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Calcineurin Inhibitors (calcineurin + inhibitor)
Kinds of Calcineurin Inhibitors Terms modified by Calcineurin Inhibitors Selected AbstractsReview of the potential photo-cocarcinogenicity of topical calcineurin inhibitorsJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2005Position statement of the European Dermatology Forum ABSTRACT, Topical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated. [source] Early Withdrawal of Calcineurin Inhibitors and Everolimus Monotherapy in de novo Liver Transplant Recipients Preserves Renal FunctionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010M. Masetti We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA-based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy-eight patients were randomized (Evr n = 52; CsA n = 26). The 1-year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ,3 (estimated glomerular filtration rate <60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications. [source] Fixed- or Controlled-Dose Mycophenolate Mofetil with Standard- or Reduced-Dose Calcineurin Inhibitors: The Opticept TrialAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009R. S. Gaston Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed-dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2-year, open-label, randomized, multicenter trial compared the efficacy and safety of concentration-controlled MMF (MMFCC) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMFCC and reduced-level calcineurin inhibitor (MMFCC/CNIRL); (B) MMFCC and standard-level CNI (MMFCC/CNISL); or (C) fixed-dose MMF and CNISL (MMFFD/CNISL). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (,= 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p , 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMFCC with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMFFD, indicating potential utility of MMFCC in CNI-sparing regimens. [source] Mycophenolate Mofetil Monotherapy for Severe Side Effects of Calcineurin Inhibitors Following Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009S. Dharancy Withdrawal of calcineurin inhibitors (CNI) followed by mycophenolate mofetil (MMF) monotherapy after liver transplantation (LT) remains controversial due to the increased risk of acute rejection and graft loss. The aim of the present study, performed in a large cohort of liver-transplanted patients with severe CNI-induced side effects, was to assess renal function recovery, and safety in terms of liver function, of complete CNI withdrawal and replacement by MMF monotherapy. Fifty-two patients treated with MMF monotherapy for CNI-induced toxicity were analyzed. Mean estimated glomerular filtration rate (eGFR) increased significantly during the period of MMF monotherapy, from 37 ± 10 to 44.7 ± 15 mL/min/1.73 m2 at 6 months (p = 0.001) corresponding to a benefit of +17.4% in renal function. eGFR stabilized or improved in 86.5%, 81% and 79% of cases, and chronic renal dysfunction worsened in 13.5%, 19% and 21% of cases, at 6, 12 and 24 months after CNI withdrawal, respectively. Only two patients experienced acute rejection. MMF monotherapy may be efficient at reversing/stabilizing CRD, and appears relatively safe in terms of liver graft function in long-term liver-transplanted patients. However, clinicians must bear in mind the potential risk of rejection and graft loss, and should be very cautious in the management of such ,difficult-to-treat patients'. [source] Are We Ready to Give Up on Calcineurin Inhibitors?AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2006H.-U. Meier-Kriesche No abstract is available for this article. [source] Combined Therapy with Atorvastatin and Calcineurin Inhibitors: No Interactions with TacrolimusAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2005W. P. D. Lemahieu Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4 + PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors. [source] Periorbital dermatitis: Causes, differential diagnoses and therapyJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 3 2010Alexandra Feser Summary Periorbital dermatitis is common and frequently difficult to treat. Patients with periorbital dermatitis often suffer severely because their disease is in such a visible location. Because of the variety of clinical appearance, the differential diagnostic considerations are often difficult. We examined the causes of