaborative studies and controlled trials using standardized preliminarily validated outcome measures, the therapy of juvenile myositis has advanced. Although daily oral corticosteroids remain the backbone of treatment, disease-modifying anti-rheumatic drugs (DMARDs) are almost always used as adjunctive therapy. Methotrexate is the conventional DMARD for the initial therapy, either alone or combined with intravenous pulse methylprednisolone, and/or intravenous immunoglobulin for patients with moderate to severe disease. Cyclosporine may be added to these or serve as an alternative to methotrexate. Other drugs and biologic therapies, including mycophenolate mofetil, tacrolimus, cyclophosphamide, rituximab, and infliximab, might benefit selected patients with recalcitrant disease, unacceptable steroid toxicity, or patients with risk factors for poor prognosis. The treatment of cutaneous disease, calcinosis, and the role for rehabilitation are also discussed. PMID:24182859

  5. Profile of epratuzumab and its potential in the treatment of systemic lupus erythematosus

    PubMed Central

    Al Rayes, Hanan; Touma, Zahi

    2014-01-01

    Management of systemic lupus erythematosus (SLE) represents a fascinating, emerging field. Research has recently provided us with a better understanding of the immunologic alterations of SLE, leading to the creation of immunomodulatory agents designed to disrupt specific cell targets and pro-inflammatory pathways. Despite the improvement in the prognosis of SLE in the last 50 years with the use of immunosuppressive therapy such as cyclophosphamide and mycophenolate mofetil, cytotoxicity remains a major complication of these medications and the need for more specific targeted immunotherapy is increasing. Early recognition and treatment of SLE with targeted immunotherapy has the potential to improve quality of life and reduce the risk of disease flare-ups and complications. In this review, we will explore the role of B-cells in the pathogenesis of SLE highlighting current insights into SLE development and management. In addition, we will discuss epratuzumab’s role in the treatment of SLE. Epratuzumab is a humanized anti-CD22 monoclonal antibody that targets CD22 on B-cell and its role in B-cell modulation, migration, function, and inhibition of B-cell receptor signaling. Epratuzumab is currently in a Phase III study evaluating its efficacy in the management of moderate to severe SLE. All published trials on epratuzumab have shown great promise with safe profiles. PMID:25429203

  6. Dramatic improvement of anti-SS-A/Ro-associated interstitial lung disease after immunosuppressive treatment.

    PubMed

    Paola, Caramaschi; Giuliana, Festi; Giovanni, Orsolini; Cristian, Caimmi; Domenico, Biasi

    2016-07-01

    The aim of the study was to report three patients affected by interstitial lung disease associated with positive anti-SS-A/Ro autoantibody who showed a dramatic improvement after immunosuppressive treatment. Medical charts were reviewed to obtain clinical data, laboratory parameters, lung function tests, high-resolution computed tomography results and response to immunosuppressive treatment. The three patients showed a clinical picture of a lung-dominant connective tissue disease characterized by a sudden onset with dyspnea, cough and subtle extrathoracic features together with positive anti-SS-A/Ro antibody and weak titer antinuclear antibodies. All three patients responded favorably to immunosuppressive therapy: Two cases were treated with a combination of corticosteroid and cyclophosphamide followed by mycophenolate mofetil; in the third patient, clinical benefit was obtained after rituximab was added to corticosteroid and immunosuppressant drug. In spite of an abrupt onset with significant lung function impairment, all three patients had a favorable clinical response to immunosuppressive therapy. This report may be useful in making therapeutic decisions in case of interstitial lung disease associated with anti-SS-A antibody. PMID:27021338

  7. Safety and Effectiveness of Mycophenolate in Systemic Sclerosis. A Systematic Review

    PubMed Central

    2015-01-01

    Background Mycophenolate is increasingly being used in the rheumatic diseases. Its main adverse effects are gastrointestinal, myelosuppression, and infection. These may limit use in systemic sclerosis (SSc) since gastrointestinal involvement is common. The objective of this study is to evaluate gastrointestinal adverse events of mycophenolate in SSc. Secondarily we evaluated other adverse events, and the effectiveness of mycophenolate in skin and lung disease. Methods A literature search of Medline, Embase, Cochrane Central Register of Controlled Trials, and CINAHL (inception-2013) was performed. Studies reporting use of mycophenolate in SSc patients, adverse events, modified Rodnan skin score (MRSS), forced vital capacity (FVC), or diffusing capacity of carbon monoxide (DLCO) were included. The primary outcome was gastrointestinal events occurring after the initiation of mycophenolate. Secondary safety outcomes included myelosuppression, infection, malignancy, and death after the initiation of mycophenolate. Results 617 citations were identified and 21 studies were included. 487 patients were exposed to mycophenolate. The mean disease duration ranged between 0.8-14.1 years. There were 18 deaths and 90 non-lethal adverse events. The non-lethal adverse events included 43 (47.7%) gastrointestinal events, 34 (26%) infections, 6 (5%) cytopenias and 2 (2%) malignancies. The most common gastrointestinal events included diarrhea (n=18 (14%)), nausea (n=12 (9%)), and abdominal pain (n=3 (2%)). The rate of discontinuation ranged between 8%-40%. Seven observational studies reported improvement or stabilization in FVC, and 5 studies report stabilization or improvement in MRSS. Conclusion Mycophenolate-associated gastrointestinal adverse events are common in SSc, but not severe enough to preclude its use. Observational data suggests mycophenolate may be effective in improving or stabilizing interstitial lung disease, and skin involvement. PMID:25933090

  8. The management of pemphigus vulgaris in a burn intensive care unit: a case report and treatment review.

    PubMed

    Miletta, Nathanial; Miller, Mary E; Lam, Thomas; Chung, Kevin K; Hivnor, Chad

    2014-01-01

    Pemphigus vulgaris is a rare, potentially fatal, autoimmune blistering disease of the skin and mucous membranes. Treatment of this disease is problematic because of a lack of high-grade, evidence-based recommendations, the side-effect profiles of the therapies available, and the extensive supportive care that afflicted patients require. The authors present the unfortunate course of a patient with severe pemphigus vulgaris who was admitted to the U.S. Army Institute of Surgical Research Burn Center, to demonstrate the potential complications of therapy. Given the patient's complex course, the authors reviewed the literature and share in this article the most up-to-date treatment recommendations for patients with pemphigus vulgaris. The authors' review of the literature supports using conventional therapy consisting of high-dose corticosteroids and an adjuvant immunosuppressant for mild to moderate cases of pemphigus vulgaris. The immunosuppresants recommended are mycophenolate mofetil, azathioprine, and cyclophosphamide, in order of preference, based on their side-effect profiles and steroid-sparing effects. For severe or recalcitrant cases of pemphigus vulgaris, the authors recommend adding rituximab as early as possible. If increased risk of infection is of particular concern, the use of intravenous immunoglobulin in place of rituximab is advised. PMID:24572296

  9. Remission of late-onset post-heart transplantation lymphoproliferative disorder following treatment with rituximab and modified mini-CHOP chemotherapy: A case report

    PubMed Central

    HUANG, QIANG; YANG, TIANXIN; JIN, XING; NI, XUMING; QI, HAIYAN; YAN, ZHIKUN

    2016-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is one of the most frequent secondary malignancies that can follow immunosuppressive therapy for solid organ transplantation, and may result in severe morbidities and even mortality. A middle-aged Han Chinese patient, prescribed with immunosuppressive cyclosporine and prednisone, developed PTLD that manifested as a painless cervical lymph node enlargement, 12 years following heart transplantation. Histology revealed monomorphic B-cell PTLD (diffuse large-cell lymphoma); as a result the immunosuppressive regimen of the patient was changed to tacrolimus and mycophenolate mofetil. In addition, the patient was changed to 6-cycle rituximab with a modified mini-CHOP (R-mini-CHOP) regimen for induction, and 8-cycle quarterly rituximab treatment and maintenance therapy. R-mini-CHOP therapy was well tolerated, and no allograft rejection occurred. The patient exhibited clinical remission as demonstrated by the results of the positron emission tomography-computed tomography at the 5-year follow-up visit following R-mini-CHOP therapy. In conclusion, R-mini-CHOP therapy following reduced immunosuppression is effective and safe for the treatment of late-onset PTLD following heart transplantation. PMID:27347047

  10. Hydroxamic acid derivatives of mycophenolic acid inhibit histone deacetylase at the cellular level.

    PubMed

    Batovska, Daniela I; Kim, Dong Hoon; Mitsuhashi, Shinya; Cho, Yoon Sun; Kwon, Ho Jeong; Ubukata, Makoto

    2008-10-01

    Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively. PMID:18838793

  11. Immunosuppressive treatment for pure membranous lupus nephropathy in a Hispanic population.

    PubMed

    Mejía-Vilet, Juan Manuel; Córdova-Sánchez, Bertha M; Uribe-Uribe, Norma O; Correa-Rotter, Ricardo

    2016-09-01

    Optimal treatment for pure membranous lupus nephritis (MLN) remains unknown. The aim of this study was to evaluate the response to immunosuppressive treatment of Hispanics with pure MLN. This was a retrospective cohort analysis from a tertiary care center. Pure MLN patients were segregated into three groups according to the received induction treatment. All patients received adjunctive steroids. Outcomes included complete remission (CR), partial remission (PR), flare incidence, adverse events, and renal and patient survival. All outcomes were analyzed by Cox regression analysis. A total of 60 patients diagnosed with pure MLN between 2004 and 2014 were segregated into mycophenolate mofetil (MMF) (n = 18), intravenous cyclophosphamide (IVC) (n = 16), or azathioprine (AZA) (n = 26) groups. Complete remission rates at 6, 12, and 24 months were 33.3, 52.9, and 76.4 %, respectively, for MMF; 26.9, 42.3, and 54.6 %, respectively, for AZA; and 6.2, 14.8, and 26.9 %, respectively, for IVC. Based on Cox-adjusted analysis, treatment with MMF was associated with higher CR rates (hazard ratio (HR) 4.43, 1.19-16.4, p = 0.026) compared to IVC. There were no differences in CR rates between MMF and AZA groups. Patients treated with adjunctive antimalarial drugs were more likely to achieve CR (HR 2.46, 1.08-5.64, p = 0.032) and had a non-significant trend to lower incidence of thrombotic events (odds ratio (OR) 0.10, 0.010-1.14, p = 0.064). There were no differences in adverse events, renal flares, and renal or patient survival between groups. MMF might be superior to IVC as induction treatment for pure MLN in Hispanics, while AZA might remain as a valid alternative for treatment. Adjunctive treatment with an antimalarial drug may enhance renal response to therapy. PMID:27475791

  12. Con: Cyclophosphamide for the treatment of lupus nephritis.

    PubMed

    Mok, Chi Chiu

    2016-07-01

    Kidney involvement is a major determinant for morbidity and mortality in patients with systemic lupus erythematosus. The treatment target of lupus renal disease is to induce and maintain remission and to minimize disease or treatment-related comorbidities. Cyclophosphamide (CYC), in conjunction with glucocorticoids, has conventionally been used for the initial treatment of lupus nephritis. However, the major concerns of CYC are its toxicities, such as infertility, urotoxicity and oncogenicity, which are particularly relevant in women of childbearing age. As a result, maintenance therapy of lupus nephritis with an extended course of CYC pulses has largely been replaced by other immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine. Recent randomized controlled trials have demonstrated non-inferiority of MMF to pulse CYC as induction therapy of lupus nephritis. Although MMF as induction-maintenance therapy has been increasingly used in lupus nephritis, its efficacy in the long-term preservation of renal function remains to be elucidated. MMF is not necessarily less toxic than CYC. Meta-analyses of clinical trials show similar incidence of infective complications and gastrointestinal adverse events in both MMF- and CYC-based regimens. However, considering the reduction in gonadal toxicity and the risk of oncogenicity, MMF may be used as first-line therapy of lupus nephritis. Tacrolimus (TAC) has recently been shown to be equivalent to either MMF or CYC for inducing remission of lupus nephritis and may be considered as another non-CYC alternative. Combined low-dose MMF and TAC appears to be more effective than CYC pulses in Chinese patients with lupus nephritis and has the potential to replace the more toxic CYC regimens in high-risk patients. Currently, CYC still plays an important role in the management of lupus nephritis patients with impaired or rapidly deteriorating renal function, crescentic glomerulonephritis or as salvage therapy for

  13. Treatment of young patients with lupus nephritis using calcineurin inhibitors

    PubMed Central

    Tanaka, Hiroshi; Tsuruga, Kazushi; Aizawa-Yashiro, Tomomi; Watanabe, Shojiro; Imaizumi, Tadaatsu

    2012-01-01

    Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contributed to a favorable outcome in children and adolescents with systemic lupus erythematosus (SLE). Nevertheless, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are reviewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide (IVCY) are effective for preserving renal function in adult patients, CPA is a potent immunosuppressive agent that induces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malignancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A (CsA) and tacrolimus (Tac) are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting the transcription of the early activation genes of interleukin (IL)-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone (PDN), Tac, and mycophenolate mofetile (MMF) has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and

  14. [Progress and perspectives in the treatment of systemic lupus erythematosus].

    PubMed

    Robak, Ewa; Sysa-Jedrzejowska, Anna; Wozniacka, Anna

    2005-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women in childbearing age. SLE tissue damage is mediated by autoantibodies, complement activation and immune complexes deposition. The disease is diagnosed on the basis of its clinical manifestations and the demonstration of characteristic immunological phenomena, especially antinuclear antibodies. Management of the disease includes regular monitoring of disease activity, avoidance of predisposing factors and therapy guided by the activity and severity of the leading organ manifestation. Treatment ranges from nonsteroidal antirheumatic drugs to intensive treatment with cytotoxic agents. Corticosteroids form the basis of all regimens. Antimalarials and azathioprine are important for treating mild and moderate SLE cases, especially for the long time. Cyclophosphamide given intravenously is the current gold standard for severe lupus nephritis. More recently new strategies for immunosuppression in SLE, that interfere with the syntesis of DNA and nucleotides have been developed (such as mycophenolate mofetil, fludarabine and cladribine). Other agents like cyclosporine and tacrolimus inhibit effect of the activation signals for T cells by inhibition of calcineurin. Some monoclonal antibodies against cytokines or components of the complement system interfere with the effector phase of the immune response. Abetimus (LJP-394) inhibits the production of anti-dsDNA antibodies and may prevent glomerulonephritis caused by anti-DNA containing immune complexes. Somatic gene therapy is also a novel approach in autoimmune disorders and my be a valuable method of SLE therapy in the future. The adrenal steroid prasterone (DHEA) has also shown benefitial effects in mild to moderate SLE. Finally, autologous stem cell transplantation can induce tolerance to self-antigens and cause significant improvement in SLE patients. However, new therapeutic strategies must be tested according to the established

  15. Immunomodulation for treatment of drug and device refractory gastroparesis

    PubMed Central

    Soota, Kaartik; Kedar, Archana; Nikitina, Yana; Arendale, Evelyn; Vedanarayanan, Vetta; Abell, Thomas L.

    2016-01-01

    Objective Patients with generalized autoimmune dysautonomia may also present with gastroparesis. Immune dysfunction in such patients can be evaluated using antibodies to glutamic acid decarboxylase (GAD) and full thickness biopsy of stomach. In this study, we utilize immunotherapy for treatment of drug and Gastric Electrical Stimulation (GES) resistant gastroparetic patients with evidence of neuroinflammation on full thickness gastric biopsy and had positive GAD65 autoantibodies. Material and methods We conducted a retrospective chart review of 11 female patients with drug and device resistant gastroparesis. Patients were treated for a total of 8–12 weeks with either intravenous immunoglobulin (IVIg), or combined mycophenolate mofetil (MM) and methylprednisolone, or only MM. Patients were excluded if they had previous side effects from steroid therapy, low scores on dual-energy X-ray absorptiometry (DEXA) scan results, immune-compromised conditions with infections like tuberculosis and zoster. Symptoms of nausea, vomiting, abdominal pain, early satiety/anorexia, bloating and total symptom score (TSS) as reported by the patients were recorded before and after the treatment at a follow up visit 2 to 16 weeks after initiation of therapy. Results Maximum symptom improvement was seen in patients treated with IVIg (67%). 6 patients (55%) had improvement in vomiting, whereas 5 patients (45%) had improvements in nausea, abdominal pain and bloating. Conclusions Immunomodulatory therapy shows positive outcomes in improving vomiting symptom in some gastroparetic patients who have coexisting positive autoimmune profiles. This preliminary data suggests the need for further investigations in immunotherapy targeted to patients with gastroparetic symptoms refractory to approved drug and device therapies. PMID:27014566

  16. [Treatment of systemic lupus erythematosus: myths, certainties and doubts].

    PubMed

    Ruiz-Irastorza, Guillermo; Danza, Alvaro; Khamashta, Munther

    2013-12-21

    Systemic lupus erythematosus (SLE) is a complex disease with different clinical forms of presentation, including a wide range of severity and organic involvement. Such circumstance, along with the fact of the uncommon nature of the disease and the absence of clinically representative response criteria, make it difficult to design controlled clinical trials in SLE patients. As a result, observational studies have a special relevance, being a source of valuable information of SLE prognosis and outcome as well as of the efficacy and adverse effects of the different therapies. Herein we update some of the main treatments used in SLE. Steroids may have more risks than benefits if used at high doses. New mechanisms of action have been described, supporting the use of lower doses, possibly with the same efficacy and less adverse effects. Intravenous pulses of cyclophosphamide still have a role in the treatment of proliferative lupus nephritis and other serious SLE manifestations. Mycophenolate mofetil has shown its efficacy both as induction and maintenance therapy of selected cases of lupus nephritis. Biological therapies have emerged as new promising options. Although clinical trials have not confirmed a clear superiority of rituximab in SLE, observational studies have shown good response rates in severe SLE manifestations or refractory forms. Belimumab has recently been added to the therapeutic armamentarium of SLE; although its place in clinical practice is not well-defined, it may be recommended in active patients with no response or good tolerance to standard therapies. Hydroxichloroquine improves survival, decreases the risk of thrombosis and flares and is safe in pregnancy, and should be considered the baseline therapy in most SLE patients. PMID:23622892

  17. Utility of monitoring mycophenolic acid in solid organ transplant patients.

    PubMed Central

    Oremus, Mark; Zeidler, Johannes; Ensom, Mary H H; Matsuda-Abedini, Mina; Balion, Cynthia; Booker, Lynda; Archer, Carolyn; Raina, Parminder

    2008-01-01

    OBJECTIVES To investigate whether monitoring concentrations of mycophenolic acid (MPA) in the serum or plasma of persons who receive a solid organ transplant will result in a lower incidence of transplant rejections and adverse events versus no monitoring of MPA. To investigate whether the incidence of rejection or adverse events differs according to MPA dose or frequency, type of MPA, the form of MPA monitored, the method of MPA monitoring, or sample characteristics. To assess whether monitoring is cost-effective versus no monitoring. DATA SOURCES The following databases were searched from their dates of inception (in brackets) until October 2007: MEDLINE (1966); BIOSIS Previews (1976); EMBASE (1980); Cochrane Database of Systematic Reviews (1995); and Cochrane Central Register of Controlled Trials (1995). REVIEW METHODS Studies identified from the data sources went through two levels of screening (i.e., title and abstract, full text) and the ones that passed were abstracted. Criteria for abstraction included publication in the English language, study design (i.e., randomized controlled trial [RCT], observational study with comparison group, case series), and patient receipt of allograft solid organ transplant. Additionally, any form of MPA had to be measured at least once in the plasma or serum using any method of measurement (e.g., AUC0-12, C0). Furthermore, these measures had to be linked to a health outcome (e.g., transplant rejection). Certain biomarkers (e.g., serum creatinine, glomular filtration rate) and all adverse events were also considered health outcomes. RESULTS The published evidence on MPA monitoring is inconclusive. Direct, head-to-head comparison of monitoring versus no monitoring is limited to one RCT in adult, kidney transplant patients. Inferences about monitoring can be made from some observational studies, although the evidence is equivocal for MPA dose and dose frequency, nonexistent for type of MPA, inconclusive for form of MPA monitored

