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Cyclosporin
Kinds of Cyclosporin Terms modified by Cyclosporin Selected AbstractsSevere adenovirus bronchiolitis in childrenACTA PAEDIATRICA, Issue 11 2000MN Pichler ABSTRACT. Severe adenoviral infections such as the necrotizing adenovirus bronchiolitis occur sporadically in infants. Ascertaining the etiologic role of adenovirus in cases of lung disease can pose a diagnostic problem. We present two cases of severe bronchiolitis in previously healthy children in which adenovirus could be shown to be the causing agent. Both children received immunosuppressive therapy with steroids and Cyclosporin for 3 mo and a course of intravenous Ribavirin for 10 d. The results were conflicting: despite therapy Patient 1 died due to respiratory failure, Patient 2 improved notably. Conclusions: Adenovirus can cause severe bronchiolitis in previously healthy children. Diagnosis may be difficult to achieve. The role of antiviral therapy in the treatment of adenoviral infections remains to be cleared. ,Adenovirus, bronchiolitis [source] Cyclosporin A can achieve immune tolerance in a patient with severe haemophilia B and refractory inhibitorsHAEMOPHILIA, Issue 1 2007D. C. A. CROSS Summary., Immune tolerance induction (ITI) is described in a patient with severe haemophilia B complicated by the presence of an inhibitor. A number of ITI regimes were attempted without success and the patient suffered from frequent relapses and bleeding episodes. Successful ITI was achieved with the additional use of cyclosporin A. The patient developed nephrotic syndrome although had a negative Bethesda titre at this time. When cyclosporin A therapy was ceased, the inhibitor titre rose and the patient suffered again from bleeding episodes. Cyclosporin A was reintroduced at a lower dose. The patient has now received cyclosporin A for 10 years, during which time he has relapsed three times for short periods (2 weeks). He is also on prophylaxis with factor IX three times a week with preinfusion levels >1% and without bleeding. [source] Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytesHEPATOLOGY, Issue 5 2003Koichi Watashi Persistent infection of hepatitis C virus (HCV) is a major cause of liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Searching for a substance with anti-HCV potential, we examined the effects of a variety of compounds on HCV replication using a HCV subgenomic replicon cell culture system. Consequently, the immunosuppressant cyclosporin A (CsA) was found to have a suppressive effect on the HCV replicon RNA level and HCV protein expression in these cells. CsA also inhibited multiplication of the HCV genome in a cultured human hepatocyte cell line infected with HCV using HCV-positive plasma. This anti-HCV activity of CsA appeared to be independent of its immunosuppressive function. In conclusion, our results suggest that CsA may represent a new approach for the development of anti-HCV therapy. [source] Effect of tacrolimus in a patient with pure red-cell aplasiaINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 1 2005S. YOSHIDA Summary A 78-year-old woman has suffered from pure red-cell aplasia (PRCA) associated with generalized myasthenia gravis and thymoma. Cyclosporin A (CyA) with corticosteroid increased numbers of erythroid cells in her bone marrow cells but she required monthly blood transfusions. Administration of tacrolimus as a substitution for CyA inhibited progression of anemia without the need for further blood transfusion. No serious side effects were observed. This case demonstrates that tacrolimus is another option of treatment for PRCA in patients who fail to respond to CyA. [source] Mycelium cultivation, chemical composition and antitumour activity of a Tolypocladium sp. fungus isolated from wild Cordyceps sinensisJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2006P.H. Leung Abstract Aims:, To examine and illustrate the morphological characteristics and growth kinetics of Cs-HK1, a Tolypocladium fungus, isolated from wild Cordyceps sinensis in solid and liquid cultures, and the major chemical constituents and antitumour effects of Cs-HK1 mycelium. Methods and Results:, The Cs-HK1 fungus was isolated from the fruiting body of a wild C. sinensis and identified as a Tolypocladium sp. fungus. It grew rapidly at 22,25°C on a liquid medium containing glucose, yeast extract, peptone and major inorganic salts, with a specific growth rate of 1·1 day,1, reaching a cell density of 23·0 g dw l,1 in 7,9 days. Exopolysaccharides accumulated in the liquid culture to about 0·3 g l,1 glucose equivalent. In comparison with natural C. sinensis, the fungal mycelium had similar contents of protein (11·7,,g) and carbohydrate (654·6,,g) but much higher contents of polysaccharide (244·2 mg vs 129·5 mg), adenosine (1116·8,,g vs 264·6 ,g) and cordycepin (65·7 ,g vs 20·8 ,g) (per gram dry weight). Cyclosporin A, an antibiotic commonly produced by Tolypocladium sp., was also detected from the mycelium extract. The hot water extract of mycelium showed low cytotoxic effect on B16 melanoma cells in culture (about 25% inhibition) but significant antitumour effect in animal tests, causing 50% inhibition of B16 cell-induced tumour growth in mice. Conclusions:, The