periorbital dermatitis and compared the data of 88 patients from the Department of Dermatology, University Hospital Erlangen to those of the German IVDK (Information Network of the Departments of Dermatology). Between 1999 and 2004, predominant causes of periorbital dermatitis were allergic contact dermatitis (Erlangen 44 %, IVDK 32 %), atopic eczema (Erlangen 25 %, IVDK 14 %), airborne contact dermatitis (Erlangen 10 %, IVDK 2 %) and irritant contact dermatitis (Erlangen 9 %, IVDK 8 %). Less frequent causes for secondary eczematous periocular skin lesions were periorbital rosacea, allergic conjunctivitis or psoriasis vulgaris. Female gender, atopic skin diathesis and age of 40 years and older were identified as risk factors for periocular dermatitis. Common elicitors of periorbital allergic contact dermatitis were leave-on cosmetic products (face cream, eye shadow) and eye drops with the usual allergens being fragrances, preservatives and drugs. Exact identification of relevant contact allergens and allergen elimination are essential for successful treatment. Calcineurin inhibitors are the first-line therapy for facial atopic eczema. They may be also effective in periocular eczematous lesions of other origins although they are not approved for such use. [source] Calcineurin inhibitors in the treatment of cutaneous infantile haemangiomasJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 5 2010E Lazaridou No abstract is available for this article. [source] Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: A prospective, randomized, multicenter trialLIVER TRANSPLANTATION, Issue 10 2009Paolo De Simone Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 ± 10.2 mL/minute; controls, 2.3 ± 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation. Liver Transpl 15:1262,1269, 2009. © 2009 AASLD. [source] Calcineurin inhibitors in renal transplantation: is tacrolimus a superior agent?NEPHROLOGY, Issue 2002Yves Vanrenterghem [source] Long-term glomerular filtration rate following pediatric liver transplantionPEDIATRIC TRANSPLANTATION, Issue 5 2005Silke Wiesmayr Abstract:, In adult patients a significant proportion of chronic renal failure after liver transplantation (LTX) has been described. This was attributed mainly to nephrotoxicity caused by Calcineurin inhibitors (CNI). If these results are transferable to pediatric patients was the aim of this study. Forty-five pediatric patients with a LTX performed between 1988 and 2003 were evaluated. Glomerular filtration rate was calculated using the Schwartz formula (calculated GFR (cGFR) (mL/min/1.73 m2) = k× height (cm)/serum creatinine (mg/dL)). Median age at LTX was 4 yr (range 0.3,18.1). Pretransplant median cGFR was significantly elevated with 157.5 mL/min/1.73 m2. Within the first 3 months after LTX median cGFR normalized to a median value of 102.7 (p < 0.05 vs. pretransplant cGFR). During long-term follow-up median cGFR remained stable with calculated values of 108.0 two years and 112.6 five years after transplantation. Using a linear and an exponential one compartment mathematical modeling of renal function the calculated GFR was stable even for very long observation times (n > 10 yr). Liver insufficiency prior to transplantation was associated with glomerular hyperfiltration. After successful liver transplantation cGFR normalized within the first 3 month and, in contrast to the reported GFR impairment in adult liver transplant recipients, remained stable, even in long-term follow-up. [source] RGS4 Controls Renal Blood Flow and Inhibits Cyclosporine-Mediated NephrotoxicityAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010A. Siedlecki Calcineurin inhibitors (CNI) are powerful immunomodulatory agents that produce marked renal dysfunction due in part to endothelin-1-mediated reductions in renal blood flow. Ligand-stimulated Gq protein signaling promotes the contraction of smooth muscle cells via phospholipase C,-mediated stimulation of cytosolic calcium release. RGS4 is a GTPase activating protein that promotes the deactivation of Gq and Gi family members. To investigate the role of G protein-mediated signaling in the pathogenesis of CNI-mediated renal injury, we used mice deficient for RGS4 (rgs4,/,). Compared to congenic wild type control animals, rgs4,/, mice were intolerant of the CNI, cyclosporine (CyA), rapidly developing fatal renal failure. Rgs4,/, mice exhibited markedly reduced renal blood flow after CyA