  18. In vitro effects of mycophenolic acid and allopurinol against Leishmania tropica in human macrophages.

    PubMed Central

    Berman, J D; Webster, H K

    1982-01-01

    The possibility that purine inhibitors or analogs might be effective antileishmanial agents led to the determination of the antileishmanial activity of mycophenolic acid and allopurinol in vitro. The drugs were tested against Leishmania tropica amastigotes (mammalian forms) within human macrophages, a model in which achievable serum concentrations of antileishmanial agents currently in use eliminate approximately 90% of the parasites. Mycophenolic acid, an inhibitor of guanosine nucleotide synthesis from inosinic acid, was shown here to inhibit guanosine nucleotide synthesis in L. tropica promastigotes (insect forms). When tested against L. tropica amastigotes within macrophages, mycophenolic acid eliminated 50% of the parasites at achievable peak human serum levels (20 micrograms/ml) and 40% of the parasites at trough serum levels (1 to 10 micrograms/ml). This demonstrates that an inhibitor of guanosine nucleotide synthesis is partially effective against L. tropica in vitro. The purine analog allopurinol was also tested and was found to eliminate 50% of L. tropica amastigotes in this model. Because mycophenolic acid and allopurinol are partially, but not completely, effective antileishmanial agents in this in vitro model, their in vivo utility remains to be determined by clinical trials. PMID:7114837

  19. State of the Art in the Treatment of Systemic Vasculitides

    PubMed Central

    Luqmani, Raashid Ahmed

    2014-01-01

    Anti-neutrophil cytoplasm antibodies (ANCA) are associated with small vessel vasculitides (AASV) affecting the lungs and kidneys. Structured clinical assessment using the Birmingham Vasculitis Activity Score and Vasculitis Damage Index should form the basis of a treatment plan and be used to document progress, including relapse. Severe disease with organ or life threatening manifestations needs cyclophosphamide or rituximab, plus high dose glucocorticoids, followed by lower dose steroid plus azathioprine, or methotrexate. Additional plasmapheresis is effective for very severe disease, reducing dialysis dependence from 60 to 40% in the first year, but with no effect on mortality or long-term renal function, probably due to established renal damage. In milder forms of ANCA-associated vasculitis, methotrexate, leflunomide, or mycophenolate mofetil are effective. Mortality depends on initial severity: 25% in patients with renal failure or severe lung hemorrhage; 6% for generalized non-life threatening AASV but rising to 30–40% at 5 years. Mortality from GPA is four times higher than the background population. Early deaths are due to active vasculitis and infection. Subsequent deaths are more often due to cardiovascular events, infection, and cancer. We need to improve the long-term outcome, by controlling disease activity but also preventing damage and drug toxicity. By contrast, in large vessel vasculitis where mortality is much less but morbidity potentially greater, such as giant cell arteritis (GCA) and Takayasu arteritis, therapeutic options are limited. High dose glucocorticoid results in significant toxicity in over 80%. Advances in understanding the biology of the vasculitides are improving therapies. Novel, mechanism based therapies such as rituximab in AASV, mepolizumab in eosinophilic granulomatosis with polyangiitis, and tocilizumab in GCA, but the lack of reliable biomarkers remains a challenge to progress in these chronic relapsing diseases. PMID

  20. Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

    PubMed Central

    Pasadhika, Sirichai; Rosenbaum, James T

    2014-01-01

    Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet’s disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. PMID:24600203

  1. Successful treatment of ileal ulcers caused by immunosuppressants in two organ transplant recipients.

    PubMed

    Guo, Yun-Wei; Gu, Hua-Ying; Abassa, Kodjo-Kunale; Lin, Xian-Yi; Wei, Xiu-Qing

    2016-06-28

    Although gastroduodenal ulcers are common in solid organ transplant patients, there are few reports on multiple giant ulcers in the distal ileum and ileocecal valve caused by immunosuppressants Herein, we report on a liver transplant recipient and a renal transplant recipient with multiple large ulcers in the distal ileum and ileocecal valve who rapidly achieved ulcer healing upon withdrawal of sirolimus or tacrolimus and administration of thalidomide. In case 1, a 56-year-old man with primary hepatocellular carcinoma had received a liver transplantation. Tacrolimus combined with sirolimus and prednisolone was used as the anti-rejection regimen. Colonoscopy was performed because of severe abdominal pain and diarrhea at post-operative month 10. Multiple giant ulcers were found at the ileocecal valve and distal ileum. The ulcers healed rapidly with withdrawal of sirolimus and treatment with thalidomide. There was no recurrence during 2 years of follow-up. In case 2, a 34-year-old man with end-stage kidney disease received kidney transplantation and was put on tacrolimus combined with mycophenolate mofetil and prednisolone as the anti-rejection regimen. Twelve weeks after the operation, the patient presented with hematochezia and severe anemia. Colonoscopy revealed multiple large ulcers in the ileocecal valve and distal ileum, with massive accumulation of fresh blood. The bleeding ceased after treatment with intravenous somatostatin and oral thalidomide. Tacrolimus was withdrawn at the same time. Colonoscopy at week 4 of follow-up revealed remarkable healing of the ulcers, and there was no recurrence of bleeding during 1 year of follow-up. No lymphoma, tuberculosis, or infection of cytomegalovirus, Epstein-Barr virus, or fungus was found in either patient. In post-transplantation cases with ulcers in the distal ileum and ileocecal valve, sirolimus or tacrolimus should be considered a possible risk factor, and withdrawing them or switching to another immunosuppressant

  2. Successful treatment of ileal ulcers caused by immunosuppressants in two organ transplant recipients

    PubMed Central

    Guo, Yun-Wei; Gu, Hua-Ying; Abassa, Kodjo-Kunale; Lin, Xian-Yi; Wei, Xiu-Qing

    2016-01-01

    Although gastroduodenal ulcers are common in solid organ transplant patients, there are few reports on multiple giant ulcers in the distal ileum and ileocecal valve caused by immunosuppressants Herein, we report on a liver transplant recipient and a renal transplant recipient with multiple large ulcers in the distal ileum and ileocecal valve who rapidly achieved ulcer healing upon withdrawal of sirolimus or tacrolimus and administration of thalidomide. In case 1, a 56-year-old man with primary hepatocellular carcinoma had received a liver transplantation. Tacrolimus combined with sirolimus and prednisolone was used as the anti-rejection regimen. Colonoscopy was performed because of severe abdominal pain and diarrhea at post-operative month 10. Multiple giant ulcers were found at the ileocecal valve and distal ileum. The ulcers healed rapidly with withdrawal of sirolimus and treatment with thalidomide. There was no recurrence during 2 years of follow-up. In case 2, a 34-year-old man with end-stage kidney disease received kidney transplantation and was put on tacrolimus combined with mycophenolate mofetil and prednisolone as the anti-rejection regimen. Twelve weeks after the operation, the patient presented with hematochezia and severe anemia. Colonoscopy revealed multiple large ulcers in the ileocecal valve and distal ileum, with massive accumulation of fresh blood. The bleeding ceased after treatment with intravenous somatostatin and oral thalidomide. Tacrolimus was withdrawn at the same time. Colonoscopy at week 4 of follow-up revealed remarkable healing of the ulcers, and there was no recurrence of bleeding during 1 year of follow-up. No lymphoma, tuberculosis, or infection of cytomegalovirus, Epstein-Barr virus, or fungus was found in either patient. In post-transplantation cases with ulcers in the distal ileum and ileocecal valve, sirolimus or tacrolimus should be considered a possible risk factor, and withdrawing them or switching to another immunosuppressant

  3. Immunosuppressive Treatment for Nephrotic Idiopathic Membranous Nephropathy: A Meta-Analysis Based on Chinese Adults

    PubMed Central

    Chen, Dongping; Xu, Chenggang; Yang, Li; Ma, Yiyi; Hu, Xiaohong; Li, Lin; Sun, Lijun; Zhao, Xuezhi; Mao, Zhiguo; Mei, Changlin

    2012-01-01

    Background Idiopathic membranous nephropathy (IMN) is the most common pathological type for nephrotic syndrome in adults in western countries and China. The benefits and harms of immunosuppressive treatment in IMN remain controversial. Objectives To assess the efficacy and safety of different immunosuppressive agents in the treatment of nephrotic syndrome caused by IMN. Methods PubMed, EMBASE, Cochrane Library and wanfang, weipu, qinghuatongfang, were searched for relevant studies published before December 2011. Reference lists of nephrology textbooks, review articles were checked. A meta-analysis of randomized controlled trials (RCTs) meeting the criteria was performed using Review Manager. Main Results 17 studies were included, involving 696 patients. Calcineurin inhibitors had a better effect when compared to alkylating agents, on complete remission (RR 1.61, 95% CI 1.13, to 2.30 P = 0.008), partial or complete remission (effective) (CR/PR, RR 1.29, 95% CI 1.09 to 1.52 P = 0.003), and fewer side effects. Among calcineurin inhibitors, tacrolimus (TAC) was shown statistical significance in inducing more remissions. When compared to cyclophosphamide (CTX), leflunomide (LET) showed no beneficial effect, mycophenolate mofetil (MMF) showed significant beneficial on effectiveness (CR/PR, RR: 1.41, 95% CI 1.16 to 1.72 P = 0.0006) but not significant on complete remission (CR, RR: 1.38, 95% CI 0.89 to 2.13 P = 0.15). Conclusions This analysis based on Chinese adults and short duration RCTs suggested calcineurin inhibitors, especially TAC, were more effective in proteinuria reduction in IMN with acceptable side effects. Long duration RCTs were needed to confirm the long-term effects of those agents in nephrotic IMN. PMID:22957065

  4. Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense.

    PubMed

    Suganuma, Keisuke; Sarwono, Albertus Eka Yudistira; Mitsuhashi, Shinya; Jąkalski, Marcin; Okada, Tadashi; Nthatisi, Molefe; Yamagishi, Junya; Ubukata, Makoto; Inoue, Noboru

    2016-07-01

    This study aimed to evaluate the trypanocidal activity of mycophenolic acid (MPA) and its derivatives for Trypanosoma congolense The proliferation of T. congolense was completely inhibited by adding <1 μM MPA and its derivatives. In addition, the IMP dehydrogenase in T. congolense was molecularly characterized as the target of these compounds. The results suggest that MPA and its derivatives have the potential to be new candidates as novel trypanocidal drugs. PMID:27139487

  5. Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation.

    PubMed

    Matz, Mareen; Lehnert, Martin; Lorkowski, Christine; Fabritius, Katharina; Unterwalder, Nadine; Doueiri, Salim; Weber, Ulrike A; Mashreghi, Mir-Farzin; Neumayer, Hans-H; Budde, Klemens

    2012-10-01

    Humoral rejection processes may lead to allograft injury and subsequent dysfunction. Today, only one B-cell-specific agent is in clinical use and the effects of standard and new immunosuppressant substances on B-cell activation and function are not fully clarified. The impact of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function was assessed by analysing proliferation, apoptosis, CD80/CD86 expression and immunoglobulin and IL-10 production in primary stimulated B cells. In addition, B-cell co-cultures with pre-activated T cells were performed to evaluate the effect of the different immunosuppressive agents on T-cell-dependent immunoglobulin production. Sotrastaurin did not inhibit B-cell proliferation, CD80/CD86 expression, and IgG production and had only minor effects on IgM levels at the highest concentration administered. In contrast, mycophenolic acid and everolimus had strong effects on all B-cell functions in a dose-dependent manner. All immunosuppressive agents caused decreased immunoglobulin levels in T-cell-dependent B-cell cultures. The data provided here suggest that mycophenolic acid and everolimus, but not sotrastaurin, are potent inhibitors of human B-lymphocyte function and activation. PMID:22816666

  6. Steroids Versus Steroids Plus Additional Agent in Frontline Treatment of Acute Graft-versus-Host Disease: A Systematic Review and Meta-Analysis of Randomized Trials.

    PubMed

    Rashidi, Armin; DiPersio, John F; Sandmaier, Brenda M; Colditz, Graham A; Weisdorf, Daniel J

    2016-06-01

    Despite extensive research in the last few decades, progress in treatment of acute graft-versus-host disease (aGVHD), a common complication of allogeneic hematopoietic cell transplantation (HCT), has been limited and steroids continue to be the standard frontline treatment. Randomized clinical trials (RCTs) have failed to find a beneficial effect of escalating immunosuppression using additional agents. Considering the small number of RCTs, limited sample sizes, and frequent early termination because of anticipated futility, we conducted a systematic review and an aggregate data meta-analysis to explore whether a true efficacy signal has been missed because of the limitations of individual RCTs. Seven reports met our inclusion criteria. The control arm in all studies was 2 mg/kg/day prednisone (or equivalent). The additional agent(s) used in the experimental arm(s) were higher-dose steroids, antithymocyte globulin, infliximab, anti-interleukin-2 receptor antibody (daclizumab and BT563), CD5-specific immunotoxin, and mycophenolate mofetil. Random effects meta-analysis revealed no efficacy signal in pooled response rates at various times points. Overall survival at 100 days was significantly worse in the experimental arm (relative risk [RR], .83; 95% confidence interval [CI], .74 to .94; P = .004, data from 3 studies) and showed a similar trend (albeit not statistically significantly) at 1 year as well (RR, .86; 95% CI, .68 to 1.09; P = .21, data from 5 studies). In conclusion, these results argue against the value of augmented generic immunosuppression beyond steroids for frontline treatment of aGVHD and emphasize the importance of developing alternative strategies. Novel forms of immunomodulation and targeted therapies against non-immune-related pathways may enhance the efficacy of steroids in this setting, and early predictive and prognostic biomarkers can help identify the subgroup of patients who would likely need treatments other than (or in addition to

  7. The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats

    PubMed Central

    Kabat-Koperska, Joanna; Kolasa-Wołosiuk, Agnieszka; Wojciuk, Bartosz; Wojciechowska-Koszko, Iwona; Roszkowska, Paulina; Krasnodębska-Szponder, Barbara; Paczkowska, Edyta; Safranow, Krzysztof; Gołembiewska, Edyta; Machaliński, Bogusław; Ciechanowski, Kazimierz

    2016-01-01

    Background In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system – the thymus and the spleen. Methods The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. Results There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Conclusion Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen–dependent manner. PMID:27471376

  8. [Drug-drug interactions in antirheumatic treatment].

    PubMed

    Krüger, K

    2012-04-01

    Clinically relevant drug-drug interactions contribute considerably to potentially dangerous drug side-effects and are frequently the reason for hospitalization. Nevertheless they are often overlooked in daily practice. For most antirheumatic drugs a vast number of interactions have been described but only a minority with clinical relevance. Several potentially important drug interactions exist for non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, azathioprine, mycophenolate-mofetil and especially for cyclosporin A. Most importantly co-medication with methotrexate and sulfmethoxazole trimethoprim as well as azathioprine and allopurinol carries the risk of severe, sometimes life-threatening consequences. Nevertheless, besides these well-known high-risk combinations in each case of polypharmacy with antirheumatic drugs it is necessary to bear in mind the possibility of drug interactions. As polypharmacy is a common therapeutic practice in older patients with rheumatic diseases, they are at special risk. PMID:22527215

  9. Treatment of Neuromyelitis Optica: Review and Recommendations.

    PubMed

    Kimbrough, Dorlan J; Fujihara, Kazuo; Jacob, Anu; Lana-Peixoto, Marco A; Leite, Maria Isabel; Levy, Michael; Marignier, Romain; Nakashima, Ichiro; Palace, Jacqueline; de Seze, Jérôme; Stuve, Olaf; Tenembaum, Silvia N; Traboulsee, Anthony; Waubant, Emmanuelle; Weinshenker, Brian G; Wingerchuk, Dean M

    2012-10-01

    Neuromyelitis optica (NMO) is an autoimmune demyelinating disease preferentially targeting the optic nerves and spinal cord. Once regarded as a variant of multiple sclerosis (MS), NMO is now recognized to be a different disease with unique pathology and immunopathogenesis that does not respond to traditional MS immunomodulators such as interferons. Preventive therapy in NMO has focused on a range of immunosuppressive medications, none of which have been validated in a rigorous randomized trial. However, multiple retrospective and a few recent prospective studies have provided evidence for the use of six medications for the prevention of NMO exacerbations: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate and mitoxantrone. This review provides a comprehensive analysis of each of these medications in NMO and concludes with a set of recommended consensus practices. PMID:24555176

  10. Treatment of Neuromyelitis Optica: Review and Recommendations

    PubMed Central

    Kimbrough, Dorlan J; Fujihara, Kazuo; Jacob, Anu; Lana-Peixoto, Marco A; Leite, Maria Isabel; Levy, Michael; Marignier, Romain; Nakashima, Ichiro; Palace, Jacqueline; de Seze, Jérôme; Stuve, Olaf; Tenembaum, Silvia N; Traboulsee, Anthony; Waubant, Emmanuelle; Weinshenker, Brian G; Wingerchuk, Dean M

    2014-01-01

    Neuromyelitis optica (NMO) is an autoimmune demyelinating disease preferentially targeting the optic nerves and spinal cord. Once regarded as a variant of multiple sclerosis (MS), NMO is now recognized to be a different disease with unique pathology and immunopathogenesis that does not respond to traditional MS immunomodulators such as interferons. Preventive therapy in NMO has focused on a range of immunosuppressive medications, none of which have been validated in a rigorous randomized trial. However, multiple retrospective and a few recent prospective studies have provided evidence for the use of six medications for the prevention of NMO exacerbations: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate and mitoxantrone. This review provides a comprehensive analysis of each of these medications in NMO and concludes with a set of recommended consensus practices. PMID:24555176

  11. Alterations of endothelial nucleotide levels by mycophenolic acid result in changes of membrane glycosylation and E-selectin expression.

    PubMed

    Bertalanffy, P; Dubsky, P; Wolner, E; Weigel, G

    1999-03-01

    The effect of the inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), mycophenolic acid, on intracellular nucleotides and the synthesis of cellular glycoproteins was evaluated in human umbilical vein endothelial cells. A clinically attainable concentration (10 micromol/l) of mycophenolic acid decreased guanosine-5'-triphosphate (GTP) levels significantly and led to a strong elevation of uridine-5'-triphosphate (UTP), whereas intracellular adenosine-5'-triphosphate (ATP) pools remained unaffected. The staining of the endothelial cell membranes with lectins specific for fucose and mannose (Ulex europaeus- and Galanthus nivalis agglutinin, respectively) was reduced, reflecting an inhibition of fucose and mannose incorporation into endothelial glycoproteins. The surface expression of E-selectin, an important determinant for leuko-endothelial interactions decreased significantly. Guanine and guanosine prevented the actions of mycophenolic acid and reversed the drug-induced decrease in GTP and its associated effects. The findings that mycophenolic acid produces alterations in the formation of glycoproteins and in the membrane architecture are indicative of metabolic lesions induced by an agent that depresses guanine nucleotide synthesis through inhibition of IMPDH. The pronounced reduction of E-selectin surface expression on endothelial cells accompanied by changes of endothelial cell fucosylation, a prerequisite for the contact with lymphocytic L-selectin, indicates an inhibitory effect of mycophenolic acid in the rolling phase of leukocyte recruitment and strongly implies a new and additional immunosuppressive mechanism of this agent. PMID:10353469

  12. Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation, and Donor Bone Marrow Transplant Followed by Donor Natural Killer Cell Therapy, Mycophenolate Mofetil, and Tacrolimus in Treating Patients With Hematologic Cancer

    ClinicalTrials.gov

    2016-06-07

    Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Diffuse Large B-Cell Lymphoma; Previously Treated Myelodysplastic Syndrome; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Indolent Adult Non-Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

  13. Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer

    ClinicalTrials.gov

    2016-01-25

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lym

  14. Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2015-11-16

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  15. Moderator's view: Cyclophosphamide in lupus nephritis.

    PubMed

    Tesar, Vladimir

    2016-07-01

    Mycophenolate mofetil was recently accepted as the effective induction treatment of lupus nephritis, with the potential to replace cyclophosphamide or at least expand our therapeutic armamentarium in patients with this lifelong disease often requiring repeated induction treatment of its relapses. Compared with cyclophosphamide, mycophenolate may be more effective in black patients, and the risk of gonadotoxicity may be significantly lower in mycophenolate-treated subjects. However, experience with mycophenolate in severe lupus nephritis is still limited and we also have insufficient data on the long-term outcome of mycophenolate-treated patients. Treatment with mycophenolate is more expensive than with cyclophosphamide, which may limit its use, especially in low- and middle-income countries. The efficacy of mycophenolate mofetil may be more dependent on the patient's compliance compared with intravenous cyclophosphamide pulses. Low-dose cyclophosphamide remains an effective and relatively safe induction treatment of active lupus nephritis, but to decrease its cumulative toxicity, repeated exposure to cyclophosphamide in relapsing patients should be (if possible) avoided. PMID:27190357

  16. [Auto-immune liver diseases and their treatment].

