Of the patients, 62.8% (n=22) were men and the overall mean age was 55 years (95% confidence interval, 48.7-62.7). The SNP distribution was: CYP3A5*3: G/G=82.9%, A/G=17.1%; CYP3A5*6: G/G=88.6%, G/A=11.4%; MDR1 C3435T: C/C=25.7%, C/T=62.9%, T/T=11.4%; for MDR1 G2677T/A: G/G=22.9%, G/T=65.7%, T/T=11.4% and for PXR: C/T=85.7%, T/T=14.3%. Tacrolimus concentration/dose ratios in heterozygote patients for CYP3A5*3 genotypes was >120% lower than for the homozygote CYP3A5*3 genotype (0.65±0.04 vs 1.45±0.05; P<.0001). Wild-type MDR1 (3435 C/C) genotype patients showed up to 40% lower concentration/dose ratios compared with heterozygote and homozygote genotypes (C/C; 1±0.07 vs C/T; 1.4±0.06 vs T/T; 1.37±0.09; P<.0001).
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We developed an oil/water-type tacrolimus (FK506) cream formulation as an alternative to Protopic ointment for atopic dermatitis treatment. We determined the effects of solvents used in topical preparations on FK506 solubility and stability, and evaluated FK506 transdermal absorption into rat skin from solutions, emulsions, and creams. Screening indicated that diethyl sebacate (DES), isopropyl myristate (IPM), propylene glycol (PG), and oleyl alcohol (OA) were adequate FK506 solvents. When FK506 solutions prepared using these solvents were transdermally administered, AUC0-24 values for DES and IPM were higher than or similar to that for 0.1% Protopic ointment. The AUC0-24 values for PG and OA were low, so these solvents did not enhance absorption. The residual ratios of FK506 in DES and IPM solutions after incubation at 70°C for 9d were 95.6% and 88.6%, respectively, so DES and IPM were chosen for emulsion preparation. When the emulsions were transdermally administered, the IPM emulsion AUC0-24 values increased 4.6-fold; DES emulsions did not show high transdermal absorption, but showed sustained characteristics. A cream formulation prepared by mixture of IPM and DES also showed high absorption and transdermal absorption increased with increasing IPM ratio. We developed an FK506 cream formulation with a controllable transdermal absorption rate by manipulating the IPM:DES ratio.
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Hyperlipidemia following successful renal transplantation is a frequent and persistent complication. Several immunosuppressive agents including cyclosporine A (CyA), corticosteroids, and tacrolimus appear to have a significant pathogenetic role. The aim of this study is to investigate the differential effects of different immunosuppressive agents on lipids in renal transplant patients.
To investigate the roles of Trx reductase 2 (TrxR2) and S-Nitrosoglutathione reductase (GSNOR) as antioxidative/nitrosative and antiapoptotic mediators of the neuroprotective effect of FK in the penis after CNI.
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We observed that the percent reduction in DNAm in the intron 1 region of Fkbp5 determined from a single blood draw strongly reflected average glucocorticoid burden generated weekly during the prior month of glucocorticoid exposure. There were also strong correlations in DNAm with glucocorticoid-induced end organ changes in spleen weight and visceral fat. We tested a subset of these animals for anxiety-like behavior in the elevated plus maze and found that DNAm in the blood also has predictive value in determining the behavioral consequences of glucocorticoid exposure.
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We evaluated 88 UC patients hospitalized at our center between April 2010 and November 2012. We compared characteristics of corticosteroid-refractory patients treated with calcineurin inhibitor and those with infliximab as second-line therapy. Furthermore, we compared the characteristics of operative and nonoperative patients. The association between perioperative treatments and complications was also investigated.
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During kidney allograft rejection, CXC chemokine ligand 10 (CXCL10)-CXC chemokine receptor 3 (CXCR3) trafficking between peripheral blood and tissues initiates alloresponse and perpetuates a self-inflammatory loop; thus, CXCL10-CXCR3 axis could represent a pharmacologic target. In this perspective, immunosuppressors targeting graft-resident cells, beside immune cells, could be very advantageous. Vitamin D receptor (VDR) agonists exhibit considerable immunomodulatory properties. This study aimed to investigate whether elocalcitol and BXL-01-0029 could decrease the expression of CXCL10 in activated renal tubular cells in vitro and thus be useful in kidney allograft rejection treatment. Experiments were performed in human tubular renal cells stimulated with interferon-gamma + tumor necrosis factor-alpha with and without VDR agonists, tacrolimus, sirolimus, hydrocortisone, methylprednisolone, cyclosporin A and mycophenolate mofetil. CXCL10 protein secretion and gene expression were measured by ELISA and by quantitative PCR. Specific inhibitors were used to investigate intracellular pathways involved in tubular cells activation. For IC(50) determination and comparison, dose-response curves with VDR agonists, tacrolimus and mycophenolic acid were performed. Elocalcitol and BXL-01-0029 inhibited CXCL10 secretion by renal cells, without affecting cell viability, while almost all the immunosuppressors were found to be ineffective, except for tacrolimus and mycophenolate mofetil. BXL-01-0029 was the most potent drug and, notably, it was found to be capable of allowing reduction in tacrolimus-inhibitory doses. Our data suggest that BXL-01-0029 could potentially be a dose-reducing agent for conventional immunosuppressors in kidney rejection management.