treatment when compared to congenic wild type control mice as measured by magnetic resonance imaging (MRI). Hypoperfusion was reversed by coadministration of CyA with the endothelin antagonist, bosentan. The MAPK/ERK pathway was activated by cyclosporine administration and was inhibited by cotreatment with bosentan. These results show that endothelin-1-mediated Gq protein signaling plays a key role in the pathogenesis of vasoconstrictive renal injury and that RGS4 antagonizes the deleterious effects of excess endothelin receptor activation in the kidney. [source] Azathioprine in Liver Transplantation: A Reevaluation of Its Use and a Comparison with Mycophenolate MofetilAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009G. Germani Calcineurin inhibitors (CNIs) combined with steroids with or without azathioprine (AZA), have been a standard immunosuppression regimen after liver transplantation (LT). Since 2000 many centers have substituted AZA by mycophenolate mofetil (MMF). However, in LT the superiority of MMF over AZA is not clearly demonstrated. Therefore, we questioned the benefit of MMF versus AZA in LT with regard to rejection, renal dysfunction and hepatitis C virus (HCV) recurrence and survival. Using a literature search, relevant randomized controlled trials (RCT) and cohort studies were identified: two RCTs compared MMF to AZA only for acute rejection. Treated rejection was less with MMF in only one RCT (38.5% vs. 47.7%; p = 0.025), with no difference in patient and graft survival. No RCTs compared MMF and AZA in patients with CNI-related chronic renal dysfunction. Among two studies evaluating MMF, with substitution of AZA, one was stopped due to severe rejection. Recurrent HCV was less severe in 5/9 studies with AZA compared with 2/17 using MMF, six of which documented worse recurrence. Published data in LT show little, if any, clinical benefit of MMF versus AZA. RCTs should reevaluate AZA in LT. Evaluation of HCV replication and recurrence will be particularly important as AZA may have advantages over MMF. [source] Calcineurin inhibitors for the treatment of skin disease: how do they work?CLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2005P. J. Hampton No abstract is available for this article. [source] Calcineurin inhibitor effects on glucose metabolism and endothelial function following renal transplantationCLINICAL TRANSPLANTATION, Issue 4 2009Anders Åsberg Abstract:,Background:, Calcineurin inhibitors (CNI) are involved in the development of post-transplant diabetes mellitus (PTDM). Changes in insulin secretion and sensitivity contribute to the development of PTDM and are associated with endothelial function. Methods:, In a pre-defined substudy of a previously published randomized trial in renal transplant recipients we compared the effect of CNI treatment (n = 23) with complete CNI-avoidance (n = 21) on insulin secretion and sensitivity (oral glucose tolerance test) as well as endothelial function (laser Doppler flowmetry), 10 wk and 12 months following transplantation. Results:, Insulin sensitivity differed 10 wk post-transplant and was significantly better after 12 months in patients never treated with CNI drugs [0.091 (0.050) vs. 0.083 (0.036) ,mol/kg/min/pmol/L, p = 0.043]. Insulin secretion tended to be higher in CNI treated patients at both time points (p = 0.068). Endothelial function was not significantly different at week 10 [540 (205) vs. 227 (565) arbitary units × minutes, p = 0.35] or month 12 [510 (620) vs. 243 (242), p = 0.33]. Conclusions:, Findings in the present study indicate that long-term CNI treatment negatively affects glucose metabolism and this may contribute to the increased risk for premature cardiovascular disease in CNI treated renal transplant recipients. Further studies to elucidate this hypothesis are, however, needed. [source] Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicityCLINICAL TRANSPLANTATION, Issue 1 2008Stuart M Flechner Abstract:, Background:, The calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. However, the CNIs have a significant adverse impact on renal function and cardiovascular disease, and extended long-term graft survival has not been achieved. The recognition of these effects sparked interest in CNI-sparing strategies. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We sought to review the impact of CNI-sparing strategies in kidney, liver, and heart transplantation. Materials and methods:, A PubMed search 1966 to August 2006 was conducted to identify relevant research articles, and the references of these articles as well as the authors' personal files were reviewed. Results:, Calcineurin inhibitor minimization using mycophenolate mofetil or sirolimus may be associated with a modest increase in creatinine clearance (CrCl) and a decrease in serum creatinine (SCr) in the short term. Despite improvement in CrCl or SCr, CNI nephrotoxicity and chronic allograft nephrotoxicity are progressive over time when CNI exposure is maintained. In kidney transplantation, the tubulo-interstitial and glomerular damage are irreversible. Mycophenolate mofetil may improve renal outcomes during CNI minimization more than sirolimus, and antibody induction may be effective to limit CNI exposure, but longer-term follow-up data are required. Use of sirolimus with mycophenolate mofetil or azathioprine to avoid CNI exposure de novo has improved glomerular filtration rate for at least two yr in most studies in kidney transplantation; however, experience is limited in liver and heart transplantation, and reports of delayed graft function and wound healing with sirolimus may have dampened enthusiasm for de novo use. Late CNI withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. Early CNI withdrawal, prior to significant graft damage, has generally improved CrCl and markers of fibrosis and decreased chronic allograft lesions, a finding also observed with sirolimus in most CNI avoidance studies. Successful withdrawal appears to be more effective than CNI minimization. Conclusions:, Calcineurin inhibitors are associated with significant nephrotoxicity and chronic kidney damage. Minimization is associated with a modest increase in renal function, but persistent damage is observed on biopsies as long as the CNIs are continued. Avoidance is hampered by lack of experience and possible sirolimus-induced side effects. CNI withdrawal may be the best option by delivering CNIs during the early period of immunologic graft injury and then converting them to less nephrotoxic agents before significant renal damage occurs. [source] Pleiotropic phenotypes caused by an opal nonsense mutation in an essential gene encoding HMG-CoA reductase in fission yeastGENES TO CELLS, Issue 6 2009Yue Fang Schizosaccharomyces pombe genome contains an essential gene hmg1+ encoding the sterol biosynthetic enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Here, we isolated an allele of the hmg1+ gene, hmg1-1/its12, as a mutant that showed sensitivities to high temperature and to FK506, a calcineurin inhibitor. The hmg1-1 allele contained an opal nonsense mutation in its N-terminal transmembrane domain, yet in spite of the mutation a full-length protein was produced, suggesting a read-through termination codon. Consistently, overexpression of the hmg1-1 mutant gene suppressed the mutant phenotypes. The hmg1-1 mutant showed hypersensitivity to pravastatin, an HMGR inhibitor, suggesting a defective HMGR activity. The mutant treated with FK506 caused dramatic morphological changes and showed defects in cell wall integrity, as well as displayed synthetic growth phenotypes with the mutant alleles of genes involved in cytokinesis and cell wall integrity. The mutant exhibited different phenotypes from those of the disruption mutants of ergosterol biosynthesis genes, and it showed normal filipin staining as well as showed normal subcellular localization of small GTPases. These data suggest that the pleiotropic phenotypes reflect the integrated effects of the reduced availability of ergosterol and various intermediates of the mevalonate pathway. [source] Calcium/calcineurin signaling in primary cortical astrocyte cultures: Rcan1-4 and cyclooxygenase-2 as NFAT target genesGLIA, Issue 7 2008Andrea Canellada Abstract The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway mediates important cell responses to calcium, but its activity and function in astrocytes have remained unclear. We show that primary cortical astrocyte cultures express the regulatory and catalytic subunits of the phosphatase calcineurin as well as the calcium-regulated NFAT family members (NFATc1, c2, c3, and c4). NFATs are activated by calcium-mobilizing agents in astrocytes, and this activation is blocked by the calcineurin inhibitor cyclosporine A. Microarray screening identified cyclooxygenase-2 (Cox-2), which is implicated