    PubMed

    Hess, J; Thorens, J; Pache, I; Troillet, F X; Moradpour, D; Gonvers, J J

    2005-01-19

    There are three main types of auto-immune liver disease, auto-immune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. In the case of auto-immune hepatitis, prednisone therapy, with or without azathioprine, can improve quality of life and halt progression to cirrhosis. If there is no response or if the therapy is poorly tolerated, mycophenolate mofetil or cyclosporin should be considered. Ursodeoxycholic acid (UDCA), at a dosage of 13 to 15 mg/kg/day slows the progression of fibrosis in patients with primary biliary cirrhosis. Pruritus may be treated with cholestyramine, rifampicin or opiate antagonists. Ursodeoxycholic acid at a dosage of 20 to 30 mg/kg/day will slow the evolution of fibrosis. PMID:15770819

  17. In vitro effects of mycophenolic acid on survival, function, and gene expression of pancreatic beta-cells.

    PubMed

    Gallo, R; Natale, M; Vendrame, F; Boggi, U; Filipponi, F; Marchetti, P; Laghi Pasini, F; Dotta, F

    2012-12-01

    Post-transplant diabetes mellitus represents an important complication of prolonged immunosuppressive treatment after solid organ transplantation. The immunosuppressive toxicity, responsible for a persistent impairment of glucose metabolism in pancreatic islet-transplanted patients, is mainly attributed to calcineurin inhibitors and steroids, while other immunosuppressive molecules (azathioprine and mycophenolic acid, MPA) are considered not to have a toxic effect. In the present study, in vitro effects of MPA have been investigated in mouse beta-cell lines (βTC-1 and βTC-6) and in purified human pancreatic islets. βTC-1, βTC-6, and human pancreatic islets were exposed to various concentrations of MPA for different times. Consequently, we evaluated the viability, the induction of apoptosis, the glucose-stimulated insulin secretion, and the expression of β-cell function genes (Isl1, Pax6, Glut-2, glucokinase) and apoptosis-related genes (Bax and Bcl2). βTC-1, βTC-6, and human islets treated, respectively, for 48 and 72 h with 15-30 nM MPA showed altered islet architecture, as compared with control cells. We observed for βTC-1 and βTC-6 almost 70% reduction in cell viability; three to sixfold induction of TUNEL/apoptotic-positive cells quantified by FACS analysis. A twofold increase in apoptotic cells was observed in human islets after MPA exposure associated with strong inhibition of glucose-stimulated insulin secretion. Furthermore, we showed significant down-regulation of gene expression of molecules involved in β-cell function and increase rate between Bax/Bcl2. Our data demonstrate that MPA has an in vitro diabetogenic effect interfering at multiple levels with survival and function of murine and human pancreatic β-cells. PMID:22249339

  18. Determination of Mycophenolic Acid in Plasma Samples Using the Terbium-Sensitized Luminescence Method

    NASA Astrophysics Data System (ADS)

    Shayanfar, A.; Ghavimi, H.; Zolali, E.; Jouyban, A.

    2015-09-01

    The objectives of this work were to provide an analytical method, for the quantitative determination of the mycophenolic acid (MFA) in plasma samples and its application to quantification of the MFA in rat plasma after oral administration. In order to remove the fluorescence interferences of the plasma, the samples were precipitated by acetonitrile in 1:8 ratio and then a few parameters were optimized and the fluorescence intensity measured at 545 nm using an excitation wavelength of 347 nm. Under the optimized concentration, the method provided a linear range between 1.0 and 10.0 mg/l with a correlation coefficient of 0.998. MFA was detected and the validation was performed according to the FDA guidelines. Linearity, accuracy, precision, and selectivity of the developed method were suitable for th determination of the MFA in plasma samples. The proposed analytical approach was applied to determine the MFA concentration in a rat plasma-time profile study.

  19. Towards new avenues in the management of lupus glomerulonephritis.

    PubMed

    Mok, C C

    2016-04-01

    Renal involvement in systemic lupus erythematosus (SLE) carries substantial morbidity and mortality. Conventional immunosuppressive agents (cyclophosphamide and azathioprine) have suboptimal efficacy and substantial toxicity. Mycophenolate mofetil has emerged as an alternative agent for both induction and maintenance therapy in lupus nephritis because of its reduced gonadal toxicity, despite its failure to demonstrate superiority over cyclophosphamide in pivotal studies. The calcineurin inhibitor tacrolimus has equivalent efficacy to cyclophosphamide and mycophenolate mofetil for inducing remission of lupus nephritis. Although rituximab has shown promise in refractory lupus nephritis, combining rituximab with mycophenolate mofetil as initial therapy offers no additional benefit. Considerable interethnic variation is evident in the efficacy and tolerability of the various immunosuppressive regimens, which necessitates individualized treatment and comparison of the efficacy of new regimens across different ethnic groups. For example, low-dose combinations of tacrolimus and mycophenolate mofetil seem to be more effective than pulse cyclophosphamide as induction therapy in Chinese patients. The same regimen has also been used successfully to treat refractory proliferative and membranous lupus nephritis in patients of various ethnic groups. Finally, novel serum and urinary biomarkers are being validated for diagnosis, prognostic stratification and early recognition of flares in lupus nephritis. PMID:26729459

  20. Comparative analysis the binding affinity of mycophenolic sodium and meprednisone with human serum albumin: Insight by NMR relaxation data and docking simulation.

    PubMed

    Ma, Xiaoli; He, Jiawei; Yan, Jin; Wang, Qing; Li, Hui

    2016-03-25

    Mycophenolic sodium is an immunosuppressive agent that is always combined administration with corticosteroid in clinical practice. Considering the distribution and side-effect of the drug may change when co-administrated drug exist, this paper comparatively analyzed the binding ability of mycophenolic sodium and meprednisone toward human serum albumin by nuclear magnetic resonance relaxation data and docking simulation. The nuclear magnetic resonance approach was based on the analysis of proton selective and non-selective relaxation rate enhancement of the ligand in the absence and presence of macromolecules. The contribution of the bound ligand fraction to the observed relaxation rate in relation to protein concentration allowed the calculation of the affinity index. This approach allowed the comparison of the binding affinity of mycophenolic sodium and meprednisone. Molecular modeling was operated to simulate the binding model of ligand and albumin through Autodock 4.2.5. Competitive binding of mycophenolic sodium and meprednisone was further conducted through fluorescence spectroscopy. PMID:26892221

  1. Comparative tolerability of treatments for inflammatory bowel disease.

    PubMed

    Stein, R B; Hanauer, S B

    2000-11-01

    , gingival hyperplasia, hyperkalaemia, paresthesias, and tremors. These adverse effects usually abate with dose reduction or cessation of therapy. Seizures and opportunistic infections have also been reported. Antibacterials are commonly employed as primary therapy for Crohn's disease. Common adverse effects of metronidazole include nausea and a metallic taste. Peripheral neuropathy can occur with prolonged administration. Ciprofloxacin and other antibacterials may be beneficial in those intolerant to metronidazole. Newer immunosuppressive agents previously reserved for transplant recipients are under investigation for IBD. Tacrolimus has an adverse effect profile similar to cyclosporin, and may cause renal insufficiency. Mycophenolate mofetil, a purine synthesis inhibitor, has primarily gastrointestinal adverse effects. Biological agents targeting specific sites in the immunoinflammatory cascade are now available to treat IBD. Infliximab, a chimeric antibody targeting tumour necrosis factor-or has been well tolerated in clinical trials and early postmarketing experience. Additional trials are needed to assess long term adverse effects. PMID:11085348

  2. Current and emerging treatments for idiopathic focal and segmental glomerulosclerosis in adults.

    PubMed

    Ponticelli, Claudio; Graziani, Giorgio

    2013-03-01

    Idiopathic focal and segmental glomerular sclerosis is a frequent cause of nephrotic syndrome and end-stage renal disease. The pathogenesis is still unknown, although the body of evidence suggests that focal and segmental glomerular sclerosis is caused by a not clearly identified circulating factor that alters the permselectivity of the glomerular barrier. Proteinuria is followed by podocyte injury. Glucocorticoids, calcineurin inhibitors, cytotoxic agents and mycophenolate mofetil, either given alone or in combination, may obtain complete or partial remission of proteinuria in 50-60% of patients and protect them from end-stage renal disease, but the remaining patients are resistant to the available drugs. A number of new drugs, including rituximab, galactose and antifibrotic agents, are under investigation. PMID:23445199

  3. Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers.

    PubMed

    Wolff, Daniel; Ayuk, Francis; Elmaagacli, Ahmet; Bertz, Hartmut; Lawitschka, Anita; Schleuning, Michael; Meyer, Ralf-Georg; Gerbitz, Armin; Hilgendorf, Inken; Hildebrandt, Gerhard C; Edinger, Matthias; Klein, Stephan; Halter, Jörg; Mousset, Sabine; Holler, Ernst; Greinix, Hildegard T

    2013-05-01

    . Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience. PMID:23376495

  4. Strain-Specific Synthesis of Mycophenolic Acid by Penicillium roqueforti in Blue-Veined Cheese

    PubMed Central

    Engel, Günter; von Milczewski, Karl Ernst; Prokopek, Dieter; Teuber, Michael

    1982-01-01

    Twenty of 80 strains of Penicillium roqueforti were able to produce up to 600 mg of mycophenolic acid (MPA) liter−1 in 2% yeast extract-5% sucrose broth. Sixty-two of these strains had been isolated from the main blue-veined cheese varieties of western Europe or from starter cultures. Of these 62 dairy strains, only 7 had MPA-producing potential in vitro. These seven strains had all been isolated during the period 1975 to 1981 from the blue cheese of one individual factory. In cheese from the market, MPA (up to 5 mg kg−1) was only found in samples of this same factory. With MPA-producing and -nonproducing strains for the experimental manufacture of blue cheese, MPA synthesis in cheese was only detected with strains which form MPA in yeast extract-sucrose broth. The maximum MPA level at 4 mg kg−1 was similar to that in commercial cheese. Toxicity of MPA was tested with two established human cell lines (Detroit 98 and Girardi Heart) and one established pig kidney cell line (AmII). PMID:16346004

  5. Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients.

    PubMed

    Martial, Lisa C; Jacobs, Bart A W; Cornelissen, Elisabeth A M; de Haan, Anton F J; Koch, Birgit C P; Burger, David M; Aarnoutse, Rob E; Schreuder, Michiel F; Brüggemann, Roger J M

    2016-06-01

    MPA is an immunosuppressive agent used to prevent graft rejection after renal transplantation. MPA shows considerable inter- and intraindividual variability in exposure in children and has a defined therapeutic window, and TDM is applied to individualize therapy. We aimed to study the exposure to MPA measured as the AUC in pediatric renal transplant patients, to identify factors influencing exposure and to assess target attainment. Children transplanted between 1998 and 2014 in a single center were included. Two groups were identified: Group 1 (AUC <3 wk post-transplantation) and Group 2 (AUC >18 months post-transplantation). Therapeutic targets were set at: AUC0-12h of 30-60 mg h/L. A total of 39 children were included in Group 1 (median age 13.3 yr) vs. 14 in Group 2 (median age 13.4 yr). AUC0-12h was 29.7 mg h/L in Group 1 and 56.6 mg h/L in Group 2, despite a lower dosage in Group 2 (584 and 426 mg/m(2) , respectively). About 46% of patients reached the target AUC0-12h in Group 1. Time since transplantation and serum creatinine were significantly associated with MPA exposure (p < 0.001), explaining 36% of the variability. Individualization of the mycophenolate dose by more intense and more early TDM could improve target attainment. PMID:26923724

  6. Identification and Functional Analysis of the Mycophenolic Acid Gene Cluster of Penicillium roqueforti.

    PubMed

    Del-Cid, Abdiel; Gil-Durán, Carlos; Vaca, Inmaculada; Rojas-Aedo, Juan F; García-Rico, Ramón O; Levicán, Gloria; Chávez, Renato

    2016-01-01

    The filamentous fungus Penicillium roqueforti is widely known as the ripening agent of blue-veined cheeses. Additionally, this fungus is able to produce several secondary metabolites, including the meroterpenoid compound mycophenolic acid (MPA). Cheeses ripened with P. roqueforti are usually contaminated with MPA. On the other hand, MPA is a commercially valuable immunosuppressant. However, to date the molecular basis of the production of MPA by P. roqueforti is still unknown. Using a bioinformatic approach, we have identified a genomic region of approximately 24.4 kbp containing a seven-gene cluster that may be involved in the MPA biosynthesis in P. roqueforti. Gene silencing of each of these seven genes (named mpaA, mpaB, mpaC, mpaDE, mpaF, mpaG and mpaH) resulted in dramatic reductions in MPA production, confirming that all of these genes are involved in the biosynthesis of the compound. Interestingly, the mpaF gene, originally described in P. brevicompactum as a MPA self-resistance gene, also exerts the same function in P. roqueforti, suggesting that this gene has a dual function in MPA metabolism. The knowledge of the biosynthetic pathway of MPA in P. roqueforti will be important for the future control of MPA contamination in cheeses and the improvement of MPA production for commercial purposes. PMID:26751579

  7. Development and application of monoclonal antibodies against the mycotoxin mycophenolic acid.

    PubMed

    Dietrich, Richard; Märtlbauer, Erwin

    2015-11-01

    Mycophenolic acid (MPA) is frequently found, often in high concentrations, in a broad range of food and feed matrices. Apart from the well-known contamination of blue-veined cheeses caused by the use of toxinogenic Penicillium roqueforti strains for manufacturing, a broad range of other Penicillium spp. is able to produce this immunosuppressive toxin. Therefore, MPA has been proposed to be a suitable marker for Penicillium-infected food commodities. In the present work, a high-affinity monoclonal antibody (mAb) for the specific detection of MPA was developed by immunizing mice with a MPA-protein conjugate coupled by an activated ester method. Under the conditions of a direct competitive enzyme immunoassay (EIA), 50% inhibition and detection limits of MPA standard curves were 1.2 and 0.3 ng/ml, respectively. Furthermore, the mAb could be successfully employed for the production of an immunoaffinity (IA) column enabling the efficient enrichment of MPA from processed foodstuffs. By combining the IA clean-up with a polyclonal antibody-based EIA, an ultrasensitive analysis method could be established which allowed the reliable and reproducible detection of MPA in artificially contaminated tomato ketchup as a model matrix at concentrations as low as 0.1 ng/g. PMID:26382857

  8. The Necrotic Signal Induced by Mycophenolic Acid Overcomes Apoptosis-Resistance in Tumor Cells

    PubMed Central

    Dilhuydy, Marie-Sarah; Pinson, Benoît; Mahfouf, Walid; Pasquet, Jean-Max; Mahon, François-Xavier; Pourquier, Philippe; Moreau, Jean-François; Legembre, Patrick

    2009-01-01

    Background The amount of inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP), is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA) are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42. Methodology/Principal Findings Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA–mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL–overexpressing cells). All tested cells remained sensitive to MPA–mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers. Conclusions/Significance These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells. PMID:19430526

  9. Determination of Mycophenolic acid in the vitreous humor using the HPLC-ESI-MS/MS method: application of intraocular pharmacokinetics study in rabbit eyes with ophthalmic implantable device.

    PubMed

    Martins Duarte Byrro, Ricardo; de Oliveira Fulgêncio, Gustavo; Rocha Chellini, Paula; da Silva Cunha, Armando; Pianetti, Gerson Antônio

    2013-10-01

    Mycophenolic acid (MPA) is an immunosuppressive agent widely used in the treatment of solid organ transplant rejection. The success of MPA in the treatment of inflammatory intraocular diseases has been reported in recent literature. The treatment of inflammatory eye diseases in the posterior chamber is a challenge due to the anatomy of the eye, which presents certain barriers to drug access. Thus, the bioavailability of drugs in the eye is quite low, and successful drug delivery may well represent a key limiting factor to attaining a successful therapeutic strategy. Ophthalmic controlled drug delivery offers the potential to enhance the efficacy of treatment for pathological conditions. Thus, a novel delivery system based on a biodegradable polymeric device, which can be implanted inside the eye and deliver MPA directly to the target, is being developed. Specific analytical methods to determine the use of effective drugs within the eye are needed to characterize this device. A liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method for the quantitation of MPA in the vitreous humor of rabbits was developed and validated. The vitreous was collected from rabbits, extracted by a protein precipitation extraction procedure and then separated on a C18 column with a mobile phase comprised of 0.15% aqueous acetic acid and methanol (60:40, v/v). The calibration curve was constructed within the range of 3-10,000 ng/mL for MPA. The mean R.S.D. values for the intra-run and inter-run precision were 5.15% and 4.35%. The mean accuracy value was 100.16%. The validated method was successfully applied to determine the MPA concentration in the vitreous humor of rabbits treated with an ocular implantable device. PMID:23797039

  10. Usefulness of mycophenolic acid monitoring with PETINIA for prediction of adverse events in kidney transplant recipients.

    PubMed

    Ham, Ji Yeon; Jung, Hee-Yeon; Choi, Ji-Young; Park, Sun-Hee; Kim, Yong-Lim; Kim, Hyung-Kee; Huh, Seung; Kim, Chan-Duck; Won, Dong Il; Song, Kyung Eun; Cho, Jang-Hee

    2016-07-01

    Background Therapeutic drug monitoring of mycophenolic acid (MPA) is required to optimize the immunosuppressive effect and minimize toxicity. We validated a new particle-enhanced turbidimetric inhibition immunoassay (PETINIA) for the determination of MPA levels and evaluated the relationship of MPA trough level with drug-related adverse events. Methods PETENIA and liquid chromatography-mass spectrometry (LC-MS) were used to determine MPA concentrations from 54 kidney transplant recipients (KTRs). Agreement between PETINIA and LC-MS results was assessed by Passing-Bablok regression and the Bland-Altman plot method. The association of adverse events with MPA trough level obtained by PETINIA was analyzed. Results PETINIA revealed a good agreement with the LC-MS; Regression analysis gave an equation of y = 1.27x - 0.12 (r(2) = 0.975, p < 0.001). PETINIA showed a systemic positive bias with a mean difference of 0.66 mg/L compared to LC-MS. However, the magnitude of the positive bias decreased to 0.44 mg/L within the therapeutic range of MPA. Multiple logistic regression showed that MPA trough level determined by PETINIA was an independent risk factor for adverse events (odds ratio 2.28, 95% CI 1.25-4.16, p = 0.007). MPA trough level predicted adverse events with a sensitivity of 77.8% and a specificity of 86.7% using a cut-off level of 5.25 mg/L. Conclusions Good correlation between the two methods indicates that PETINIA is an acceptable method for the monitoring of MPA therapeutic levels. Furthermore, MPA trough level obtained by PETINIA is a useful monitoring tool to minimize toxicity in KTRs. PMID:26981890

  11. [Allogeneic hematopoietic stem cell transplantation for the treatment of mucopolysaccharidosis type 1: a case report].