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The study included 136 patients (71.3% men), with mean (SD) age of 36.3 (12.2) years. The most frequently prescribed immunosuppression therapy included prednisolone plus cyclosporine, tacrolimus, or rapamycin. Fifteen patients developed complications during the first year after surgery including respiratory infections in 12 (80%), namely, bacterial pneumonia in 10 (66.6%), and tuberculosis (caused by Mycobacterium tuberculosis) in 2 (33.3%). Pneumonia developed within the first 5 months after transplantation in 6 patients, and tuberculosis after the third month. Microbiologic agents were detected in 3 of the 6 patients (20%), and empyema, postoperative atelectasis, and pulmonary embolism, respectively, in the other 3 patients. No association was observed between complications and baseline pulmonary function test results. C-reactive protein concentration was significantly increased in patients with pulmonary complications. No invasive procedures were performed to diagnose complications, all of which resolved with appropriate treatment.
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Current strategies for immunosuppression in liver transplant (LT) recipients include the design of protocols targeting a more individualized approach to reduce risk factors such as renal failure, cardiovascular complications and malignancies. Renal injury in LT recipients may be often multifactorial and is associated with increased risk of post-transplant morbidity and mortality. The quest for low toxicity immunosuppressive regimens has been challenging and resulted in CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil (MMF) and/or mammalian target of rapamycin inhibitor-based immunosuppressive regimens. Use of antibody induction to delay CNI administration may be an option in particular in immunocompromized, critically ill patients with high MELD scores. Protocols including MMF introduction and concomitant CNI minimization have the potential to recover renal function even in the medium and long term after LT. We review on hot topics in the prevention and management of acute and chronic renal injury in LT patients. For this purpose, we present and critically discuss results from immunosuppressive studies published in the current literature or presented at recent LT meetings.
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To uphold visual acuity, an early, fast and accurate diagnosis is necessary, followed by an aggressive and lengthy immunosuppressive treatment.
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The Kings College group was the first to describe a clinical syndrome similar to autoimmune hepatitis in children and young adults transplanted for non-immune mediated liver diseases. They coined the term "de novo autoimmune hepatitis". Several other liver transplant centres confirmed this observation. Even though the condition is uncommon, patients with de novo AIH are now seen in most of the major transplant centres. The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The most characteristic laboratory hallmark is a marked hypergammaglobulinaemia. Autoantibodies are common, mostly ANA. We described also a case of LKM1-positivity in a patients transplanted for Wilson's disease, however this patients did not develop clinical or histological features of AIH. Development of SLA/LP-autoantibodies is also not described. Therefore, serologically de novo AIH appears to correspond to type 1 AIH. Like classical AIH patients respond promptly to treatment with increased doses of prednisolone and azathioprine, while the calcineurin inhibitors cyclosporine or tacrolimus areof very limited value - which is not surprising, as almost all patients develop de novo AIH while receiving these drugs. Despite the good response to treatment, most patients remain a clinical challenge as complete stable remissions are uncommon and flares, relapses and chronic disease activity can often occur. Pathogenetically this syndrome is intriguing. It is not clear, if the immune response is directed against allo-antigens, neo-antigens in the liver, or self-antigens, possibly shared by donor and host cells. It is very likely that the inflammatory milieu due to alloreactive cells in the transplanted organ contribute to the disease process. Either leading to aberrant antigen presentation, or providing co-stimulatory signals leading to the breaking of self-tolerance. The development of this disease in the presence of treatment with calcineurin inhibitors supports the view held by most specialists in autoimmune hepatitis that these drugs, even though effective in acute disease, are not helpful in the long-term management of autoimmune liver diseases.
Inhaled nanoparticle tacrolimus treatment of lung donors is associated with an attenuation of ischemia-reperfusion injury on a functional and cellular level in lung transplant.
FKBP12 is a critical regulator of I(Na) and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of I(Na) may underlie clinical arrhythmias associated with FK506 administration.
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Medical records of 343 liver transplantation cases, which were followed between January 2001 and January 2010 at Dokuz Eylul University, were retrospectively analyzed. Patient pre-liver transplantation height, body weight, body mass index (BMI) measurements, as well as changes in body weight at the beginning, 6 months, 12 months, and 5 years post-transplantation were observed. BMI measurements with records of immunosuppressive therapies were obtained.
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Obesity prevalence before and after liver transplantation was comparable. Education of obese patients prior to surgery and recommendation of medical nutrition therapy should be appropriate. Similar medical care for the non-obese subjects could prevent increase in obesity prevalence. Non-corticosteroid immunosuppressive agents had no significant effect on the development of weight gain and obesity. Avoiding the use of long-term steroid therapy and obesity education are the key measures for preventing obesity after liver transplantation.