in brain injury, and Rcan 1-4, an endogenous calcineurin inhibitor, as genes up-regulated by calcineurin-dependent calcium signals in astrocytes. Mobilization of intracellular calcium with ionophore potently augments the promoter activity and mRNA and protein expression of Rcan 1-4 and Cox-2 induced by combined treatment with phorbol esters. Moreover, Rcan 1-4 expression is efficiently induced by calcium mobilization alone. For both the genes, the calcium signal component is dependent on calcineurin and is replicated by exogenous expression of a constitutively active NFAT, strongly suggesting that the calcium-induced gene activation is mediated by NFATs. Finally, we report that calcineurin-dependent expression of Cox-2 and Rcan 1-4 is induced by physiological calcium mobilizing agents, such as thrombin, agonists of purinergic and glutamate receptors, and L-type voltage-gated calcium channels. These findings provide insights into calcium-initiated gene transcription in astrocytes, and have implications for the regulation of calcium responses in astrocytes. © 2008 Wiley-Liss, Inc. [source] Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells,HEPATOLOGY, Issue 2 2006Yao-Ming Wu Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression. It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing long-term survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy. (HEPATOLOGY 2006;44:410,419.) [source] Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor-AT and Ca2+IMMUNOLOGY, Issue 1 2003Mee H. Lee Summary Bisphenol A (BPA) and p -nonylphenol (NP) are representative endocrine disruptors (EDs) that may have adverse effects on human health. The influence of these compounds on allergic immune responses remains unclear. In this study, we have examined the effects of BPA and NP on production of interleukin-4 (IL-4), a pro-inflammatory cytokine closely associated with allergic immune responses. Both BPA and NP significantly enhanced IL-4 production in keyhole limpet haemocyanin (KLH)-primed CD4+ T cells in a concentration-dependent manner. Treatment with BPA or NP in vivo resulted in significant increase of IL-4 production in CD4+ T cells and of antigen-specific immunoglobulin E (IgE) levels in the sera of KLH-primed mice. Furthermore, BPA and NP enhanced the activation of IL-4 gene promoter in EL4 T cells transiently transfected with IL-4 promoter/reporter constructs, and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for nuclear factor (NF)-AT. Activation of T lymphocytes by phorbol 12-myristate 13-acetate/ionomycin resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of BPA or NP, as demonstrated by the electrophoretic mobility shift assay, indicating that the transcription factor NF-AT was involved in the enhancing effect of BPA and NP on IL-4 production. The enhancement of IL-4 production by BPA or NP was significantly reduced by nitrendipine, a blocker of Ca2+ influx, and by FK506, a calcineurin inhibitor. FK506 inhibited the NF-AT,DNA binding activity and IL-4 gene promoter activity enhanced by BPA or NP. These results represent the first report describing possible enhancement of allergic response by EDs through increasing IL-4 production in CD4+ T cells and antigen-specific IgE levels in the sera via the stimulation of Ca2+/calcineurin-dependent NF-AT activation. [source] Pimecrolimus in dermatology: atopic dermatitis and beyondINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 8 2005Paolo Gisondi Summary Pimecrolimus is a calcineurin inhibitor developed for the topical therapy of inflammatory skin diseases, particularly atopic dermatitis (AD). Pimecrolimus selectively targets T cells and mast cells. Pimecrolimus inhibits T-cell proliferation, as well as production and release of interleukin-2 (IL-2), IL-4, interferon-, and tumour necrosis factor-,. Moreover, pimecrolimus inhibits mast cell degranulation. In contrast to tacrolimus, pimecrolimus has no effects on the differentiation, maturation and functions of dendritic cells. In contrast to corticosteroids, pimecrolimus does not affect endothelial cells and fibroblasts and does not induce skin atrophy. Given the low capacity of pimecrolimus to permeate through the skin, it has a very low risk of systemic exposure and subsequent systemic side-effects. In different randomised controlled trials, topical pimecrolimus as cream 1% (Elidel®) has been shown to be effective, well tolerated and safe in both