    PubMed

    Ou, Rui-Ming; Wang, Ling; Zheng, Li-Ling; Yao, Meng-Dong; Jiang, Wei-Tao; Zhou, Chang-Hua

    2006-06-01

    Mucopolysaccharidosis type I (MPS-I) is an inborn error of metabolism with progressive multisystem involvement. Hurler syndrome is the most severe form of MPS-I that causes progressive deterioration of the central nervous system with ensuing death. This study reported the therapeutic effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on Hurler syndrome in one case. The patient was a 25-month-old boy. He underwent allo-HSCT. The donor was his elder sister whose HLA-B locus was not matching. The reduced-intensity of BuCy conditioning regimen in allo-HSCT for this patient was as follows: busulfan 3.7 mg/kg daily at 9 to 6 days before transplantation, cyclophosphamide 42.8 mg/kg daily at 5 to 2 days before transplantation, and rabbit antithymocyte globulin 3.5 mg/kg daily at 1, 3, 5, and 7 days before transplantation. Human granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (CD34+ cells 12.8 x10(6)/kg) were infused and cyclosporine (CSA), short-course methotrexate, daclizumab and mycophenolate mofetil (MMF) were administered to prevent graft-versus-host disease (GVHD). Complete donor-type engraftment was confirmed by Short Tandem Repeat-Polymerase Chain Reaction (STR-PCR) on day 14 after transplantation. Neutrophil and platelet engraftment occurred on days 11 and 19 after transplantation respectively. Only grade I regimen-related toxicity of live and gastrointestinal tract occurred. GVHD and graft failure were not observed. After transplantation, the clinical symptoms and the neurocognitive function were greatly improved in this patient. It was concluded that allo-HSCT was effective for the treatment of MPS-I. The reduced-intensity conditioning regimen was helpful to decrease the regimen-related toxicity. Sufficient immunosuppressive therapy and adequate hematopoietic stem cells infusion may be beneficial to the donor cell engraftment and reducing the incidence of graft failure and GVHD. PMID:16787585

  12. Immunosuppressive agents versus steroids in the treatment of IgA nephropathy-induced proteinuria: A meta-analysis

    PubMed Central

    LIU, YANLI; XIAO, JUN; SHI, XINTIAN; HAO, GUOJUN; CHEN, QINKAI; ZHOU, JING; WEI, XIN

    2016-01-01

    Immunoglobulin A nephropathy (IgAN) is one of the most common types of primary glomerular disease. Immunosuppressive treatment for patients with IgAN remains controversial. The present meta-analysis aimed to assess the efficacy and safety of various immunosuppressive agents compared with steroids in patients with IgAN and moderate to severe proteinuria. PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, Weipu, Chinese Biomedical Literature Database and Qinghuatongfang were searched for relevant randomized controlled trials (RCTs) published between 1990 and September 2013. All eligible studies (biopsy proven IgA nephropathy, use of immunosuppressive agents) measured urinary protein excretion and proteinuria remission. Data were analyzed with the random effects model using Review Manager. A total of 29 RCTs were included, involving 1,466 patients. Compared with steroids, immunosuppressive agents, including acetazolamide (AZA) [complete response (CR)/partial response (PR); relative risk (RR), 3.43; 95% confidence interval (CI) 1.92–6.12; P<0.0001], mycophenolate mofetil (MMF) (CR/PR; RR, 2.19; 95% CI, 1.25–3.85; P=0.006) and leflunomide (LET) (CR/PR; RR, 2.64; 95% CI, 1.80–3.86; P<0.00001) resulted in increased partial or complete proteinuria remission. Cyclophosphamide (CTX) resulted in a higher reduction of urinary protein excretion than steroids (SMD, 0.91; 95% CI, 0.41–1.41; P=0.0004)). Compared to CTX, LET showed higher effectiveness (CR/PR; RR, 2.01; 95% CI, 1.08–3.75; P=0.03) with a lower incidence of adverse events. The present meta-analysis, which is based on IgAN patients, suggested that AZA, MMF, LET and CTX are effective in reducing proteinuria levels, with acceptable side effects. Therefore, immunosuppressive agents may be considered promising therapeutic agents for the treatment of IgAN and should be investigated further in large sample size, high-quality studies. PMID:26889216

  13. Successful therapy with rituximab of refractory acute humoral renal transplant rejection: a case report.

    PubMed

    Celik, A; Saglam, F; Cavdar, C; Sifil, A; Atila, K; Sarioglu, S; Bora, S; Gulay, H; Camsari, T

    2008-01-01

    Acute humoral rejection (AHR) is generally less responsive to conventional anti-rejection treatment with consequent allograft losses. Therapeutic options include antilymphocyte antibody (ATG), intravenous immunglobulin (IVIG), plasmapheresis, or immunoadsorption with protein A together with intensification of immunsuppression with a tacrolimus/mycophenolate mofetil combination. This report describes a transplant recipient who responded to rituximab therapy as treatment for steroid-, ATG-, IVIG-, and plasmapheresis-resistant AHR. PMID:18261611

  14. Severe Refractory Immune Thrombocytopenia Successfully Treated with High-Dose Pulse Cyclophosphamide and Eltrombopag

    PubMed Central

    Anwer, Faiz; Yun, Seongseok; Nair, Anju; Ahmad, Yusuf; Krishnadashan, Ravitharan; Deeg, H. Joachim

    2015-01-01

    Severe refractory ITP is clinically challenging and a variety of single or combination chemotherapies have been tried with limited outcome. We report a case of ITP that was unresponsive to multiple agents including high-dose steroid, IVIG, Rho(D) immune globulin, rituximab, cyclosporine, azathioprine, vincristine, mycophenolate mofetil, romiplostim, and eltrombopag; however, it achieved complete remission with combination treatment of cyclophosphamide and eltrombopag. PMID:26180646

  15. Severe Refractory Immune Thrombocytopenia Successfully Treated with High-Dose Pulse Cyclophosphamide and Eltrombopag.

    PubMed

    Anwer, Faiz; Yun, Seongseok; Nair, Anju; Ahmad, Yusuf; Krishnadashan, Ravitharan; Deeg, H Joachim

    2015-01-01

    Severe refractory ITP is clinically challenging and a variety of single or combination chemotherapies have been tried with limited outcome. We report a case of ITP that was unresponsive to multiple agents including high-dose steroid, IVIG, Rho(D) immune globulin, rituximab, cyclosporine, azathioprine, vincristine, mycophenolate mofetil, romiplostim, and eltrombopag; however, it achieved complete remission with combination treatment of cyclophosphamide and eltrombopag. PMID:26180646

  16. Sequential therapy with cyclophosphamide and mycophenolic acid in patients with progressive immunoglobulin A nephropathy: a long-term follow-up.

    PubMed

    Rasche, F M; Keller, F; Rasche, W G; Schiekofer, S; Kahn, T; Fahnert, J

    2016-02-01

    In progressive immunoglobulin (Ig)A nephropathy (IgAN), cyclophosphamide pulse therapy (CyP), high-dose intravenous immunoglobulins (IVIg) and mycophenolic acid (MPA) have been used to stop progressive loss of renal function, but disease progression may occur after the end of the initial treatment. Here, we report the long-term follow-up of patients with progressive IgAN with MPA as maintenance therapy after CyP (CyP-MPA). In a median observation time of 6·2 years, we analysed the slopes of the loss of renal function of 47 patients with biopsy-proven IgAN and treated with CyP. Thirty-one patients with further progression were treated with MPA maintenance for a median time of 5·2 years. Follow-up was compared with symptomatic therapy and IVIg as historically matched control groups. Median loss of renal function was reduced significantly from 0·9 ml/min to 0·1 ml/min per month with CyP (P < 0·05), and with MPA in patients with a relapse from -0·4 ml/min to -0·1 ml/min per month (P < 0·05) until the end of the study. Proteinuria decreased significantly from 1·6 g/l to 1·0 g/l after CyP, and during MPA treatment to 0·6 g/l (P = 0·001 Friedman test). Median renal survival time was in patients with CyP 10·5 years (range = 3·2-17·8), with CyP-MPA 10·7 years (range = 8·3-13·1), with IVIg 4·7 years (range = 2·6-6·6), and in untreated patients 1·2 years (range = 0·8-1·6; log-rank test P < 0·01). In patients with progressive IgAN, our long-term follow-up observation indicates that sequential CyP-MPA therapy maintains renal survival significantly. PMID:26439797

  17. Clinical trial of focal segmental glomerulosclerosis in children and young adults.

    PubMed

    Gipson, Debbie S; Trachtman, Howard; Kaskel, Frederick J; Greene, Tom H; Radeva, Milena K; Gassman, Jennifer J; Moxey-Mims, Marva M; Hogg, Ronald J; Watkins, Sandra L; Fine, Richard N; Hogan, Susan L; Middleton, John P; Vehaskari, V Matti; Flynn, Patti A; Powell, Leslie M; Vento, Suzanne M; McMahan, June L; Siegel, Norman; D'Agati, Vivette D; Friedman, Aaron L

    2011-10-01

    This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect. PMID:21734640

  18. Clinical trial of focal segmental glomerulosclerosis in children and young adults

    PubMed Central

    Gipson, Debbie S.; Trachtman, Howard; Kaskel, Frederick J.; Greene, Tom H.; Radeva, Milena K.; Gassman, Jennifer J.; Moxey-Mims, Marva M.; Hogg, Ronald J.; Watkins, Sandra L.; Fine, Richard N.; Hogan, Susan L.; Middleton, John P.; Vehaskari, V. Matti; Flynn, Patti A.; Powell, Leslie M.; Vento, Suzanne M.; McMahan, June L.; Siegel, Norman; D’Agati, Vivette D.; Friedman, Aaron L.

    2012-01-01

    This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect. PMID:21734640

  19. Corticosteroid-Free Primary Treatment of Chronic Extensive Graft-versus-Host Disease Incorporating Rituximab.

    PubMed

    Solomon, Scott R; Sizemore, Connie A; Ridgeway, Michelle; Zhang, Xu; Smith, Judith; Brown, Stacey; Holland, H Kent; Morris, Lawrence E; Bashey, Asad

    2015-09-01

    Chronic graft-versus-host disease (cGVHD) is a significant determinant of overall outcome and quality of life in survivors of allogeneic hematopoietic cell transplantation. Standard initial therapy of cGVHD is based on prolonged use of corticosteroids and a calcineurin inhibitor and has not changed for over 3 decades, despite limited efficacy and long-term toxicity. Rituximab is an attractive agent for the upfront treatment of cGVHD because of its favorable toxicity profile, efficacy in steroid-refractory cGVHD, and ability to serve as a steroid-sparing agent in autoimmune diseases. We hypothesized that a corticosteroid-free regimen incorporating rituximab would result in improved outcomes when used for the initial treatment of cGVHD. Twenty-five patients (median age, 56 years; range, 29 to 77) with extensive cGVHD were enrolled on a prospective phase II trial. Enrollment was limited to patients with first onset extensive cGVHD requiring systemic immunosuppression and without residual or concurrent acute graft-versus-host disease. cGVHD was classified as de novo, interrupted, and progressive in 12, 11, and 2 patients, respectively. cGVHD severity (National Institutes of Health grade) was mild, moderate, and severe in 3, 14, and 8 patients, respectively. All patients received rituximab 375 mg/m(2) × 4 weekly doses, then 1 dose every 3 months × 4 doses, in addition to mycophenolate mofetil and either tacrolimus or sirolimus. No other systemic immunosuppression was permitted, and only a short-course of steroids (≤4 weeks) was allowed at physician discretion; otherwise, treatment was deemed a failure and patients were treated off study. Twenty-two of 25 patients (88%) responded to treatment. Of the 22 responding patients, the median time to maximum response was 161 days (range, 35 to 300 days) with maximum response being complete in 21 of 22 patients and partial in 1 patient. Excluding the 3 patients taken off study for treatment failure, corticosteroids were used

  20. Estimation of abbreviated mycophenolic acid area under the concentration-time curve during early posttransplant period by limited sampling strategy.

    PubMed

    Mohammadpour, A-H; Nazemian, F; Abtahi, B; Naghibi, M; Gholami, K; Rezaee, S; Nazari, M-R A; Rajabi, O

    2008-12-01

    Area under the concentration curve (AUC) of mycophenolic acid (MPA) could help to optimize therapeutic drug monitoring during the early post-renal transplant period. The aim of this study was to develop a limited sampling strategy to estimate an abbreviated MPA AUC within the first month after renal transplantation. In this study we selected 19 patients in the early posttransplant period with normal renal graft function (glomerular filtration rate > 70 mL/min). Plasma MPA concentrations were measured using reverse-phase high-performance liquid chromatography. MPA AUC(0-12h) was calculated using the linear trapezoidal rule. Multiple stepwise regression analysis was used to determine the minimal and convenient time points of MPA levels that could be used to derive model equations best fitted to MPA AUC(0-12h). The regression equation for AUC estimation that gave the best performance was AUC = 14.46 C(10) + 15.547 (r(2) = .882). The validation of the method was performed using the jackknife method. Mean prediction error of this model was not different from zero (P > .05) and had a high root mean square prediction error (8.06). In conclusion, this limited sampling strategy provided an effective approach for therapeutic drug monitoring during the early posttransplant period. PMID:19100462

  1. Successful tocilizumab treatment in a child with refractory Takayasu arteritis.

    PubMed

    Bravo Mancheño, Beatriz; Perin, Francesca; Guez Vázquez Del Rey, María Del Mar Rodrí; García Sánchez, Antonio; Alcázar Romero, Pedro Pablo

    2012-12-01

    Takayasu arteritis (TA) in the child remains a therapeutic challenge because corticosteroids and conventional immunosuppressive agents are not always safe or efficacious. The complex formed by interleukin-6 (IL-6) and soluble IL-6 receptor appears to play a pivotal role in the pathogenesis of TA. We describe a favorable response to the anti-IL-6 receptor antibody tocilizumab (TCZ) in a child with aggressive and refractory TA including an assessment of the proinflammatory cytokine profile. A 3-year-old girl with TA consisting of thickening of the aortic arch wall, severe obstruction of the supra-aortic branches, and complete occlusion of both common carotid arteries failed to respond to corticosteroids, methotrexate, tumor necrosis factor α blockade, cyclophosphamide, and mycophenolate mofetil, and 3 years later, the disease remained active with severe manifestations (brain ischemia). The patient underwent percutaneous angioplasty, although significant restenosis was soon documented. After a severe relapse, the patient started TCZ infusions (8 mg/kg for 2 weeks), and a rapid clinical remission was observed, associated with a drastic reduction of inflammatory markers and IL-6 levels. Corticosteroids were withdrawn, the patient's weight and height improved, and bone mineral density values returned to normal. Two years later, TCZ infusions were extended, with no significant side effects. Cerebral ischemia resolved, and recanalization of the previously occluded supra-aortic branches was performed. PMID:23147976

  2. High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients

    PubMed Central

    Jaklič, Alenka; Collins, Carol J.; Mrhar, Aleš; Sorror, Mohamed L.; Sandmaier, Brenda M.; Bemer, Meagan J.; Locatelli, Igor; McCune, Jeannine S.

    2013-01-01

    Objective: Mycophenolic acid (MPA) exposure is associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients. Various drug interaction studies, predominantly in healthy volunteers or solid organ transplant recipients, have identified medications which impact MPA pharmacokinetics. Recipients of nonmyeloablative HCT, however, have an increased burden of comorbidities, potentially increasing the number of concomitant medications and potential drug interactions (PDI) affecting MPA exposure. Thus, we sought to be the first to characterize these PDI in nonmyeloablative HCT recipients. Materials and methods: We compiled PDI affecting MPA pharmacokinetics and characterized the prevalence of PDI in nonmyeloablative HCT recipients. A comprehensive literature evaluation of four databases and PubMed was conducted to identify medications with PDI affecting MPA pharmacokinetics. Subsequently, a retrospective medication review was conducted to characterize the cumulative PDI burden, defined as the number of PDI for an individual patient over the first 21 days after allogeneic graft infusion, in 84 nonmyeloablative HCT recipients. Results: Of the 187 concomitant medications, 11 (5.9%) had a PDI affecting MPA pharmacokinetics. 87% of 84 patients had one PDI, with a median cumulative PDI burden of 2 (range 0 – 4). The most common PDI, in descending order, were cyclosporine, omeprazole and pantoprazole. Conclusion: Only a minority of medications (5.9%) have a PDI affecting MPA pharmacokinetics. However, the majority of nonmyeloablative HCT recipients had a PDI, with cyclosporine and the proton pump inhibitors being the most common. A better understanding of PDI and their management should lead to safer medication regimens for nonmyeloablative HCT recipients. PMID:23782584

  3. Successful treatment of renal allograft and bladder malakoplakia with minimization of immunosuppression and prolonged antibiotic therapy.

    PubMed

    Graves, Angela L; Texler, Michael; Manning, Laurens; Kulkarni, Hemant

    2014-04-01

    Malakoplakia is an unusual granulomatous inflammatory disorder associated with diminished bactericidal action of leucocytes that occurs in immunosuppressed hosts. Cases of renal allograft malakoplakia are generally associated with a poor graft and patient survival. We present the case of a 56-year-old female with allograft and bladder malakoplakia occurring two years after renal transplantation complicated by an early antibody mediated rejection. Following a number of symptomatic urinary tract infections caused by resistant Gram-negative bacilli, a diagnosis of malakoplakia was made by biopsy of a new mass lesion of the renal allograft. Cystoscopy also revealed malakoplakia of the bladder wall. Immunosuppressant regimen was modified. Mycophenolate mofetil was ceased, prednisolone reduced to 5 mg/day and tacrolimus concentrations were carefully monitored to maintain trough serum concentrations of 2-4 μg/L. Concurrently, she received a prolonged course of intravenous antibiotics followed by 13 months of dual oral antibiotic therapy with fosfomycin and faropenem. This joint approach resulted in almost complete resolution of allograft malakoplakia lesions and sustained regression of bladder lesions on cystoscopy with histological resolution in bladder lesions. Her renal function has remained stable throughout the illness. If treated with sustained antimicrobial therapy and reduction of immunosuppression, cases of allograft malakoplakia may not necessarily be associated with poor graft survival. PMID:24460630

  4. Update on the management of chronic eczema: new approaches and emerging treatment options

    PubMed Central

    Walling, Hobart W; Swick, Brian L

    2010-01-01

    Atopic dermatitis (AD) is a common disease with worldwide prevalence, affecting up to 20% of children and 3% of adults. Recent evidence regarding pathogenesis has implicated epidermal barrier defects deriving from filagrin mutations with resulting secondary inflammation. In this report, the authors comprehensively review the literature on atopic dermatitis therapy, including topical and systemic options. Most cases of AD will benefit from emollients to enhance the barrier function of skin. Topical corticosteroids are first-line therapy for most cases of AD. Topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream) are considered second line therapy. Several novel barrier-enhancing prescription creams are also available. Moderate to severe cases inadequately controlled with topical therapy may require phototherapy or systemic therapy. The most commonly employed phototherapy modalites are narrow-band UVB, broadband UVB, and UVA1. Traditional systemic therapies include short-term corticosteroids, cyclosporine (considered to be the gold standard), methotrexate, azathioprine, mycophenolate mofetil, and most recently leflunamide. Biologic therapies include recombinant monoclonal antibodies acting on the immunoglobulin E / interleukin-5 pathway (omalizumab, mepolizumab), acting as tumor necrosis factor-α inhibitors (infliximab, etanercept, adalimumab), and acting as T-cell (alefacept) and B-cell (rituxumab) inhibitors, as well as interferon γ and intravenous immunoglobulin. Efficacy, safety, and tolerability are reviewed for each medication. PMID:21437065

  5. Mycophenolic Derivatives from Eupenicilliumparvum

    PubMed Central

    2008-01-01

    A new compound, euparvic acid (1, C14H16O6), and the known compounds 5,7-dihydroxy-4-methylphthalide (2), 6-(3-carboxybutyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (3), 6-(5-carboxy-3-methylpent-2-enyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (4), and 6-(5-carboxy-4-hydroxy-3-methylpent-2-enyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (5) were isolated from the EtOAc extract of Eupenicillium parvum. The structure of 1 was determined by interpretation of MS and homo- and heteronuclear 2D NMR spectroscopic data and confirmed by X-ray crystallography. The absolute configuration of 5 was determined via MPA ester derivatization. PMID:18991460

  6. Population pharmacokinetic–pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period

    PubMed Central

    Dong, Min; Fukuda, Tsuyoshi; Cox, Shareen; de Vries, Marij T; Hooper, David K; Goebel, Jens; Vinks, Alexander A

    2014-01-01

    Aim The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK−PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period. Methods A total of 214 MPA plasma concentrations−time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n = 97) in peripheral blood mononuclear cells were available for PK−PD modelling. The PK−PD model was developed using non-linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK−PD model using post hoc Bayesian PK parameter estimates. Covariate analysis included patient demographics, co-medication and clinical laboratory data. Non-parametric bootstrapping and prediction-corrected visual predictive checks were performed to evaluate the final models. Results A two compartment model with a transit compartment absorption best described MPA PK. A non-linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) l h−1 70 kg−1; Vc/F, 45.4 (29.6, 55.6) l; Vp/F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) l h−1; Ka, 2.5 (1.45, 4.93) h−1. Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory Emax model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK−PD parameter estimates (and their 95% confidence intervals) were: E0, 3.45 (2.61, 4.56) nmol h−1 mg−1 protein and EC50, 1.73 (1.16, 3.01) mg l−1. Emax was fixed to 0. There were two African-American patients in our study cohorts and both had low IMPDH baseline activities (E0) compared

  7. Quantification of free mycophenolic acid and its glucuronide metabolite in human plasma by liquid-chromatography using mass spectrometric and ultraviolet absorbance detection.