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To investigate the incidence of neoplasms in inflammatory bowel disease (IBD) patients and the potential causative role of thiopurines.
Mean follow-up was 1395.3 +/- 179.3 days and 1488.9 +/- 225.1 days for cyclosporine (CsA) and FK506 groups, respectively. Mean values for alkaline phosphatase and osteocalcin were 108.8 +/- 6.0 versus 98.4 +/- 9.7 U/L and 10.1 +/- 1.2 versus 9.8 +/- 1.5 ng/mL for the CsA and FK506 groups, respectively. Both CsA and FK506 caused mild osteoblastic proliferation and matrix mineralization activity, as reflected by increased osteocalcin and alkaline phosphatase levels in 22.6% and 12.5% of patients, respectively. This bone formation activity was counterbalanced by a three-fold increase in urine deoxypyridinoline levels in both groups. Mean deoxypyridinoline levels were, respectively, 13.8 +/- 4.4 versus 11.3 +/- 2.1 nM/mMCr in the CsA and FK506 groups. Thirty-four (68%) patients in the CsA and 10 (62.5%) in the FK506 groups had elevated deoxypyridinoline levels. A strong correlation existed between deoxypyridinoline levels and BMD scores for the CsA group (P < .0001). Despite the presence of relatively greater elevations in deoxypyridinoline and BMD values among CsA-treated patients, there was no significant difference in terms of bone resorption potential of both groups. No correlation existed between iPTH values (<65 pg/mL or among 65 to 98.2 pg/mL) at any time versus osteocalcin, alkaline phosphatase, deoxypyridinoline, or BMD levels. The symptomatic bone disease and fracture rates were 0% in this series.
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We conducted a systematic review and meta-analysis to evaluate the efficacy and adverse event (AE)-associated tolerability of treatment with immunomodulators and biologics in ulcerative colitis clinical trials.
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The incidence rates of SCC and BCC, per 1000 persons/year, were 8.5 and 5.2, respectively. Males had a higher risk of SCC but not BCC. Induction therapy increased the risk of SCC and BCC. The relative risk of mycophenolate mofetil (MMF) was 0.3 (0.2-0.6; P<.0005) and azathioprine (AZA) 1.8 (1.2-2.7; P<.0032) for SCC, whereas tacrolimus and cyclosporine showed no difference. The relative risk of BCC was not affected by any immunosuppressant.
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Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4(+) CD25(-) cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4(+) CD25(-) cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4(+) CD25(-) cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .
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The study enrolled 48 Chinese liver transplant recipients (45 male, 3 female) with a mean (SD) age of 50 (12) years, mean weight of 64 (12) kg, and mean height of 169 (6) cm. Twenty-four models that included blood sampling at 1 through 4 time points were developed (r(2) = 0.015-0.950). Four models with the highest r(2) values were selected; the lack of significant differences from the original dataset on bootstrap analysis indicated acceptable accuracy and robustness. The best model for predicting the MPA AUC(0-12) employed concentrations at 1, 2, 4, and 8 hours; 40 of 48 (83.3%) MPA AUC(0-12) values estimated using this model were within 15% of the full 12-hour MPA AUC. This model had a minimal mean prediction error (mean [SD], 0.27% [1.79%]) and mean absolute prediction error (8.83% [1.24%]). On Bland-Altman analysis, this model also had the best agreement between the estimated MAP AUC(0-12) and the full 12-hour MPA AUC, with a mean error of 9.02 mg . h/L.
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Our proposed three-sampling-point estimate of AUCs is clinically acceptable. However, the sampling times are inconvenient for outpatients, and is recommended only for monitoring MMF treatment of inpatients with suspected toxicity or at high risk of organ rejection.
A trained librarian performed two searches: (1) PubMed for all lupus nephritis trials from the end dates for the systematic review for the 2012 American College of Rheumatology (ACR) lupus nephritis treatment guidelines and the 2012 Cochrane Systematic Review on treatments for lupus nephritis, to September 2013; and (2) PubMed and SCOPUS for all lupus trials (excluding lupus nephritis) from inception to February 2014, to obtain additional trials for harms data in any lupus patient. The search was updated to May 2016. Duplicate title/abstract review and duplicate data abstractions by two abstractors independently was performed for all eligible studies, including those studies abstracted for the 2012 ACR lupus nephritis treatment guidelines and the 2012 Cochrane Systematic Review on lupus nephritis treatments. We performed a systematic review and a Bayesian NMA, including randomized controlled trials (RCTs) of immunosuppressive drugs or glucocorticoids in patients with lupus nephritis assessing serious infection risk. Markov chain Monte Carlo methods were used to model 95 % credible intervals (CrI). Sensitivity analyses examined the robustness of estimates.
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This study shows that, in a prednisone-free immunosuppressive regimen, long-term renal graft survival and function are significantly worse in the tacrolimus/sirolimus group than the tacrolimus/mycophenolate mofetil group. The synergistic nephrotoxic effect and higher acute rejection rates in the tacrolimus/sirolimus compared with the tacrolimus/mycophenolate mofetil group adversely affect graft survival.