adults and children with mild to moderate AD. In addition, pimecrolimus has been successfully used in inflammatory skin diseases other than AD, including seborrheic dermatitis, intertriginous psoriasis, lichen planus and cutaneous lupus erythematosus. [source] Renal function and cardiovascular risk profile after conversion from ciclosporin to tacrolimus: prospective study in 80 liver transplant recipientsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2009S. BECKEBAUM Aliment Pharmacol Ther,30, 834,842 Summary Background, Increased risk of cardiovascular and cerebrovascular disease in liver transplant recipients results in particular from the side effects of calcineurin inhibitor-based immunosuppressive therapy. Several studies have demonstrated a more favourable outcome for patients receiving tacrolimus (TAC) as compared with ciclosporin (CS). Aim, To investigate the effects of conversion from CS to TAC on cardiovascular risk factors and renal function in liver transplant recipients. Methods, In a prospective study, all except two patients had chronic kidney disease stages 2,4 (n = 80), according to estimated glomerular filtration rate using the abbreviated Modification of Diet in Renal Disease equation. Results, Conversion was accompanied with a mean decrease of total cholesterol from 194.6 ± 54.0 mg/dL to 175.8 ± 44.2 mg/dL (P < 0.001), low density lipoprotein cholesterol from 106.7 ± 39.2 mg/dL to 90.9 ± 28.6 mg/dL (P < 0.001) and mean arterial blood pressure values from 102.2 ± 13.2 mm Hg to 95.9 ± 11.7 mm Hg (P < 0.001). Renal function remained stable. No cases of de novo diabetes mellitus were identified. The Framingham risk score was significantly reduced from 5.2 ± 4.4 at baseline to 4.4 ± 5.3 after 12 months (P = 0.006). Conclusions, Conversion from CS to TAC has been shown to improve the cardiovascular risk profile and may retard further decline of renal function after liver transplantation. [source] A comparison of sirolimus vs. calcineurin inhibitor-based immunosuppressive therapies in liver transplantationALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2006H. ZAGHLA Summary Background, Sirolimus is a potent immunosuppressive agent whose role in liver transplantation has not been well-described. Aim, To evaluate the efficacy and side-effects of sirolimus-based immunosuppression in liver transplant patients. Methods, Retrospective analysis of 185 patients who underwent orthotopic liver transplantation. Patients were divided into three groups: group SA, sirolimus alone (n = 28); group SC, sirolimus with calcineurin inhibitors (n =56) and group CNI, calcineurin inhibitors without sirolimus (n = 101). Results, One-year patient and graft survival rates were 86.5% and 82.1% in group SA, 94.6% and 92.9% in group SC, and 83.2% and 75.2% in group CNI (P = N.S.). The rates of acute cellular rejection at 12 months were comparable among the three groups. At the time of transplantation, serum creatinine levels were significantly higher in group SA, but mean creatinine among the three groups at 1 month was similar. More patients in group SA required dialysis before orthotopic liver transplantation (group SA, 25%; group SC, 9%; group CNI, 5%; P = 0.008), but at 1 year, post-orthotopic liver transplantation dialysis rates were similar. Conclusions, Sirolimus given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies to evaluate the efficacy and side-effect profile of sirolimus in liver transplant patients are warranted. [source] Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: A prospective, randomized, multicenter trialLIVER TRANSPLANTATION, Issue 10 2009Paolo De Simone Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 ± 10.2 mL/minute; controls, 2.3 ± 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation. Liver Transpl 15:1262,1269, 2009. © 2009 AASLD. [source] Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation,LIVER TRANSPLANTATION, Issue 12 2006Georges-Philippe Pageaux The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 ,mol/L and <300 ,mol/L. Patients were randomized in 2 groups. Study group: combination of MMF (2 to 3 g/day) and reduced dose of CNI ,50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 ± 24.2 ,mol/L at day 0 to 143.4 ± 19 ,mol/L at month 12 and a significant increase in creatinine clearance, from 42.6 ± 10.9 mL/min to 51.7 ± 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 ± 23.4 ,mol/L at day 0 to 