    PubMed

    Atcheson, Bronwyn; Taylor, Paul J; Mudge, David W; Johnson, David W; Pillans, Peter I; Tett, Susan E

    2004-01-01

    The immunosuppressant drug mycophenolic acid (MPA) and its major metabolite, mycophenolic acid glucuronide (MPAG), are highly bound to albumin. An HPLC-tandem-MS (HPLC/MS/MS) and an HPLC-UV assay were developed to measure free (unbound) concentrations of MPA and MPAG, respectively. Ultrafiltrate was prepared from plasma (500 microl) by ultrafiltration at 3000 x g for 20 min (20 degrees C). Both MPA and MPAG were isolated from ultrafiltrate (100 microl) by acidification and C18 solid-phase extraction. Free MPA was measured by electrospray tandem mass spectrometry using selected reactant monitoring (MPA: m/z 338.2--> 206.9) in positive ionisation mode. Chromatography was performed on a PFPP column (50 mm x 2 mm, 5 microm). Total analysis time was 7 min. The assay was linear over the range 1-200 microg/l with a limit of quantification of 1 microg/l. The inter-day accuracy and imprecision of quality controls (7.5, 40, 150 microg/l) were 94-99% and < 7%, respectively. Free MPAG was chromatographed on a C18 Nova-Pak column (150 mm x 3.9 mm, 5 microm) using a binary gradient over 20 min. The eluent was monitored at 254 nm. The assay was linear over the range 1-50 mg/l with the limit of quantification at 2.5 mg/l. The inter-day accuracy and imprecision of quality controls (5, 20, 45 mg/l) was 101-107% and < 8% (n = 4), respectively. For both methods no interfering substances were found in ultrafiltrate from patients not receiving MPA. The methods described have a suitable dynamic linear range to facilitate the investigation of free MPA and MPAG pharmacokinetics in transplant patients. Further, this is the first reported HPLC-UV method to determine free MPAG concentrations. PMID:14659448

  8. Do we still need renal biopsy in lupus nephritis?

    PubMed Central

    Cervera, Ricard

    2016-01-01

    The natural course of systemic lupus erythematosus (SLE) is characterized by periods of disease activity and remissions. Prolonged disease activity results in cumulative organ damage. Lupus nephritis is one of the most common and devastating manifestations of SLE. In the era of changing therapy to less toxic regimens, some authors have stated that if mycophenolate mofetil can be used for the induction and maintenance treatment in all histological classes of lupus nephritis, renal biopsy can be omitted. This article aims to answer the question of what brings the bigger risk: renal biopsy or its abandonment. PMID:27407281

  9. Superior Orbital Fissure Syndrome and Ophthalmoplegia Caused by Varicella Zoster Virus with No Skin Eruption in a Patient Treated with Tumor Necrosis Alpha Inhibitor

    PubMed Central

    Jensen, Helene; Thomsen, Sidsel Thorup; Hansen, Stine Scott; Munksgaard, Signe Bruun; Lindelof, Mette

    2015-01-01

    Varicella zoster virus lies dormant in the dorsal root ganglia after symptomatic chicken pox infection, usually in childhood. If the virus reactivates in the trigeminal ganglia, it can cause varicella zoster ophthalmicus, which can have severe ocular complications. We report a case of a 73-year-old woman in severe immunosuppression due to treatment with mycophenolate mofetil, glucocorticosteroids and a tumor necrosis factor alpha inhibitor. The reactivation caused superior orbital fissure syndrome, which has only rarely been described in relation to varicella zoster virus reactivation. In our case, the syndrome was seen along with severe encephalitis. PMID:26600786

  10. Type 4 renal tubular acidosis in a kidney transplant recipient.

    PubMed

    Kulkarni, Manjunath

    2016-02-01

    We report a case of a 66-year-old diabetic patient who presented with muscle weakness 2 weeks after kidney transplantation. Her immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and steroids. She was found to have hyperkalemia and normal anion gap metabolic acidosis. Tacrolimus levels were in therapeutic range. All other drugs such as beta blockers and trimethoprim - sulfamethoxazole were stopped. She did not respond to routine antikalemic measures. Further evaluation revealed type 4 renal tubular acidosis. Serum potassium levels returned to normal after starting sodium bicarbonate and fludrocortisone therapy. Though hyperkalemia is common in kidney transplant recipients, determining exact cause can guide specific treatment. PMID:27105603

  11. Superior Orbital Fissure Syndrome and Ophthalmoplegia Caused by Varicella Zoster Virus with No Skin Eruption in a Patient Treated with Tumor Necrosis Alpha Inhibitor.

    PubMed

    Jensen, Helene; Thomsen, Sidsel Thorup; Hansen, Stine Scott; Munksgaard, Signe Bruun; Lindelof, Mette

    2015-01-01

    Varicella zoster virus lies dormant in the dorsal root ganglia after symptomatic chicken pox infection, usually in childhood. If the virus reactivates in the trigeminal ganglia, it can cause varicella zoster ophthalmicus, which can have severe ocular complications. We report a case of a 73-year-old woman in severe immunosuppression due to treatment with mycophenolate mofetil, glucocorticosteroids and a tumor necrosis factor alpha inhibitor. The reactivation caused superior orbital fissure syndrome, which has only rarely been described in relation to varicella zoster virus reactivation. In our case, the syndrome was seen along with severe encephalitis. PMID:26600786

  12. Cutaneous Necrotic Papule as Invasive Aspergillosis in a Heart Transplant Patient.

    PubMed

    Kaminska, Edidiong C N; Pei, Susan; Kenkare, Sonya; Petronic-Rosic, Vesna; Tsoukas, Maria M

    2015-01-01

    A 46-year-old African American man presented with a 3- to 4-day history of a new painful lesion on his left lower extremity. Other reported symptoms included a productive cough and chest pain; the patient denied fever and chills. His medical history was significant for a heart transplant 4 months prior to presentation followed by transplant rejection 2 weeks after the transplant. Medications included an antirejection/immunosuppressive regimen consisting of prednisone, tacrolimus, mycophenolate mofetil, and prophylaxis treatment with valganciclovir and trimethoprim-sulfamethoxazole. PMID:26861437

  13. A comprehensive review of the published assays for the quantitation of the immunosuppressant drug mycophenolic acid and its glucuronidated metabolites in biological fluids.

    PubMed

    Syed, Muzeeb; Srinivas, Nuggehally R

    2016-05-01

    Therapeutic use of mycophenolic acid (MPA) is steadily on the rise in combination with other immunosuppressant drugs in transplantation patients. The biotransformation of MPA resulted in the formation of glucuronide metabolites, MPAG and AcMPAG. There are a plethora of assays validated for the analysis of MPA alone or with MPAG/AcMPAG in various biological specimens including plasma/serum, urine, ultrafiltrate, saliva, PBMC, dried blood spots, tissue extract, tumor biopsies and vitreous humor. Based on the need for experimental work, a proper choice of the assay and internal standard may be made using the choices in the literature. While the chemical methods involving high-performance liquid chromatography (HPLC) or LC coupled with triple quadrupole mass spectrometry (LC-MS/MS) are popular, enzymatic assays, in spite of their higher bias, have been used for the routine drug monitoring of MPA. The objectives of the present review are: (a) to provide a focused systematic compilation of the HPLC or LC-MS/MS methods for MPA, MPAG and/or AcMPAG published in the last decade (2005 to current) to enable visual comparison of the methods; (b) to compare and contrast a few enzymatic assays with those of the chemical methods; and (c) to discuss relevant issues/limitations and perspectives on select assays under various subheadings. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26766308

  14. Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus.

    PubMed

    Patel, Chirag G; Ogasawara, Ken; Akhlaghi, Fatemeh

    2013-03-01

    1. The purpose of this study was to investigate the contribution of MRP2 to the efflux of mycophenolic acid (MPA), and its phenyl glucuronide (MPAG) and acyl glucuronide (AcMPAG) metabolites, using Madin-Darby canine kidney II cells stably transfected with human MRP2 gene (MDCKII/MRP2 cells). 2. Compared to parental MDCKII cells, MPAG was significantly translocated from basolateral (BL) to apical (AP) side in MDCKII/MRP2 cells, indicating MPAG is a substrate for MRP2. AcMPAG is highly translocated from BL to AP side in both cells, suggesting that AcMPAG is actively secreted possibly through an efflux transporter other than MRP2. Appreciable translocation of MPA was not observed in MDCKII/MRP2 cells. 3. Furthermore, using MRP2-expressing Sf9 membrane vesicles, the Michaelis-Menten constant (Km) value for MRP2-mediated MPAG transport was calculated at 224.2 ± 42.7 µM. In the vesicle system, cyclosporine, tacrolimus and sirolimus did not inhibit the uptake of MPAG via MRP2. 4. These findings indicate that only MPAG not MPA and AcMPAG is a substrate for MRP2 and that the interaction between MPAG and concomitantly administered immunosuppressive agents does not occur at MRP2 level. PMID:22934787

  15. Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans.

    PubMed

    To, Kelvin K W; Mok, Ka-Yi; Chan, Andy S F; Cheung, Nam N; Wang, Pui; Lui, Yin-Ming; Chan, Jasper F W; Chen, Honglin; Chan, Kwok-Hung; Kao, Richard Y T; Yuen, Kwok-Yung

    2016-08-01

    Immunomodulators have been shown to improve the outcome of severe pneumonia. We have previously shown that mycophenolic acid (MPA), an immunomodulator, has antiviral activity against influenza A/WSN/1933(H1N1) using a high-throughput chemical screening assay. This study further investigated the antiviral activity and mechanism of action of MPA against contemporary clinical isolates of influenza A and B viruses. The 50 % cellular cytotoxicity (CC50) of MPA in Madin Darby canine kidney cell line was over 50 µM. MPA prevented influenza virus-induced cell death in the cell-protection assay, with significantly lower IC50 for influenza B virus B/411 than that of influenza A(H1N1)pdm09 virus H1/415 (0.208 vs 1.510 µM, P=0.0001). For H1/415, MPA interfered with the early stage of viral replication before protein synthesis. For B/411, MPA may also act at a later stage since MPA was active against B/411 even when added 12 h post-infection. Virus-yield reduction assay showed that the replication of B/411 was completely inhibited by MPA at concentrations ≥0.78 µM, while there was a dose-dependent reduction of viral titer for H1/415. The antiviral effect of MPA was completely reverted by guanosine supplementation. Plaque reduction assay showed that MPA had antiviral activity against eight different clinical isolates of A(H1N1), A(H3N2), A(H7N9) and influenza B viruses (IC50 <1 µM). In summary, MPA has broad-spectrum antiviral activity against human and avian-origin influenza viruses, in addition to its immunomodulatory activity. Together with a high chemotherapeutic index, the use of MPA as an antiviral agent should be further investigated in vivo. PMID:27259985

  16. Diabetes Mellitus Reduces Activity of Human UDP-Glucuronosyltransferase 2B7 in Liver and Kidney Leading to Decreased Formation of Mycophenolic Acid Acyl-Glucuronide Metabolite

    PubMed Central

    Dostalek, Miroslav; Court, Michael H.; Hazarika, Suwagmani

    2011-01-01

    Mycophenolic acid (MPA) is an immunosuppressive agent commonly used after organ transplantation. Altered concentrations of MPA metabolites have been reported in diabetic kidney transplant recipients, although the reason for this difference is unknown. We aimed to compare MPA biotransformation and UDP-glucuronosyltransferase (UGT) expression and activity between liver (n = 16) and kidney (n = 8) from diabetic and nondiabetic donors. Glucuronidation of MPA, as well as the expression and probe substrate activity of UGTs primarily responsible for MPA phenol glucuronide (MPAG) formation (UGT1A1 and UGT1A9), and MPA acyl glucuronide (AcMPAG) formation (UGT2B7), was characterized. We have found that both diabetic and nondiabetic human liver microsomes and kidney microsomes formed MPAG with similar efficiency; however, AcMPAG formation was significantly lower in diabetic samples. This finding is supported by markedly lower glucuronidation of the UGT2B7 probe zidovudine, UGT2B7 protein, and UGT2B7 mRNA in diabetic tissues. UGT genetic polymorphism did not explain this difference because UGT2B7*2 or *1c genotype were not associated with altered microsomal UGT2B7 protein levels or AcMPAG formation. Furthermore, mRNA expression and probe activities for UGT1A1 or UGT1A9, both forming MPAG but not AcMPAG, were comparable between diabetic and nondiabetic tissues, suggesting the effect may be specific to UGT2B7-mediated AcMPAG formation. These findings suggest that diabetes mellitus is associated with significantly reduced UGT2B7 mRNA expression, protein level, and enzymatic activity of human liver and kidney, explaining in part the relatively low circulating concentrations of AcMPAG in diabetic patients. PMID:21123165

  17. Mycophenolate antagonizes IFN-γ-induced catagen-like changes via β-catenin activation in human dermal papilla cells and hair follicles.

    PubMed

    Ryu, Sunhyo; Lee, Yonghee; Hyun, Moo Yeol; Choi, Sun Young; Jeong, Kwan Ho; Park, Young Min; Kang, Hoon; Park, Kui Young; Armstrong, Cheryl A; Johnson, Andrew; Song, Peter I; Kim, Beom Joon

    2014-01-01

    Recently, various immunosuppressant drugs have been shown to induce hair growth in normal hair as well as in alopecia areata and androgenic alopecia; however, the responsible mechanism has not yet been fully elucidated. In this study, we investigate the influence of mycophenolate (MPA), an immunosuppressant, on the proliferation of human dermal papilla cells (hDPCs) and on the growth of human hair follicles following catagen induction with interferon (IFN)-γ. IFN-γ was found to reduce β-catenin, an activator of hair follicle growth, and activate glycogen synthase kinase (GSK)-3β, and enhance expression of the Wnt inhibitor DKK-1 and catagen inducer transforming growth factor (TGF)-β2. IFN-γ inhibited expression of ALP and other dermal papillar cells (DPCs) markers such as Axin2, IGF-1, and FGF 7 and 10. MPA increased β-catenin in IFN-γ-treated hDPCs leading to its nuclear accumulation via inhibition of GSK3β and reduction of DKK-1. Furthermore, MPA significantly increased expression of ALP and other DPC marker genes but inhibited expression of TGF-β2. Therefore, we demonstrate for the first time that IFN-γ induces catagen-like changes in hDPCs and in hair follicles via inhibition of Wnt/β-catenin signaling, and that MPA stabilizes β-catenin by inhibiting GSK3β leading to increased β-catenin target gene and DP signature gene expression, which may, in part, counteract IFN-γ-induced catagen in hDPCs. PMID:25247578

  18. Mycophenolate Antagonizes IFN-γ-Induced Catagen-Like Changes via β-Catenin Activation in Human Dermal Papilla Cells and Hair Follicles

    PubMed Central

    Ryu, Sunhyo; Lee, Yonghee; Hyun, Moo Yeol; Choi, Sun Young; Jeong, Kwan Ho; Park, Young Min; Kang, Hoon; Park, Kui Young; Armstrong, Cheryl A.; Johnson, Andrew; Song, Peter I.; Kim, Beom Joon

    2014-01-01

    Recently, various immunosuppressant drugs have been shown to induce hair growth in normal hair as well as in alopecia areata and androgenic alopecia; however, the responsible mechanism has not yet been fully elucidated. In this study, we investigate the influence of mycophenolate (MPA), an immunosuppressant, on the proliferation of human dermal papilla cells (hDPCs) and on the growth of human hair follicles following catagen induction with interferon (IFN)-γ. IFN-γ was found to reduce β-catenin, an activator of hair follicle growth, and activate glycogen synthase kinase (GSK)-3β, and enhance expression of the Wnt inhibitor DKK-1 and catagen inducer transforming growth factor (TGF)-β2. IFN-γ inhibited expression of ALP and other dermal papillar cells (DPCs) markers such as Axin2, IGF-1, and FGF 7 and 10. MPA increased β-catenin in IFN-γ-treated hDPCs leading to its nuclear accumulation via inhibition of GSK3β and reduction of DKK-1. Furthermore, MPA significantly increased expression of ALP and other DPC marker genes but inhibited expression of TGF-β2. Therefore, we demonstrate for the first time that IFN-γ induces catagen-like changes in hDPCs and in hair follicles via inhibition of Wnt/β-catenin signaling, and that MPA stabilizes β-catenin by inhibiting GSK3β leading to increased β-catenin target gene and DP signature gene expression, which may, in part, counteract IFN-γ-induced catagen in hDPCs. PMID:25247578

  19. Treatment

    MedlinePlus

    ... Prevention Treatment 2003 U.S. Outbreak African Rodent Importation Ban For Clinicians Clinical Recognition Specimen Collection Treatment Smallpox ... Examining Animals with Suspected Monkeypox African Rodent Importation Ban Resources Related Links Poxvirus Molluscum Contagiosum Orf Virus ( ...

  20. Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPAR{gamma}-LXR{alpha}-ABCA1 pathway

    SciTech Connect

    Xu, Yanni; Lai, Fangfang; Xu, Yang; Wu, Yexiang; Liu, Qi; Li, Ni; Wei, Yuzhen; Feng, Tingting; Zheng, Zhihui; Jiang, Wei; Yu, Liyan; Hong, Bin; Si, Shuyi

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Using an ABCA1p-LUC HepG2 cell line, we found that MPA upregulated ABCA1 expression. Black-Right-Pointing-Pointer MPA induced ABCA1 and LXR{alpha} protein expression in HepG2 cells. Black-Right-Pointing-Pointer PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. Black-Right-Pointing-Pointer The effect of MPA upregulating ABCA1 was due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 pathway. -- Abstract: ATP-binding cassette transporter A1 (ABCA1) promotes cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I and plays an important role in atherosclerosis. In a previous study, we developed a high-throughput screening method using an ABCA1p-LUC HepG2 cell line to find upregulators of ABCA1. Using this method in the present study, we found that mycophenolic acid (MPA) upregulated ABCA1 expression (EC50 = 0.09 {mu}M). MPA upregulation of ABCA1 expression was confirmed by real-time quantitative reverse transcription-PCR and Western blot analysis in HepG2 cells. Previous work has indicated that MPA is a potent agonist of peroxisome proliferator-activated receptor gamma (PPAR{gamma}; EC50 = 5.2-9.3 {mu}M). Liver X receptor {alpha} (LXR{alpha}) is a target gene of PPAR{gamma} and may directly regulate ABCA1 expression. Western blot analysis showed that MPA induced LXR{alpha} protein expression in HepG2 cells. Addition of PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. These data suggest that MPA increased ABCA1 expression mainly through activation of PPAR{gamma}. Thus, the effects of MPA on upregulation of ABCA1 expression were due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 signaling pathway. This is the first report that the antiatherosclerosis activity of MPA is due to this mechanism.

  1. Multifocal Epstein-Barr Virus-Negative Posttransplantation Lymphoproliferative Disorder Treated With Reduction of Immunosuppression.

    PubMed

    Miyazono, Akinori; Okamoto, Yasuhiro; Nagasako, Hironobu; Hamasaki, Yuko; Shishido, Seiichiro; Yoshioka, Takako; Kawano, Yoshifumi

    2016-09-01

    Posttransplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. PTLD cases associated with poor prognostic factors that are refractory to reduction of immunosuppression generally require chemotherapy and immunotherapy. We present a patient with PTLD who achieved complete remission after reduction of immunosuppression alone despite having a poor prognosis. A boy with a mutation in the WT1 gene developed bilateral Wilms tumor at 15 months and received a kidney transplant at the age of 4 years. At 13 years of age, the patient's condition was managed with methylprednisolone, tacrolimus, and mycophenolate mofetil. He developed Epstein-Barr virus-negative monomorphic PTLD with numerous nodular lesions in the liver, vertebral bodies, and gastric wall. To reduce immunosuppression, we discontinued mycophenolate mofetil treatment, decreased tacrolimus dosage to 1mg/d, and increased methylprednisolone dosage to 2mg/d. The PTLD lesions drastically diminished in size within several days and disappeared 144 days after reduction of immunosuppression, although the patient had several factors indicating a poor prognosis. As of 13 months after reduction of immunosuppression for PTLD, the transplanted kidney was still functional. We conclude that even when patients with PTLD have a poor prognosis, reduction of immunosuppression alone may result in complete remission when the early response is excellent. PMID:27178679

  2. Effect of Immunosuppressive Therapy on Proteinogram in Rats

    PubMed Central

    Kędzierska, Karolina; Sindrewicz, Krzysztof; Sporniak-Tutak, Katarzyna; Bober, Joanna; Stańczyk-Dunaj, Małgorzata; Dołęgowska, Barbara; Kaliszczak, Robert; Sieńko, Jerzy; Kabat-Koperska, Joanna; Gołembiewska, Edyta; Ciechanowski, Kazimierz

    2016-01-01

    Background It has been observed that the use of immunosuppressive drugs in patients after transplantation of vascularized organs may be associated with changes in the concentration of certain fractions of plasma proteins. The concentration of these proteins was correlated with an increased risk of occurrence of stage 3 chronic kidney disease (CKD). This article examines the effect of the most commonly used immunosuppressive drugs on the concentration of plasma proteins in Wistar rats. Material/methods The study involved 36 rats grouped according to the immunosuppressive regimen used (tacrolimus, mycophenolate mofetil, cyclosporine A, rapamycin, and prednisone). The rats in all study groups were treated with a 3-drug protocol for 6 months. The treatment dose was adjusted based on available data in the literature. No drugs were administered to the control group. The rats were sacrificed and blood samples collected to determine the concentration of plasma proteins using electrophoresis technique. Results Statistically significant differences were observed between protein concentrations within the studied groups. The differences related to the proteins with masses of 195 kDa, 170 kDa, 103 kDa, and 58 kDa. Conclusions (1) Immunosuppressive drugs caused changes in the proteinogram of plasma proteins. (2) The strongest effect on rat plasma proteins was exerted by a regimen based on rapamycin. Intermediate, weak, and weakest effects were observed in regimens based on cyclosporine A, tacrolimus, and mycophenolate mofetil, respectively. PMID:27288069

  3. Effect of Immunosuppressive Therapy on Proteinogram in Rats.

    PubMed

    Kędzierska, Karolina; Sindrewicz, Krzysztof; Sporniak-Tutak, Katarzyna; Bober, Joanna; Stańczyk-Dunaj, Małgorzata; Dołęgowska, Barbara; Kaliszczak, Robert; Sieńko, Jerzy; Kabat-Koperska, Joanna; Gołembiewska, Edyta; Ciechanowski, Kazimierz

    2016-01-01

    BACKGROUND It has been observed that the use of immunosuppressive drugs in patients after transplantation of vascularized organs may be associated with changes in the concentration of certain fractions of plasma proteins. The concentration of these proteins was correlated with an increased risk of occurrence of stage 3 chronic kidney disease (CKD). This article examines the effect of the most commonly used immunosuppressive drugs on the concentration of plasma proteins in Wistar rats. MATERIAL AND METHODS The study involved 36 rats grouped according to the immunosuppressive regimen used (tacrolimus, mycophenolate mofetil, cyclosporine A, rapamycin, and prednisone). The rats in all study groups were treated with a 3-drug protocol for 6 months. The treatment dose was adjusted based on available data in the literature. No drugs were administered to the control group. The rats were sacrificed and blood samples collected to determine the concentration of plasma proteins using electrophoresis technique. RESULTS Statistically significant differences were observed between protein concentrations within the studied groups. The differences related to the proteins with masses of 195 kDa, 170 kDa, 103 kDa, and 58 kDa. CONCLUSIONS (1) Immunosuppressive drugs caused changes in the proteinogram of plasma proteins. (2) The strongest effect on rat plasma proteins was exerted by a regimen based on rapamycin. Intermediate, weak, and weakest effects were observed in regimens based on cyclosporine A, tacrolimus, and mycophenolate mofetil, respectively. PMID:27288069

  4. Successful treatment with foscarnet for ganciclovir-resistant cytomegalovirus infection in a kidney transplant recipient: A case report.

    PubMed

    Iwami, Daiki; Ogawa, Yayoi; Fujita, Hiromi; Morita, Ken; Sasaki, Hajime; Oishi, Yuichiro; Higuchi, Haruka; Hatanaka, Kanako; Shinohara, Nobuo

    2016-07-01

    Cytomegalovirus (CMV) infection is the most common infectious complication following solid organ transplantation. Ganciclovir (GCV)-resistant CMV infection may be fatal, and is difficult to treat while avoiding allograft rejection. A 31-year-old woman received a second ABO-incompatible kidney transplant, from her father. Induction therapy consisted of basiliximab and rituximab followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Her CMV serostatus was D(+) /R(-) at second transplant and she received prophylactic low-dose valganciclovir (VGCV). BK polyoma virus nephropathy (BKVN) developed 7 months after transplant concurrent with CMV hepatitis and retinitis. VGCV was increased to a therapeutic dose combined with reduced immunosuppression with minimal methylprednisolone (2 mg/day) and everolimus (0.5 mg/day). However, pp65 antigenaemia continued to increase for 6 weeks. Her CMV was defined as ganciclovir (GCV)-resistant. Foscarnet was therefore administered and her CMV disease resolved within 2 weeks. Kidney allograft dysfunction developed 9 months after transplant, and graft biopsy showed tubulointerstitial injury with crystal deposition suggesting foscarnet nephrotoxicity, with no findings of BKVN or rejection. Kidney function recovered after cessation of foscarnet and the patient had good graft function 18 months after transplant. This case demonstrates the successful use of foscarnet to treat GCV-resistant CMV infection after ABO-incompatible kidney transplant complicated with BKVN, without acute allograft rejection. This case further highlights the need to establish appropriate management for CMV D(+) /R(-) patients to avoid the acquisition of GCV-resistant gene mutations. PMID:26970406

  5. The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease.

    PubMed

    Sherwin, Catherine M T; Fukuda, Tsuyoshi; Brunner, Hermine I; Goebel, Jens; Vinks, Alexander A

    2011-01-01

    With the increasing use of mycophenolic acid (MPA) as an immunosuppressant in solid organ transplantation and in treating autoimmune diseases such as systemic lupus erythematosus, the need for strategies to optimize therapy with this agent has become increasingly apparent. This need is largely based on MPA's significant between-subject and between-occasion (within-subject) pharmacokinetic variability. While there is a strong relationship between MPA exposure and effect, the relationship between drug dose, plasma concentration and exposure (area under the concentration-time curve [AUC]) is very complex and remains to be completely defined. Population pharmacokinetic models using various approaches have been proposed over the past 10 years to further evaluate the pharmacokinetic and pharmacodynamic behaviour of MPA. These models have evolved from simple one-compartment linear iterations to complex multi-compartment versions that try to include various factors, which may influence MPA's pharmacokinetic variability, such as enterohepatic recycling and pharmacogenetic polymorphisms. There have been major advances in the understanding of the roles transport mechanisms, metabolizing and other enzymes, drug-drug interactions and pharmacogenetic polymorphisms play in MPA's pharmacokinetic variability. Given these advances, the usefulness of empirical-based models and the limitations of nonlinear mixed-effects modelling in developing mechanism-based models need to be considered and discussed. If the goal is to individualize MPA dosing, it needs to be determined whether factors which may contribute significantly to variability can be utilized in the population pharmacokinetic models. Some pharmacokinetic models developed to date show promise in being able to describe the impact of physiological processes such as enterohepatic recycling. Most studies have historically been based on retrospective data or poorly designed studies which do not take these factors into consideration

  6. Management of pemphigus vulgaris: challenges and solutions

    PubMed Central

    Gregoriou, Stamatis; Efthymiou, Ourania; Stefanaki, Christina; Rigopoulos, Dimitris

    2015-01-01

    The main objective in the treatment of pemphigus vulgaris is to control the disease, prevent relapses, and avoid adverse events associated with the prolonged use of steroids and immunosuppressive agents. Systemic corticosteroids remain the gold standard treatment for pemphigus vulgaris. Azathioprine and mycophenolate mofetil are the first line of steroid-sparing treatment. Rituximab is extremely effective in recalcitrant pemphigus, when other treatments fail to control the disease. The European Dermatology Forum recommends tapering prednisolone by 25% every 2 weeks after the consolidation phase, and a 5 mg reduction every 4 weeks when the dose is reduced to <20 mg. If the patient relapses, options include increasing steroids back to the previous dose, adding an immunosuppressant if using steroid monotherapy, or replacing a first-line immunosuppressant by another if already on combination therapy. PMID:26543381

  7. Refractory postsurgical pyoderma gangrenosum in a patient with Beckwith Wiedemann syndrome: response to multimodal therapy

    PubMed Central

    Fakhar, Faiza; Memon, Sehrish; Deitz, Diane; Abramowitz, Richard; Alpert, Deborah R

    2013-01-01

    Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that may be difficult to diagnose and treat. We presented a 41-year-old woman who required skin grafting following third-degree burns to her left breast. She suffered recurrent graft dehiscence and infections over many years, prompting elective bilateral reduction mammoplasty. She subsequently developed suture margin ulcerations unresponsive to topical therapies and antibiotics. Skin biopsies were non-specific, and a clinical diagnosis of PG was established. Although initially responsive to corticosteroids, wounds promptly recurred following steroid taper. She was treated unsuccessfully with various immunomodulatory agents and underwent elective bilateral mastectomy. Following a mastectomy, she developed progressive deep chest wall ulcerations. She failed numerous immunomodulatory treatments, surgical wound closure and negative pressure wound therapy. Ultimately, treatment with adalimumab, mycophenolate mofetil and prednisone, in addition to hyperbaric oxygen therapy facilitated progressive healing. Our case highlights the role of collaborative multimodal therapy for the treatment of refractory PG. PMID:24154999

  8. Renal Function and Proteinuria after Successful Immunosuppressive Therapies in Patients with FSGS

    PubMed Central

    Friedman, Aaron; Greene, Tom; Radeva, Milena; Budisavljevic, Milos N.; Gassman, Jennifer; Gipson, Debbie S.; Jefferson, J. Ashley; John, Eunice G.; Kaskel, Frederick J.; Moudgil, Asha; Moxey-Mims, Marva; Ortiz, Luis A.; Schelling, Jeffrey R.; Schnaper, William; Srivastava, Tarak; Trachtman, Howard; Vehaskari, V. Matti; Wong, Craig; Woronieki, Robert P.; Van Why, Scott K.; Zolotnitskaya, Anna

    2013-01-01

    Summary Background and objectives In the FSGS Clinical Trial, 22 cyclosporine-treated and 20 mycophenolate/dexamethasone-treated patients experienced a complete or partial remission after 26 weeks, completed 52 weeks of treatment, and were studied through 78 weeks. Herein, changes in the urine protein/creatinine ratio (UP/C) and estimated GFR (eGFR) throughout the entire study period are defined. Design, setting, participants, and measurements The FSGS Clinical Trial, which was conducted from November 2004 to January 2010, enrolled patients aged 2–40 years, with eGFR ≥40 ml/min per 1.73 m2 and UP/C >1 mg/mg after ≥4 weeks of corticosteroid therapy. Both groups received lisinopril or losartan throughout the study. UP/C and eGFR were measured at 0, 26, 52, and 78 weeks. Results The median UP/C in the cyclosporine- and mycophenolate/dexamethasone-responsive patients fell by 89.8% and 82.7% at 52 weeks; the fall was largely sustained at 78 weeks (74.7% and 80.3%, respectively). The mean eGFR fell by 19.4% in the cyclosporine group and rose by 7.0% in the mycophenolate mofetil/dexamethasone group at 52 weeks, but subsequently rose by 16.4% and fell by 2.6%, respectively, in the two groups from 52 to 78 weeks. Conclusions In this subset of responding FSGS patients, the improvement in UP/C after cyclosporine or mycophenolate/dexamethasone treatment was largely sustained for 6 months after therapy. Reduction in eGFR in the cyclosporine group was improved 6 months after cyclosporine was stopped although the levels were lower than baseline in seven patients who entered the study with decreased eGFR. PMID:23143503

  9. Unusual cause of flare in antineutrophil cytoplasmic antibody-associated vasculitis.

    PubMed

    Glanville, James Robert William; Penn, Henry

    2016-01-01

    A 53-year-old woman attended for a routine outpatient appointment for follow-up of antineutrophil cytoplasmic antibody-positive vasculitis. Her disease had relapsed despite appropriate medical management with mycophenolate mofetil (MMF), as evidenced by rising acute phase response and antimyeloperoxidase titre with ongoing symptoms. On further questioning, she had been taking oral charcoal as part of a detoxification diet, which we postulate was causing significantly impaired MMF absorption. This case report summarises the presentation and highlights the importance of a thorough drug history, and should prompt the reader to keep an open mind with regard to drug interactions and treatment regimen adherence when treatment is, unexpectedly, seemingly failing. PMID:26746838

  10. Immunotherapy of systemic sclerosis

    PubMed Central

    Manno, Rebecca; Boin, Francesco

    2011-01-01

    Scleroderma is a multisystem autoimmune disease characterized by an abnormal immune activation associated with the development of underlying vascular and fibrotic disease manifestations. This article highlights the current use of drugs targeting the immune system in scleroderma. Nonselective immunosuppression, and in particular cyclophosphamide, remains the main treatment for progressing skin involvement and active interstitial lung disease. Mycophenolate mofetil is a promising alternative to cyclophosphamide. The use of cyclosporine has been limited by modest efficacy and serious renal toxicity. Newer T-cell (sirolimus and alefacept) and B-cell (rituximab)-targeted therapies have provided some encouraging results in small pilot studies. Hematopoietic stem cell transplantation can be effective for severe fibrotic skin disease, but toxicity remains a concern. Clinical efficacy and safety of antifibrotic treatments (e.g., imatinib) await confirmation. Newer biological agents targeting key molecular or cellular effectors in scleroderma pathogenesis are now available for clinical testing. PMID:21091117

  11. Methotrexate-Induced Nasal Septal Perforation.

    PubMed

    Kaminska, Edidiong Ntuen; Sansaricq, Freda; Petronic-Rosic, Vesna

    2016-01-01

    A 58-year-old woman with a 31-year history of Hailey-Hailey (HH) disease that was refractory to treatment with mycophenolate mofetil, cyclosporine, dapsone, sulfasalazine, topical/oral antibiotics, and topical/oral steroids presented for alternative treatment options. Active erythematous, malodorous, eroded, and crusted plaques were present in the axillae, inframammary region, groin, and back (Figure 1). The patient had an undulant course, with acute exacerbations and partial remissions. During a 3-year period, she was prescribed oral methotrexate at a dose of 10 mg to 15 mg per week with daily oral folic acid (1 mg) supplementation, except on the day she took methotrexate. Oral clarithromycin and prednisone were also used intermittently for antibacterial and anti-inflammatory effects. PMID:27319962

  12. Immunoglobulin Replacement Therapy in Secondary Hypogammaglobulinemia

    PubMed Central

    Compagno, Nicolò; Malipiero, Giacomo; Cinetto, Francesco; Agostini, Carlo

    2014-01-01

    Immunoglobulin (Ig) replacement therapy dramatically changed the clinical course of primary hypogammaglobulinemias, significantly reducing the incidence of infectious events. Over the last two decades its use has been extended to secondary antibody deficiencies, particularly those related to hematological disorders as lymphoproliferative diseases (LPDs) and multiple myeloma. In these malignancies, hypogammaglobulinemia can be an intrinsic aspect of the disease or follow chemo-immunotherapy regimens, including anti-CD20 treatment. Other than in LPDs the broadening use of immunotherapy (e.g., rituximab) and immune-suppressive therapy (steroids, sulfasalazine, and mycophenolate mofetil) has extended the occurrence of iatrogenic hypogammaglobulinemia. In particular, in both autoimmune diseases and solid organ transplantation Ig replacement therapy has been shown to reduce the rate of infectious events. Here, we review the existing literature about Ig replacement therapy in secondary hypogammaglobulinemia, with special regard for subcutaneous administration route, a safe, effective, and well-tolerated treatment approach, currently well established in primary immunodeficiencies and secondary hypogammaglobulinemias. PMID:25538710

  13. Sjögren Sensory Neuronopathy (Sjögren Ganglionopathy)

    PubMed Central

    Pereira, P. Ricardo; Viala, Karine; Maisonobe, Thierry; Haroche, Julien; Mathian, Alexis; Hié, Miguel; Amoura, Zahir; Cohen Aubart, Fleur

    2016-01-01

    Abstract Primary Sjögren syndrome (SS) is an autoimmune disease mainly affecting the exocrine glands causing a sicca syndrome. Neurological manifestations are rarely seen in SS although they are debilitating. Peripheral neuropathies namely sensory axonal neuropathy and painful small fiber neuropathy are the most frequent neurological manifestations. Sensory neuronopathy (SN) is less frequently seen although leading to more severe handicap. The aim of the study was to analyze the clinical presentation and treatment efficacy in a series of SS-related SN. We retrospectively studied patients with SS fulfilling the American–European Classification Criteria and SN according to recent criteria. Studied variables were neurological findings, associated autoimmune diseases, biological profiles, nerve conduction and sensory/motor amplitudes study, treatments received, and outcomes. Handicap scores were studied at beginning and end of each treatment using the modified Rankin Scale (mRS). Thirteen patients were included (12 women, 1 man; median age 55 years at SN diagnosis) presenting with SN with a median follow-up of 3 years (range 2–17). In 11 patients, SN preceded or coincided with SS diagnosis. Most common neurological findings were ataxia and areflexia followed by paresthesia and pain. Lower limbs were more affected than upper limbs, neurological deficits were often symmetric and cranial nerves were affected in 3 patients. Seven patients were treated with corticosteroids, 7 with mycophenolate mofetil, 6 with hydroxychloroquine, 5 with intravenous immunoglobulins, 4 with cyclophosphamide, and 2 patients received other immunosuppressive drugs. At the beginning and at the end of follow-up, average mRS was 2.15 (median 2) and 2.38 (median 2), respectively. SS-related SN progression is heterogeneous but tends to be chronic, insidious, and debilitating despite treatment. From these data concerning a small number of patients, treatment strategies with corticosteroids in

  14. The effect of different immunosuppressants on alloantigen dependent and independent factors involved in the development of chronic rejection in an animal model.

    PubMed Central

    Cole, O.; Rigg, K.; Shehata, M.

    2001-01-01

    The aim of this study was to compare the effects of cyclosporine, tacrolimus, mycophenolate mofetil and SDZ RAD on an animal model of transplant arteriosclerosis involving alloantigen dependent and independent mechanisms. Images Figure 1 Figure 1 (continued) Figure 2 Figure 2 (continued) PMID:11518369

  15. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.9.2. Haematological complications. Leukopenia.