181.6 ± 63 ,mol/L at month 12, and in creatinine clearance, from 42.8 ± 12.8 mL/min to 44.8 ± 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects. Liver Transpl 12:1755,1760, 2006. © 2006 AASLD. [source] Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C,LIVER TRANSPLANTATION, Issue 7 2006Marina Berenguer There are unresolved issues regarding sustained virological response (SVR), tolerance and risk of rejection following antiviral therapy in liver transplantation (LT). The aim of our study was to determine efficacy, rejection risk and factors associated with SVR. HCV-infected LT patients with at least 6 months of follow-up following end-of-therapy (EOT) received combination therapy of ribavirin (Rbvr) + standard (n=31)/pegIFN (n=36) between 1999 and 2004 (95% genotype 1). An EOT and SVR was obtained in 46% and 33%, respectively. Type of antiviral therapy, use of erythropoietin, compliance, and early virologic response (EVR) were predictive of SVR, but only the latter remained in the multivariate analysis. Premature discontinuation, not impacted by the use of erythropoietin or GCSF, occurred in 40% patients. None of the variables predicted rejection (acute n=2, chronic n=4). A SVR occurred in 3/4 patients with chronic rejection. In conclusion, the efficacy of pegIFN-Rbvr is similar to the non-transplant population. An EVR at 3 months is useful to predict lack of response. The type of calcineurin inhibitor and history of prior non-response to IFN before LT do not influence the outcome of therapy. Severe rejection may lead to graft loss, a complication difficult to predict. Liver Transpl 12:1067,1076, 2006. © 2006 AASLD. [source] The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin functionMOLECULAR MICROBIOLOGY, Issue 5 2003Peter R. Kraus Summary Cell wall integrity is crucial for fungal growth, development and stress survival. In the model yeast Saccharomyces cerevisiae, the cell integrity Mpk1/Slt2 MAP kinase and calcineurin pathways monitor cell wall integrity and promote cell wall remodelling under stress conditions. We have identified the Cryptococcus neoformans homologue of the S. cerevisiae Mpk1/Slt2 MAP kinase and have characterized its role in the maintenance of cell integrity in response to elevated growth temperature and in the presence of cell wall synthesis inhibitors. C. neoformans Mpk1 is required for growth at 37°C in vitro, and this growth defect is suppressed by osmotic stabilization. C. neoformans mutants lacking Mpk1 are attenuated for virulence in the mouse model of cryptococcosis. Phosphorylation of Mpk1 is induced in response to perturbations of cell wall biosynthesis by the antifungal drugs nikkomycin Z (a chitin synthase inhibitor), caspofungin (a ,-1,3-glucan synthase inhibitor), or FK506 (a calcineurin inhibitor), and mutants lacking Mpk1 display enhanced sensitivity to nikkomycin Z and caspofungin. Lastly, we show that calcineurin and Mpk1 play complementing roles in regulating cell integrity in C. neoformans. Our studies demonstrate that pharmacological inhibition of the cell integrity pathway would enhance the activity of antifungal drugs that target the cell wall. [source] Association of parental pretransplant psychosocial assessment with post-transplant morbidity in pediatric heart transplant recipients,PEDIATRIC TRANSPLANTATION, Issue 5 2006David Stone Abstract:, Because parents assume the primary responsibility for providing ambulatory post-transplant care to pediatric patients, pretransplant psychosocial evaluation in these recipients is usually focused on parents rather than on patients themselves. We sought to determine whether pretransplant parental psychosocial evaluation predicts post-transplant medical outcome at current levels of psychosocial support. We compared relative risk (RR) of rejection and hospitalizations (days of all-cause hospitalization) following initial discharge in patients in ,risk' and ,control' groups defined by their pretransplant parental psychosocial evaluation. We also compared the two groups of patients for the proportion of all outpatient trough cyclosporine A (CSA) or tacrolimus (FK) levels that were <50% of the target level (defined as the mid-therapeutic range level). There were seven patients in the ,risk' group with a median age 0.25 yr (range 0.19,14.7 yr) and total follow up 20.5 patient-yr. There were 21 patients in the ,control' groups with a median age of 2.1 yr (range 0.05,16.2 