    PubMed

    2002-01-01

    GUIDELINE: Because leukopenia is relatively common after kidney transplantation, regular screening and careful evaluation of its causes are recommended. Azathioprine and mycophenolate mofetil may lead to leukopenia. The combination of allopurinol and azathioprine should be avoided. Leukopenia is often associated with viral infections. PMID:12091648

  16. Biotherapies in large vessel vasculitis.

    PubMed

    Ferfar, Y; Mirault, T; Desbois, A C; Comarmond, C; Messas, E; Savey, L; Domont, F; Cacoub, P; Saadoun, D

    2016-06-01

    Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) and aortic involvement is not uncommon in Behcet's disease (BD) and relapsing polychondritis (RP). Glucocorticosteroids are the mainstay of therapy in LVV. However, a significant proportion of patients have glucocorticoid dependance, serious side effects or refractory disease to steroids and other immunosuppressive treatments such as cyclophosphamide, azathioprine, mycophenolate mofetil and methotrexate. Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with LVV. Anti-tumor necrosis factor-α drugs seem effective in patients with refractory Takayasu arteritis and vascular BD but have failed to do so in giant cell arteritis. Preliminary reports on the use of the anti-IL6-receptor antibody (tocilizumab), in LVV have been encouraging. The development of new biologic targeted therapies will probably open a promising future for patients with LVV. PMID:26883459

  17. Isolated heart transplantation for familial transthyretin (TTR) V122I cardiac amyloidosis.

    PubMed

    Thenappan, Thenappan; Fedson, Savitri; Rich, Jonathan; Murks, Catherine; Husain, Aliya; Pogoriler, Jennifer; Anderson, Allen S

    2014-06-01

    Transthyretin (TTR) cardiac amyloidosis is characterized by deposition of either mutant or wild type TTR amyloid protein in the myocardium ultimately leading to progressive cardiomyopathy and heart failure. The most common TTR gene mutation that leads to TTR cardiac amyloidosis is the valine-to-isoleucine substitution at position 122 (V122I or Ile122). Currently, the only definitive treatment suggested for mutant TTR cardiac amyloidosis is the combined or sequential liver-heart transplantation in eligible patients, since liver is the source of TTR production. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation. Abbreviations MMF mycophenolate mofetil NYHA New York Heart Association TTR transthyretin VE minute ventilation. PMID:24818650

  18. Posterior Reversible Encephalopathy Syndrome in Pediatric Hematologic-Oncologic Disease: Literature Review and Case Presentation

    PubMed Central

    ARZANIAN, Mohammad Thaghi; SHAMSIAN, Bibi Shahin; KARIMZADEH, Parvaneh; KAJIYAZDI, Mohammad; MALEK, Fatima; HAMMOUD, Mohammad

    2014-01-01

    Objective Posterior reversible encephalopathy syndrome (PRES) is a cliniconeuroradiological disease entity, which is represented by characteristic magnetic resonance imaging (MRI) findings of subcortical/cortical hyperintensity in T2-weighted sequences. It is more often seen in parietaloccipital lobes, and is accompanied by clinical neurological changes. PRES is a rare central nervous system (CNS) complication in patients with childhood hematologic-oncologic disese and shows very different neurological symptoms between patients, ranging from numbness of extremities to generalized seizure. In this article, we will review PRES presentation in hematologic-oncologic patients. Then, we will present our patient, a 7-year-old boy with Evans syndrome on treatment with cyclosporine, mycophenolate mofetil (MMF) and prednisone, with seizure episodes and MRI finding in favour of PRES. PMID:24949044

  19. Novel therapy for anti-glomerular basement membrane disease with IgA nephropathy: A case report

    PubMed Central

    XU, DECHAO; WU, JIANXIANG; WU, JUN; XU, CHENGGANG; ZHANG, YUQIANG; MEI, CHANGLIN; GAO, XIANG

    2016-01-01

    Anti-glomerular basement membrane (GBM) disease is characterized by circulating anti-GBM antibodies and deposition of these antibodies in the renal GBM. Renal involvement in anti-GBM is more severe when compared with other types of immune-mediated glomerulonephritis, and the majority of patients manifest progressive renal failure, leading to end-stage renal disease. In a limited number of cases, anti-GBM disease has been shown to be accompanied with other immune-mediated glomerulonephritis. The present study reported the case of a 50-year-old female patient presenting with rapidly progressive glomerulonephritis, who was diagnosed with anti-GBM disease with IgA nephropathy. The patient achieved a relatively good therapeutic outcome with administration of corticosteroids plus mycophenolate mofetil (MMF), which may prove to be a novel treatment option for this rare disease; however, the exact underlying mechanism requires further in-depth investigation. PMID:27168822

  20. Pro: Cyclophosphamide in lupus nephritis.

    PubMed

    Kallenberg, Cees G M

    2016-07-01

    Based on efficacy and toxicity considerations, both low-dose pulse cyclophosphamide as part of the Euro-Lupus Nephritis protocol and mycophenolate mofetil (MMF) with corticosteroids may be considered for induction of remission in patients with proliferative lupus nephritis. The long-term follow-up data available for low-dose pulse cyclophosphamide, the fact that compliance is guaranteed with this regimen and economic issues all favour the Euro-Lupus regimen in this author's opinion. For maintenance treatment, either azathioprine (AZA) or MMF may be used; AZA is preferred in case pregnancy is planned, while MMF is preferred when the disease relapses during use of AZA and, possibly, after successful induction of remission with MMF. PMID:27190359

  1. Severe hepatotoxicity associated with the combination of spiramycin plus metronidazole.

    PubMed

    Hussein, Rola; El-Halabi, Mustapha; Ghaith, Ola; Jurdi, Nawaf; Azar, Cecilio; Mansour, Nabil; Sharara, Ala I

    2011-03-01

    Drug-induced liver injury (DILI) is a leading cause of acute liver failure and is the most frequent reason for post-marketing drug withdrawal. The spectrum of liver injury is wide, ranging from mild and subclinical injury, noticeable only on routine biochemical testing, to fulminant liver failure and death. Antibiotics, as a group, are a leading cause of DILI. We herein describe 4 patients who developed moderate to severe hepatotoxicity after exposure to a commercially - available combination of two antibiotics - spiramycin and metronidazole - commonly used for the treatment and prevention of periodontal infections. No other aetiology for liver injury could be identified in all cases. Two patients recovered spontaneously, and two had a more severe course, one responding to corticosteroids and mycophenolate mofetil and the other requiring liver transplantation for subacute massive necrosis. PMID:21429456

  2. Late adult onset of Langerhans cell histiocytosis mimicking glioblastoma multiforme.

    PubMed

    Perren, F; Fankhauser, L; Thiévent, B; Pache, J-C; Delavelle, J; Rochat, T; Landis, T; Chizzolini, C

    2011-02-15

    Langerhans cell histiocytosis (LCH) with multiple organ involvement is a rare disorder in adults. Extrapituitary involvement of the central nervous system (CNS) is uncommon. We report the unusual case of a 55-year-old woman presenting with a left-sided hemiataxia-hemiparesis, left hemisensory loss and short-lasting episodes of an alien left hand due to lesions of the internal capsule and the right thalamus, extending into the mesencephalon associated with extensive surrounding edema, without pituitary involvement. The neuroradiological image suggested glioblastoma multiforme. Brain biopsy revealed inflammatory tissue and "pseudotumoral" multiple sclerosis was suspected. Biopsy of concomitant lung and bone lesions disclosed Langerhans cell histiocytosis. The treatment with pulsed steroids in association with mycophenolate mofetil led to a sustained, clinical neurological remission. PMID:21131007

  3. Update on pathogenesis and treatment of CLE

    PubMed Central

    Privette, Emily D.; Werth, Victoria P.

    2014-01-01

    Purpose of review Cutaneous Lupus Erythematous (CLE) is an autoimmune disease in which patients may present with isolated skin findings or have CLE associated with underlying systemic disease. The most significant recent studies on its pathogenesis and therapeutic management are reviewed here. Recent findings Patients with subacute and Discoid Lupus Erythematous had elevated IFN score, about a third of all cases of SCLE could be attributed to previous drug exposure, and smoking may be more closely associated with CLE than Systemic Lupus Erythematous (SLE). An underlying genetic defect in some subsets of CLE patients may also be shared with SLE. Efficacy of antimalarial therapy is enhanced by increasing treatment duration or maintaining higher blood drug concentrations. Combination antimalarials that include quinacrine, thalidomide analogs, and Mycophenalate Mofetil may also be effective in refractory CLE. Summary The pathogenesis of CLE remains unclear, and is likely multifactorial. Identified associations with subsets of CLE suggest future research questions in CLE pathogenesis. Subsets of CLE associated with interface dermatitis may share an underlying genetic defect in interferon signaling with SLE. The Cutaneous Lupus Disease Area and Severity Index is a valuable and widely used tool allowing for standardized assessment and reporting of cutaneous disease activity and damage. More evidence is available to guide treatment of refractory CLE, but larger studies are needed. PMID:23872903

  4. Calcineurin Inhibitors Associated Posterior Reversible Encephalopathy Syndrome in Solid Organ Transplantation: Report of 2 Cases and Literature Review.

    PubMed

    Song, Turun; Rao, Zhengsheng; Tan, Qiling; Qiu, Yang; Liu, Jinpeng; Huang, Zhongli; Wang, Xianding; Lin, Tao

    2016-04-01

    Posterior reversible encephalopathy syndrome (PRES) is a rare neurologic side effect of calcineurin inhibitors (CNIs) with poorly understood clinical features.We report cases of 2 patients with PRES developing after kidney transplantation and summarize PRES clinical features through a literature review.The 1st case was a 28-year-old man who received a kidney transplant from a deceased donor. Initial immunosuppressive therapy consisted of tacrolimus/mycophenolate mofetil/prednisolone. He developed headache and blurred vision with visual field loss15 days after transplantation and generalized seizures 4 days later. The 2nd case was a 34-year-old man who received a living kidney transplant. His initial immunosuppressive therapy comprised tacrolimus/mycophenolate mofetil/prednisolone. Two months after transplantation, he developed seizures. Both patients were diagnosed with PRES based on neurological symptoms and magnetic resonance imaging (MRI) findings; they recovered after switching from tacrolimus to either a cyclosporine or a lower tacrolimus dose. CNI-associated PRES is an acute neurological syndrome with seizures, encephalopathy, visual abnormalities, headache, focal neurological deficits, and nausea/vomiting. It is always accompanied by hypertension. A fluid-attenuated inversion recovery signal MRI scan typically shows reversible subcortical white matter changes in the posterior cerebral hemisphere that usually occur within the 1st month after transplantation. CNI-associated PRES has a generally favorable prognosis with early diagnosis and prompt treatment including alternating or discontinuing CNIs and blood pressure control.CNI-associated PRES should be considered in patients exhibiting acute neurological symptoms after transplantation. Early diagnosis and immediate treatment are critical for a favorable prognosis. PMID:27057842

  5. The importance of assessing medication exposure to the definition of refractory disease in systemic lupus erythematosus.

    PubMed

    Arnaud, Laurent; Zahr, Noël; Costedoat-Chalumeau, Nathalie; Amoura, Zahir

    2011-09-01

    Treatment of patients with Systemic Lupus Erythematosus (SLE) who have active disease refractory to current therapeutic strategies continues to be a real challenge. Here, we propose that the classic definition of refractory SLE patients - failure to achieve adequate response to the standard of care - should be further refined to incorporate the dimension of adequate drug exposure. Inter-individual pharmacokinetic variability may induce insufficient exposure to many drugs used in SLE, leading to both apparent inefficacy of treatments and inappropriate therapeutic escalation. Among others, we have shown that individual assessment of exposure to mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF) could be used to determine whether a given patient received adequate doses of MMF. We have also shown that measuring blood concentrations of hydroxychloroquine could be used as an efficient way to assess observance, which is a critical issue since a significant proportion of refractory SLE patients is likely to have poor observance as the primary source of treatment failure. Finally, we have underlined the importance of assessing drug interactions as SLE patients often require, in addition to immunosuppressants, several other drugs to prevent or treat associated conditions, which may result in decreased exposure to immunosuppressants. Considering these data, we believe that refractory SLE patients should not only be defined as the failure to achieve adequate therapeutic response to the standard of care, but should also incorporate the dimension of inadequate pharmacokinetic exposure and include drug blood level, interaction and observance monitoring. PMID:21575744

  6. Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial

    PubMed Central

    Winkler, Cheryl A.; Zhao, Xiongce; Radeva, Milena K.; Gassman, Jennifer J.; D’Agati, Vivette D.; Nast, Cynthia C.; Wei, Changli; Reiser, Jochen; Guay-Woodford, Lisa M.; Pollak, Martin R.; Hildebrandt, Friedhelm; Moxey-Mims, Marva; Gipson, Debbie S.; Trachtman, Howard; Friedman, Aaron L.; Kaskel, Frederick J.

    2015-01-01

    Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone. PMID:25573908

  7. Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial.

    PubMed

    Kopp, Jeffrey B; Winkler, Cheryl A; Zhao, Xiongce; Radeva, Milena K; Gassman, Jennifer J; D'Agati, Vivette D; Nast, Cynthia C; Wei, Changli; Reiser, Jochen; Guay-Woodford, Lisa M; Pollak, Martin R; Hildebrandt, Friedhelm; Moxey-Mims, Marva; Gipson, Debbie S; Trachtman, Howard; Friedman, Aaron L; Kaskel, Frederick J

    2015-06-01

    Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone. PMID:25573908

  8. Immunosuppression in Solid-Organ Transplantation: Essentials and Practical Tips.

    PubMed

    Jasiak, Natalia M; Park, Jeong M

    2016-01-01

    A multidisciplinary team approach is essential for successful management of patients with solid-organ transplant. Transplant nursing encompasses care and support of transplant recipients as well as caregivers and organ donors through all phases of transplantation, from pretransplant evaluation to posttransplant recovery and maintenance. The field of solid-organ transplantation has advanced rapidly, and new treatments continue to emerge. Nurses who are responsible for the care of transplant recipients should have a knowledge base in transplant immunology and pharmacology. This review discusses mechanism of action, indication, side effects, and drug interactions of commonly used immunosuppressive medications in solid-organ transplantation. Nonoral routes of drug administration, therapeutic drug monitoring, and patient monitoring strategies are also included as practical tips for bedside nurses who are responsible for delivery of direct patient care and education of patients and their caregivers. This review focuses on the following medications: antithymocyte globulins, basiliximab, alemtuzumab, corticosteroids, tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil/mycophenolate sodium, sirolimus, everolimus, belatacept, intravenous immunoglobulin, and rituximab. PMID:27254639

  9. A Case Series Study of Eighty-Five Chronic Spontaneous Urticaria Patients Referred to a Tertiary Care Center

    PubMed Central

    Kibsgaard, Line; Lefevre, Anna Cecile; Deleuran, Mette

    2014-01-01

    Background Chronic spontaneous urticaria is a debilitating disease for the patients and often considered by the doctors a very difficult disease to treat. In 2009 the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European network/European Dermatology Forum/World Allergy Organization (EAACI/GA2LEN/EDF/WAO) published a revised version of the guidelines for the treatment of urticaria which included an algorithm for the treatment. Objective The objective of this study was to examine the clinical effect and the practical use of the algorithm. Methods The study was performed as a case-series study of all newly referred patients to our urticaria clinic over a period of 18 months. Results Our results show that the single most important and efficient treatment of urticaria patients is up dosing non-sedating antihistamines as recommended by the EAACI/GA2LEN/EDF/WAO guidelines. We did not find any predicting factors for responders to the antihistamine treatment, but about one third of the patients did not respond to the up-dosing of the antihistamines. Conclusion Antihistamines seems to be the most efficient treatment for urticaria; other treatments such as montelukast, azathioprine, and mycophenolate mofetil may also be used, but only in combination with antihistamines and only in the case of an independent antihistamines treatment failure. The EAACI/GA2LEN/EDF/WAO guideline for the treatment of urticaria offers an efficient and simple guidelines for the treatment of urticaria. PMID:24648689

  10. What's in the Literature?

    PubMed

    Silvestri, Nicholas J; Wolfe, Gil I; Bromberg, Mark; Lacomis, David

    2016-03-01

    In this issue, we review clinical features associated with an elevated serum creatine kinase level found in a percentage of patients with amyotrophic lateral sclerosis (ALS). The treatment of ALS remains problematic, and issues with offerings on the internet for unregulated stem cell treatment and the movement for right-to-try experimental drugs are discussed. The last What's in the Literature? discussed information about recording from stimulating electrodes implanted in the diaphragm of ALS patients, and this issue discusses the results of a randomized trial using diaphragm pacing. Chronic inflammatory demyelinating polyradiculoneuropathy is important to diagnose, as it is one of the few treatable chronic neuropathies. However, the diagnosis can be challenging to make, and a review of diagnostic errors is discussed. Once diagnosed, treatment management can be difficult, and endpoint measures are discussed. Updates on the use of mycophenolate mofetil and cyclophosphamide in the treatment of myasthenia gravis are reviewed, as they are the use of cell-based assays for detecting antibodies to clustered acetylcholine receptors. Factors associated with life-threatening events in myasthenia, ethnic differences in the course of the disease, and treatment in very elderly patients are also discussed. Hematopoietic stem cell transplantation as a treatment of mitochondrial neurogastrointestinal encephalomyopathy is reviewed. A natural history study in boys with Duchenne muscular dystrophy looking at the age of loss of ambulation and side effect profiles associated with corticosteroid treatments is discussed, as it is a comprehensive study looking at the clinical features and treatment of necrotizing autoimmune myopathy. PMID:26905916

  11. Ultraviolet B Phototherapy for Psoriasis: Review of Practical Guidelines.

    PubMed

    Mehta, Dhwani; Lim, Henry W

    2016-04-01

    Psoriasis is an inflammatory skin condition that affects approximately 2 % of people worldwide. Topical treatments, systemic treatments, biologic agents, and phototherapy are all treatment options for psoriasis. Ultraviolet (UV) B phototherapy is most appropriate for patients with >10 % affected body surface area who have not responded to topical treatments. This review outlines the use, dosage, safety, and efficacy of narrowband UVB (NB-UVB) and targeted phototherapy. NB-UVB and excimer laser are effective treatment options for psoriasis; they are administered two to three times weekly until clearance followed by maintenance treatment before discontinuation. Long-term data on NB-UVB indicate that it has a good safety profile. NB-UVB is commonly used with adjunctive topical treatments such as emollients, calcipotriene, cortico-steroids, retinoids, and tar. NB-UVB can be used in selected patients with traditional systemic agents such as methotrexate, mycophenolate mofetil, and cyclosporine, although the duration of the combined treatment should be kept to a minimum and patients need to be closely monitored. Acitretin can be safely used with phototherapy, but robust data on the combination use of biologic agents or phosphodiesterase inhibitors with phototherapy are lacking. PMID:26872953

  12. Emerging Drugs for Uveitis

    PubMed Central

    Larson, Theresa; Nussenblatt, Robert B.; Sen, H. Nida

    2010-01-01

    Importance of the Field Uveitis is a challenging disease covering both infectious and noninfectious conditions. The current treatment strategies are hampered by the paucity of randomized controlled trials (RCTs) and few trials comparing efficacy of different agents. Areas Covered in this Review This review describes the current and future treatments of uveitis. A literature search was performed in PUBMED from 1965 to 2010 on drugs treating ocular inflammation with emphasis placed on more recent, larger studies. What the Reader Will Gain Readers should gain a basic understanding of current treatment strategies beginning with corticosteroids and transitioning to steroid sparing agents. Steroid sparing agents include the antimetabolites which include methotrexate, azathioprine, and mycophenolate mofetil; the calcineurin inhibitors which include cyclosporine, tacrolimus; alkylating agents which include cyclophosphamide and chlorambucil; and biologics which include the TNF-α inhibitors infliximab, adalimumab, and etanercept; daclizumab, interferon α2a, and rituximab. Take Home Message Newer agents are typically formulated from existing drugs or developed based on new advances in immunology. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects. PMID:21210752

  13. Therapeutic variability in adult minimal change disease and focal segmental glomerulosclerosis

    PubMed Central

    Fernandez-Juarez, Gema; Villacorta, Javier; Ruiz-Roso, Gloria; Panizo, Nayara; Martinez-Marín, Isabel; Marco, Helena; Arrizabalaga, Pilar; Díaz, Montserrat; Perez-Gómez, Vanessa; Vaca, Marco; Rodríguez, Eva; Cobelo, Carmen; Fernandez, Loreto; Avila, Ana; Praga, Manuel; Quereda, Carlos; Ortiz, Alberto

    2016-01-01

    Background Variability in the management of glomerulonephritis may negatively impact efficacy and safety. However, there are little/no data on actual variability in the treatment of minimal change disease (MCD)/focal segmental glomerulosclerosis (FSGS) in adults. We assessed Spanish practice patterns for the management of adult nephrotic syndrome due to MCD or FSGS. The absence of reasonably good evidence on treatment for a disease often increases the variability substantially. Identification of evidence–practice gaps is the first necessary step in the knowledge-to-action cyclical process. We aim to analyse the real clinical practice in adults in hospitals in Spain and compare this with the recently released Kidney Disease: Improving Global Outcomes clinical practice guideline for glomerulonephritis. Methods Participating centres were required to include all adult patients (age >18 years) with a biopsy-proven diagnosis of MCD or FSGS from 2007 to 2011. Exclusion criteria included the diagnosis of secondary nephropathy. Results We studied 119 Caucasian patients with biopsy-proven MCD (n = 71) or FSGS (n = 48) from 13 Spanish hospitals. Of these patients, 102 received immunosuppressive treatment and 17 conservative treatment. The initial treatment was steroids, except in one patient in which mycophenolate mofetil was used. In all patients, the steroids were given as a single daily dose. The mean duration of steroid treatment at initial high doses was 8.7 ± 13.2 weeks and the mean global duration was 38 ± 32 weeks. The duration of initial high-dose steroids was <4 weeks in 41% of patients and >16 weeks in 10.5% of patients. We did find a weak and negative correlation between the duration of whole steroid treatment in the first episode and the number of the later relapses (r = −0.24, P = 0.023). There were 98 relapses and they were more frequent in MCD than in FSGs patients (2.10 ± 1.6 versus 1.56 ± 1.2; P = 0.09). The chosen treatment was mainly steroids (95

  14. Incontinence Treatment: Surgical Treatments

    MedlinePlus

    ... Incontinence Managing Incontinence: A Survey The Patient's Perspective Barriers on Diagnosis and Treatment Personal Stories Contact Us ... Incontinence Managing Incontinence: A Survey The Patient's Perspective Barriers on Diagnosis and Treatment Personal Stories Contact Us ...

  15. [First case of phaeohyphomycosis due to Pleurostoma ootheca in a kidney transplant recipient in Martinique (French West Indies)].

    PubMed

    Amazan, E; Desbois, N; Fidelin, G; Baubion, E; Derancourt, C; Thimon, S; Ekindi, N; Quist, D

    2014-01-01

    Phaeohyphomycosis is a group of superficial and deep infections due to dematiaceous fungi. They are most common in tropical environments, especially in immunocompromised hosts. We describe the first case of phaeohyphomycosis due to Pleurostoma ootheca in a kidney transplant recipient in Martinique (French West Indies). A 59-year-old man with a kidney graft, treated with mycophenolate mofetil, tacrolimus, and prednisone, presented suppurative tumefaction of the left ankle. Cutaneous and osseous phaeohyphomycosis caused by P. ootheca was diagnosed, based on mycological, histological, and radiological testing. The patient's condition improved with posaconazole treatment. P. ootheca is a known environmental fungus. Immunocompromised hosts are more vulnerable to many infections, due to opportunistic pathogens. Bacteriological, histological, and mycological testing is required for accurate diagnosis and appropriate treatment. Treatment is not well defined and usually relies on antifungal agents or surgical resection or both. An important point to consider is that azole antifungal agents may cause major drug-drug interactions with immunosuppressive agents such as tracrolimus. PMID:24918350

  16. Initial experience of dual maintenance immunosuppression with steroid withdrawal in vascular composite tissue allotransplantation.

    PubMed

    Diaz-Siso, J R; Fischer, S; Sisk, G C; Bueno, E; Kueckelhaus, M; Talbot, S; Carty, M J; Treister, N S; Marty, F; Milford, E L; Pomahac, B; Tullius, S G

    2015-05-01

    Current immunosuppression in VCA is largely based on the experience in solid organ transplantation. It remains unclear if steroids can be reduced safely in VCA recipients. We report on five VCA recipients who were weaned off maintenance steroids after a median of 2 months (mean: 4.8 months, range 2-12 months). Patients were kept subsequently on a low dose, dual maintenance consisting of tacrolimus and mycophenolate mofetil/mycophenloic acid with a mean follow-up of 43.6 months (median = 40 months, range 34-64 months). Early and late acute rejections responded well to temporarily augmented maintenance, topical immunosuppression, and/or steroid bolus treatment. One late steroid-resistant acute rejection required treatment with thymoglobulin. All patients have been gradually weaned off steroids subsequent to the treatment of acute rejections. Low levels of tacrolimus (<5 ng/mL) appeared as a risk for acute rejections. Although further experience and a cautious approach are warranted, dual-steroid free maintenance immunosuppression appears feasible in a series of five VCA recipients. PMID:25777324

  17. Skimmin, a Coumarin from Hydrangea paniculata, Slows down the Progression of Membranous Glomerulonephritis by Anti-Inflammatory Effects and Inhibiting Immune Complex Deposition

    PubMed Central

    Xin, Hongqi; Li, Yan; Zhang, Dongming; Shi, Jing; Yang, Jingzhi

    2013-01-01

    Skimmin is one of the major pharmacologically active molecules present in Hydrangea paniculata, a medical herb used in the traditional Chinese medicine as an anti-inflammatory agent. In the current study, we attempted to investigate its renoprotective activity and underlying mechanisms in a rat model of membranous glomerulonephritis induced by cationic bovine serum albumin (c-BSA). Sprague-Dawley (SD) rats were divided into five groups, including normal control, model control, Mycophenolate Mofetil-treated group, and two skimming-treated groups (15 mg/kg and 30 mg/kg). Our research showed that treatment with skimmin significantly reduced the levels of blood urea nitrogen (BUN), urinary albumin excretion (UAE), and serum creatinine (Scr) as compared with model control after experimental induction of membranous glomerulonephritis (P < 0.01). Moreover, glomerular hypercellularity, tubulointerstitial injury, and glomerular deposition of IgG were less intense after skimmin treatment. By immunochemistry analysis, we demonstrated that skimmin could significantly inhibit interleukin-1β (IL1β) and IL-6 expression (P < 0.05), reduce the loss of nephrin and podocin, and suppress the infiltration of renal interstitium by CD3-positive T cell and CD20-positive B cell. These results suggest that treatment with skimmin can significantly improve renal function and suppress the IgG deposition as well as the development of glomerular lesions in a rat model of membranous glomerulonephritis. PMID:23990847

  18. Voltage-gated calcium channel autoimmune cerebellar degeneration

    PubMed Central

    McKasson, Marilyn; Clawson, Susan A.; Hill, Kenneth E.; Wood, Blair; Carlson, Noel; Bromberg, Mark; Greenlee, John E.

    2016-01-01

    Objectives: To describe response to treatment in a patient with autoantibodies against voltage-gated calcium channels (VGCCs) who presented with autoimmune cerebellar degeneration and subsequently developed Lambert-Eaton myasthenic syndrome (LEMS), and to study the effect of the patient's autoantibodies on Purkinje cells in rat cerebellar slice cultures. Methods: Case report and study of rat cerebellar slice cultures incubated with patient VGCC autoantibodies. Results: A 53-year-old man developed progressive incoordination with ataxic speech. Laboratory evaluation revealed VGCC autoantibodies without other antineuronal autoantibodies. Whole-body PET scans 6 and 12 months after presentation detected no malignancy. The patient improved significantly with IV immunoglobulin G (IgG), prednisone, and mycophenolate mofetil, but worsened after IV IgG was halted secondary to aseptic meningitis. He subsequently developed weakness with electrodiagnostic evidence of LEMS. The patient's IgG bound to Purkinje cells in rat cerebellar slice cultures, followed by neuronal death. Reactivity of the patient's autoantibodies with VGCCs was confirmed by blocking studies with defined VGCC antibodies. Conclusions: Autoimmune cerebellar degeneration associated with VGCC autoantibodies may precede onset of LEMS and may improve with immunosuppressive treatment. Binding of anti-VGCC antibodies to Purkinje cells in cerebellar slice cultures may be followed by cell death. Patients with anti-VGCC autoantibodies may be at risk of irreversible neurologic injury over time, and treatment should be initiated early. PMID:27088118

  19. Complications of nephrotic syndrome.

    PubMed

    Park, Se Jin; Shin, Jae Il

    2011-08-01

    Nephrotic syndrome (NS) is one of the most common glomerular diseases that affect children. Renal histology reveals the presence of minimal change nephrotic syndrome (MCNS) in more than 80% of these patients. Most patients with MCNS have favorable outcomes without complications. However, a few of these children have lesions of focal segmental glomerulosclerosis, suffer from severe and prolonged proteinuria, and are at high risk for complications. Complications of NS are divided into two categories: disease-associated and drug-related complications. Disease-associated complications include infections (e.g., peritonitis, sepsis, cellulitis, and chicken pox), thromboembolism (e.g., venous thromboembolism and pulmonary embolism), hypovolemic crisis (e.g., abdominal pain, tachycardia, and hypotension), cardiovascular problems (e.g., hyperlipidemia), acute renal failure, anemia, and others (e.g., hypothyroidism, hypocalcemia, bone disease, and intussusception). The main pathomechanism of disease-associated complications originates from the large loss of plasma proteins in the urine of nephrotic children. The majority of children with MCNS who respond to treatment with corticosteroids or cytotoxic agents have smaller and milder complications than those with steroid-resistant NS. Corticosteroids, alkylating agents, cyclosporin A, and mycophenolate mofetil have often been used to treat NS, and these drugs have treatment-related complications. Early detection and appropriate treatment of these complications will improve outcomes for patients with NS. PMID:22087198

  20. Anti-Inflammatory Therapy Modulates Nrf2-Keap1 in Kidney from Rats with Diabetes

    PubMed Central

    Arellano-Buendía, Abraham Said; Tostado-González, Montserrat; García-Arroyo, Fernando Enrique; Cristóbal-García, Magdalena; Loredo-Mendoza, María Lilia; Tapia, Edilia; Sánchez-Lozada, Laura-Gabriela; Osorio-Alonso, Horacio

    2016-01-01

    This study addressed the relationship of proinflammatory cytokines and Nrf2-Keap1 system in diabetic nephropathy. The experimental groups were control, diabetic, and diabetic treated with mycophenolate mofetil (MMF). The renal function, proinflammatory and profibrotic cytokines, oxidative stress, morphology, and nephrin expression were assessed. Diabetic group showed impaired renal function in association with oxidative stress and decreased Nrf2 nuclear translocation. These results were associated with increased mesangial matrix index, interstitial fibrosis, and increased nephrin expression in cortex and urine excretion. Additionally, interleukin-1β, IL-6, and transforming growth factor-β1 were increased in plasma and kidney. MMF treatment conserved renal function, prevented renal structural alterations, and partially prevented the proinflammatory and profibrotic cytokines overexpression. Despite that MMF treatment induced nephrin overexpression in renal tissue, preventing its urinary loss. MMF salutary effects were associated with a partial prevention of oxidative stress, increased Nrf2 nuclear translocation, and conservation of antioxidant enzymes in renal tissue. In conclusion, our results confirm that inflammation is a key factor in the progression of diabetic nephropathy and suggest that treatment with MMF protects the kidney by an antioxidant mechanism, possibly regulated at least in part by the Nrf2/Keap1 system, in addition to its well-known anti-inflammatory effects. PMID:26955430

  1. Regulated expression of the MRP8 and MRP14 genes in human promyelocytic leukemic HL-60 cell treated with the differentiation-inducing agents mycophenolic acid and 1{alpha},25-Dihydroxyvitamin D{sub 3}

    SciTech Connect

    Warner-Bartnicki, A.L.; Murao, S.; Collart, F.R.; Huberman, E.

    1992-12-31

    The calcium-binding proteins MRP8 and MEP14 are present in mature monomyelocytic cells and are induced during differentiation. Previous studies have demonstrated that the proteins may mediate the growth arrest in differentiating HL-60 cells. We determined the levels of a protein complex (PC) containing MRP8 and MRP14 and investigated the mechanism by which the genes encoding these proteins are regulated in HL-60 cells treated with the differentiation-inducing agent mycophenorc acid (MPA)While the PC was barely detectable in untreated cells, MPA treatment resulted in elevated levels of the PC which were maximal at 3-4 d, and were found to directly parallel gains in the steady-state levels of MRP8 and MRP14 MRNA. Transcription studies with the use of nuclear run-on experiments revealed increased transcription initiation at the MRP8 and MRP14 promoters after MPA treatment. 1{alpha},25-Dihydroxyvitamin D{sub 3}, which induces HL-60 cell differentiation by another mechanism, was also found to increase transcription initiation at the MRP8 and MRP14 promoters. Our results suggest that this initiation is the major control of maturation agent-mediated increases in MRP8 and MRPl4 gene expression, and support a role for the PC in terminal differentiation of human monomyelocytic cells.

  2. [Lupus anticoagulant-hypoprothrombinemia syndrome revealing systemic lupus in an 11-year old girl in a context of clinical and biological emergency].

    PubMed

    Favier, Rémi; Kheyar, Tassadit; Renolleau, Sylvain; Tabone, Marie Dominique; Favier, Marie; Ulinski, Tim

    2012-01-01

    We report a case of lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) in an 11 year old girl initially hospitalized for bleeding. The patient presented with petechia, persisting bleeding after tooth extraction performed two days before, nephritic syndrome (renal failure, proteinuria and macroscopic hematuria), severe anemia, thrombocytopenia, lymphopenia. The association of these abnormalities suggested LAHPS secondary to severe systemic lupus. Immediate treatment with fresh frozen plasma and intravenous immunoglobulins (400 mg/kg/5d) was started and followed by steroid (500 mg/d) and cyclophosphamide (800 mg/m(2)) pulse therapy leading to rapid improvement of bleeding, renal involvement and prothrombin levels within 13 days. Lupus diagnosis was confirmed by immunological investigations and renal biopsy. Two early relapses occurred despite adequate treatment. After a follow-up of two years, no further disease activity is noted while the patient is treated only by mycophenolate mofetil (1 200 mg/m(2)/d). LAHPS did not relapse during this follow-up. PMID:22484537

  3. The role of early colonoscopy in CMV colitis of transplant recipients.

    PubMed

    Korkmaz, M; Kunefeci, G; Selcuk, H; Unal, H; Gur, G; Yilmaz, U; Arslan, H; Demirhan, B; Boyacioglu, S; Haberal, M

    2005-09-01

    Cytomegalovirus (CMV)-associated diseases remain a major problem in transplant recipients. Early diagnosis is critical. Presentation of early CMV colitis can be mild and nonspecific in transplant recipients. Although serology is helpful in the diagnosis, sometimes it is inadequate. Because the endoscopic features of CMV colitis are specific, colonoscopy facilitates the histopathologic examination. We present the clinical properties and advantages of early colonoscopy in transplant recipients with CMV colitis. The study group included seven patients (six men, one woman of mean age, 36.7 years (range, 22 to 64 years) whose mean transplant duration was 12.3 months (range, 1 to 72 months). Six of the seven patients experienced an acute graft rejection treated with high doses of steroids; one patient had a herpes simplex virus infection. All patients were on steroid treatment with a various combinations of immunosuppressive agents, including cyclosporine, mycophenolate mofetil, and tacrolimus. All patients presented with mild diarrhea without any blood or mucous discharge. Four patients had fever exceeding 38 degrees C; two had abdominal pain. Stool examinations revealed normal findings in six patients, while one patient had white blood cells and amoebic cysts. Serum CMV IgM and CMV pp65 antigenemia were negative in five of seven patients and two had positive results. All patients showed typical colonoscopic and histopathologic findings compatible with CMV colitis. Standard ganciclovir treatment was successful in all patients. Early and rapid colonoscopy is beneficial for the early diagnosis and management of CMV colitis in transplant recipients. PMID:16213304

  4. [Membranous nephropathy].

    PubMed

    Mercadal, Lucile

    2013-12-01

    Membranous nephropathy is characterized by immune complex deposits on the outer side of the glomerular basement membrane. Activation of complement and of oxidation lead to basement membrane lesions. The most frequent form is idiopathic. At 5 and 10 years, renal survival is around 90 and 65% respectively. A prognostic model based on proteinuria, level and duration, progression of renal failure in a few months can refine prognosis. The urinary excretion of C5b-9, β2 and α1 microglobuline and IgG are strong predictors of outcome. Symptomatic treatment is based on anticoagulation in case of nephrotic syndrome, angiotensin conversion enzyme inhibitors, angiotensin II receptor blockers and statins. Immunosuppressive therapy should be discussed for patients having a high risk of progression. Corticoids alone has no indication. Treatment should include a simultaneous association or more often alternating corticoids and alkylant agent for a minimum of 6 months. Adrenocorticoid stimulating hormone and steroids plus mycophenolate mofetil may be equally effective. Steroids plus alkylant decrease the risk of end stage renal failure. Cyclosporine and tacrolimus decrease proteinuria but are associated with a high risk of recurrence at time of withdrawal and are nephrotoxic. Rituximab evaluated on open studies needs further evaluations to define its use. PMID:24315535

  5. Guideline of Chronic Urticaria Beyond

    PubMed Central

    Fine, Lauren M.

    2016-01-01

    Urticaria is a relatively common condition that if chronic can persist for weeks, months or years and affect quality of life significantly. The etiology is often difficult to determine, especially as it becomes chronic. Many cases of chronic urticaria are thought to be autoimmune, although there is no consensus that testing for autoimmunity alters the diagnostic or management strategies or outcomes. Many times, urticaria is easily managed with antihistamines and/or short courses of oral corticosteroids, but too often control is insufficient and additional therapies must be added. For years, immune modulating medications, such as cyclosporine and Mycophenolate Mofetil, have been used in cases refractory to antihistamines and oral corticosteroids, although the evidence supporting their efficacy and safety has been limited. Omalizumab was recently approved for the treatment of chronic urticaria unresponsive to H1-antagonists. This IgG anti-IgE monoclonal antibody has been well demonstrated to safely and effectively control chronic urticaria at least partially in approximately 2/3 of cases. However, the mechanism of action and duration of treatment for omalizumab is still unclear. It is hoped that as the pathobiology of chronic urticaria becomes better defined, future therapies that target specific mechanistic pathways will be developed that continue to improve the management of these often challenging patients. PMID:27334777

  6. Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation

    PubMed Central

    Panagiotellis, Konstantinos; Iniotaki, Aliki; Boletis, John N.

    2013-01-01

    Kidney transplantation has evolved over more than half a century and remarkable progress has been made in patient and graft outcomes. Despite these advances, chronic allograft dysfunction remains a major problem. Among other reasons, de novo formation of antibodies against donor human leukocyte antigens has been recognized as one of the major risk factors for reduced allograft survival. The type of treatment in the presence of donor specific antibodies (DSA) posttransplantation is largely related to the clinical syndrome the patient presents with at the time of detection. There is no consensus regarding the treatment of stable renal transplant recipients with circulating de novo DSA. On the contrast, in acute or chronic allograft dysfunction transplant centers use various protocols in order to reduce the amount of circulating DSA and achieve long-term graft survival. These protocols include removal of the antibodies by plasmapheresis, intravenous administration of immunoglobulin, or depletion of B cells with anti-CD20 monoclonal antibodies along with tacrolimus and mycophenolate mofetil. This review aims at the comprehension of the clinical correlations of de novo DSA in kidney transplant recipients, assessment of their prognostic value, and providing insights into the management of these patients. PMID:24348683

  7. Relapsing CD8+ encephalitis-looking for a solution.

    PubMed

    Salam, Sharfaraz; Mihalova, Tatiana; Ustianowski, Andrew; McKee, David; Siripurapu, Rehka

    2016-01-01

    CD8+ encephalitis (CD8+E) is an emerging and incompletely understood HIV-associated neurological syndrome, typically presenting as a steroid-responsive subacute encephalopathy with prominent white matter changes in patients with apparently well-controlled HIV infection. Some cases can be associated with the phenomenon of 'viral escape' (disproportionate replication within the cerebrospinal fluid), but the most important pathophysiology of CD8+E is thought to involve an attack on HIV-infected CD4+ lymphocytes by autoreactive CD8+ cells. We report a case of CD8+E where the initial positive response to steroid treatment was followed by several relapses on withdrawal. This led to the use of mycophenolate mofetil (MMF) as a long-term steroid-sparing agent, which is the first time this approach has been reported in the literature. The patient has now been on treatment with MMF for 10 months and it has been possible to taper the steroids down to a minimal maintenance dose without further relapse. PMID:27335359

  8. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions

    PubMed Central

    Czaja, Albert J.

    2016-01-01

    Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms. PMID:26934884

  9. Myasthenia gravis: an update for the clinician.

    PubMed

    Sieb, J P

    2014-03-01

    This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis (MG). Nowadays the term 'myasthenia gravis' includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte- macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective. PMID:24117026

  10. Classification, diagnosis, and management of idiopathic inflammatory myopathies.

    PubMed

    Lazarou, Ilias N; Guerne, Pierre-André

    2013-05-01

    The detection and characterization of a large array of autoantibodies, including at least 8 different antisynthetase, anti-SRP, -200/100 (HMGCR), -Mi-2, -CADM-140 (MDA5), -SAE, -p155, -MJ (NXP-2), and -PMS1, frequently associated with distinct and well-defined clinicopathological features, allowed for significant improvement in the definition and diagnosis of idiopathic inflammatory myopathies (IIM). Classification remains difficult, with lingering divergence between the different specialties involved in IIM care, but several categories clearly stand out, including dermatomyositis (DM), overlap myositis (OM), polymyositis, necrotizing myositis, and sporadic inclusion body myositis (s-IBM). Biopsy and histological analysis remain crucial, particularly in the absence of autoantibodies, to accurately specify the diagnosis and rule out mimics such as muscular dystrophies and metabolic myopathies. Numerous infectious agents (in particular human immunodeficiency virus and human T cell lymphotrophic virus-1) and drugs (statins, tumor necrosis factor inhibitors, and proton pump inhibitors) can cause mimic IIM that must also be excluded. Pharmacological treatment, in addition to glucocorticoids and immunoglobulins, now includes mycophenolate mofetil and rituximab, which proved helpful in resistant cases, particularly rituximab in DM and OM. Exercise, initially seen as potentially deleterious, recently was shown to be efficacious and safe. IIM can thus be reasonably well controlled in most cases, although aggressive disease remains refractory to treatment, including some cases of necrotizing myopathy. Sporadic IBM still seems resistant to all medications tested to date. PMID:23504386