yr) and total follow up of 71.3 patient-yr. There was no significant difference between the groups in rejection-risk or days of all-cause hospitalization early after transplant (first six months). During the late period (after the first six months), there were 11 rejection episodes in the ,risk' group over 17.4 patient-yr and four rejection episodes in control group over 61.8 patient-yr of follow up. After adjustment for age and race, patients in the ,risk' category had a RR of 3.4 for developing a rejection episode (p = 0.06) and 3.1 for being inpatient (p < 0.001) during the late period. Patients in the risk group were 2.9 times more likely to have subtherapeutic trough levels (<50% target level) of calcineurin inhibitor (CSA or FK) during both early and late periods (p < 0.01 for both periods) after adjustment for patient age and race. We conclude that pretransplant parental psychosocial risk assessment is associated with post-transplant morbidity in children after cardiac transplantation. These patients may benefit from closer outpatient monitoring and a higher level of psychosocial support. [source] Short-term efficacy of tacrolimus ointment and impact on quality of lifePEDIATRICS INTERNATIONAL, Issue 3 2009Yasuto Kondo Abstract Background:, Topical calcineurin inhibitor (TCI) was reported to be an effective therapeutic agent for patients with atopic dermatitis (AD), for not only improving clinical findings but also for reducing pruritus. Recently in Japan tacrolimus ointment (0.03%) as a TCI was approved for use in children aged ,2 years. There have been no reports, however, on the impact of TCI on quality of life (QOL) in pediatric AD in Japan. The purpose of the present study was therefore to evaluate the efficacy of tacrolimus ointment (0.03%) in the short-term and the impact on patient QOL. Methods:, A total of 30 pediatric patients with AD, whose skin problems were not sufficiently controlled by mid-high potency topical glucocorticosteroids, were enrolled. Efficacy was assessed on score of cutaneous findings, pruritus, sleeping disorder, and QOL. Results:, Three patients discontinued because of skin burning (n = 1), generalized herpes infection (n = 1), and feeling of lack of efficacy (n = 1), leaving a final total of 27 patients who were evaluated. Significant improvements in clinical findings, pruritus, and sleeplessness were observed within 1 week of treatment and consequently each QOL category was also improved. These improvements continued for the duration of the study. Conclusions:, Tacrolimus ointment therapy is rapidly effective for not only clinical symptoms (cutaneous findings, pruritus and sleeplessness) but also in QOL of AD pediatric patients aged 2 years. [source] Clinical efficacies of topical agents for the treatment of seborrheic dermatitis of the scalp: A comparative studyTHE JOURNAL OF DERMATOLOGY, Issue 3 2009Hyoseung SHIN ABSTRACT Previous studies have shown that topical steroid and shampoo containing zinc pyrithione provide clinical benefits for treatment of scalp seborrheic dermatitis. But the clinical efficacy of topical tacrolimus, a newly developed calcineurin inhibitor on seborrheic dermatitis, is not well investigated yet. We wanted to compare the clinical efficacy of topical tacrolimus with that of conventional treatment (zinc pyrithione shampoo and topical betamethasone) for treatment of seborrheic dermatitis of the scalp. Patients with seborrheic dermatitis of the scalp were randomly allocated to receive topical betamethasone, topical tacrolimus or zinc pyrithione shampoo. Some patients were instructed to continue the treatments for 8 weeks and the others to discontinue the treatments at week 4. We evaluated the efficacy using a clinical severity score, dandruff score and sebum secretion at baseline, week 4 and week 8. All treatment groups showed significant improvements in clinical assessment after 4 weeks. While the patients treated by zinc pyrithione improved continuously even after cessation of the treatment, the patients treated by betamethasone lotion or tacrolimus ointment were aggravated clinically. Topical tacrolimus was as effective as topical betamethasone, and showed more prolonged remission than topical betamethasone. To treat seborrheic dermatitis of the scalp, we think that the combination therapy of topical steroid or topical tacrolimus, and zinc pyrithione is recommended. [source] | ||||||||||||||||||||||||||||