Tolypocladium sp. fungus, Cs-HK1, can be easily cultivated by liquid fermentation. The mycelium biomass contained the major bioactive compounds of C. sinensis, and the mycelium extract had significant antitumour activity. Significance and Impact of the Study:, The Cs-HK1 fungus may be a new and promising medicinal fungus and an effective and economical substitute of the wild C. sinensis for health care. [source] Hepatotoxic effect of cyclosporin A in the mitochondrial respiratory chainJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2007Lilia Cristina De la Cruz Rodríguez Abstract Cyclosporin A (CyA), a potent immunosuppressant, was used to determine the hepatotoxic effect in long-term treatments. Male Wistar rats were used in these experiments. They were given CyA chronically at doses used in patients for 120 days, and at doses of 5, 10, 15 and 20 mg kg,1 day,1. These doses amount to CyA values in blood of 200 ± 24, 314 ± 40, 445 ± 33 and 598 ± 53 ng ml,1, respectively. A significant increase in glutamate dehydrogenase (GLDH) was found in the groups treated with 15 and 20 mg kg,1 day,1, which would point to mitochondria as the potential target of the toxic action of CyA. The mitochondrial respiratory chain of rat livers was studied in enzyme complexes I and II. Enzyme complex I was determined by spectrophotometry at 340 nm using NADH oxidase with the respirable substrate 10 mm NADH; enzyme complex II was determined by monitoring succinate dehydrogenase by oxymetry using the respirable substrate 10 mm succinate. The results show the inhibition of NADH oxidase in the groups treated with 10, 15 and 20 mg kg,1 day,1, an effect dependent both on time and on CyA concentration. Enzyme complex II showed a decrease in oxygen consumption. These findings were confirmed by histological studies (hematoxylin-eosin technique). Conclusions: Long-term treatment with CyA at doses of 15 and 20 mg kg,1 day,1, amounting to concentrations in blood of 445 ± 33 and 598 ± 53 ng ml,1, causes alterations in the mitochondria, revealed by the increase in serum GLDH and by the functional alteration of enzyme complexes I and II of the mitochondrial respiratory chain. Copyright © 2007 John Wiley & Sons, Ltd. [source] Relationship between IL-1A polymorphisms and gingival overgrowth in renal transplant recipients receiving Cyclosporin AJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 11 2006Nagihan Bostanci Abstract Aim: Levels of interleukin-1, (IL-1,) are elevated in periodontal inflammation. IL-1A gene polymorphisms are associated with inflammatory diseases. This study aimed to investigate IL-1A gene polymorphism in Cyclosporin A (CsA)-treated renal transplant patients and investigate the association between this polymorphism and gingival crevicular fluid (GCF) levels of several cytokines. Materials and Methods: Fifty-one renal transplant patients on CsA treatment (25 with and 26 without gingival overgrowth) and 29 healthy controls were recruited for the study. Demographic, pharmacological and periodontal parameters were recorded and gingival overgrowth was assessed. Results: Multiple regression analysis showed that genotype was significantly associated with gingival overgrowth (p=0.02). Carriage of the IL-1A (,889) T allele was strongly protective [95% confidence interval (CI): 0.046,0.77], although not significantly associated with IL-1, protein levels in GCF. IL-1,, IL-1, and IL-8, but not IL-6, were detected in GCF of CsA-treated patients, but none of them was significantly associated with gingival overgrowth. Conclusions: This study is the first to associate a gene polymorphism as a risk factor for CsA-induced gingival overgrowth in renal transplant patients, demonstrating that IL-1A polymorphism might alter individual susceptibility to CsA. However, there was no association between GCF cytokine levels and the presence of gingival overgrowth or patient IL-1A genotype. [source] Nitric oxide regulates cell survival in purified cultures of avian retinal neurons: involvement of multiple transduction pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 2 2007T. A. Mejía-García Abstract Nitric oxide (NO) is an important signaling molecule in the CNS, regulating neuronal survival, proliferation and differentiation. Here, we explored the mechanism by which NO, produced from the NO donor S -nitroso-acetyl- d - l -penicillamine (SNAP), exerts its neuroprotective effect in purified cultures of chick retinal neurons. Cultures prepared from 8-day-old chick embryo retinas and incubated for 24 h (1 day in culture, C1) were treated or not with SNAP, incubated for a further 72 h (up to 4 days in culture, C4), fixed, and the number of cells estimated, or processed for cell death estimation, by measuring the reduction of the metabolic dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Experimental cultures were run in parallel but were re-fed with fresh medium in the absence or presence of SNAP at culture day 3 (C3), incubated for a further 24 h up to C4, then fixed or processed for the MTT assay. Previous studies showed that the re-feeding procedure promotes extensive cell death. SNAP prevented this death in a concentration- and time-dependent manner through the activation of soluble guanylate cyclase; this protection was significantly reversed by the enzyme inhibitors 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) or LY83583, and mimicked by 8-bromo cyclic guanosine 5,-phosphate (8Br-cGMP) (GMP) or 3-(5,-hydroxymethyl-2,-furyl)-1-benzyl indazole (YC-1), guanylate cyclase activators. The effect was blocked by the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). The effect of NO was also suppressed by LY294002, Wortmannin, PD98059, KN93 or H89, indicating the involvement, respectively, of phosphatidylinositol-3 kinase, extracellular-regulated kinases, calmodulin-dependent kinases and protein kinase A signaling pathways. NO also induced a significant increase of neurite outgrowth, indicative of neuronal differentiation, and blocked cell death induced by hydrogen peroxide. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore considered an important mediator of apoptosis and necrosis, as well as boc-aspartyl (OMe) fluoromethylketone (BAF), a caspase inhibitor, also blocked cell death induced by re-feeding the cultures. These findings demonstrate that NO inhibits apoptosis of retinal neurons in a cGMP/protein kinase G (PKG)-dependent way, and strengthens the notion that NO plays an important role during CNS development. [source] Ca2+ -induced permeabilization promotes free radical release from rat brain mitochondria with partially inhibited complex IJOURNAL OF NEUROCHEMISTRY, Issue 3 2005Tatyana V. Votyakova Abstract Mitochondrial complex I dysfunction has been implicated in a number of brain pathologies, putatively owing to an increased rate of reactive oxygen species (ROS) release. However, the mechanisms regulating the ROS burden are poorly understood. In this study we investigated the effect of Ca2+ loads on ROS release from rat brain mitochondria with complex I partially inhibited by rotenone. The addition of 20 nm rotenone to brain mitochondria increased ROS release. Ca2+ (100 µm) alone had no effect on ROS release, but greatly potentiated the effects of rotenone. The effect of Ca2+ was decreased by ruthenium red. Ca2+ -challenged mitochondria lose about 88% of their glutathione and 46% of their cytochrome c under these conditions, although this depends only on Ca2+ loading and not complex I inhibition. ADP in combination with oligomycin decreased the loss of glutathione and cytochrome c and free radical generation. Cyclosporin A alone was ineffective in preventing these effects, but augmented the protection provided by ADP and oligomycin. Non-specific permeabilization of mitochondria with alamethicin also increased the ROS signal, but only when combined with partial inhibition of complex I. These results demonstrate that Ca2+ can greatly increase ROS release by brain mitochondria when complex I is impaired. [source] Cyclosporin A prevents calpain activation despite increased intracellular calcium concentrations, as well as translocation of apoptosis-inducing factor, cytochrome c and caspase-3 activation in neurons exposed to transient hypoglycemiaJOURNAL OF NEUROCHEMISTRY, Issue 6 2003Michel Ferrand-Drake Abstract Blockade of mitochondrial permeability transition protects against hypoglycemic brain damage. To study the mechanisms downstream from mitochondria that may cause neuronal death, we investigated the effects of cyclosporin A on subcellular localization of apoptosis-inducing factor and cytochrome c, activation of the cysteine proteases calpain and caspase-3, as well as its effect on brain extracellular calcium concentrations. Redistribution of cytochrome c occurred at 30 min of iso-electricity, whereas translocation of apoptosis-inducing factor to nuclei occurred at 30 min of recovery following 30 min of iso-electricity. Active caspase-3 and calpain-induced fodrin breakdown products were barely detectable in the dentate gyrus and CA1 region of the hippocampus of rat brain exposed to 30 or 60 min of insulin-induced hypoglycemia. However, 30 min or 3 h after recovery of blood glucose levels, fodrin breakdown products and active caspase-3 markedly increased, concomitant with a twofold increase in caspase-3-like enzymatic activity. When rats were treated with neuroprotective doses of cyclosporin A, but not with FK 506, the redistribution of apoptosis-inducing factor and cytochrome c was reduced and fodrin breakdown products and active caspase-3 immuno-reactivity was diminished whereas the extracellular calcium concentration was unaffected. We conclude that hypoglycemia leads to mitochondrial permeability transition which, upon recovery of energy metabolism, mediates the activation of caspase-3 and calpains, promoting cell death. [source] Interactions of cyclosporines with lipid membranes as studied by solid-state nuclear magnetic resonance spectroscopy and high-sensitivity titration calorimetryJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Uwe Schote Abstract Cyclosporin A (CyA) interacts with lipid membranes. Binding reaction and membrane location of CyA and analogs were examined with 2H-NMR, high-sensitivity isothermal titration calorimetry (ITC), and CD spectroscopy. Effects of CyA and charged analogs on the phosphocholine head group and on the membrane interior were investigated using selectively deuterated phospholipids. Incorporation of cyclosporin generated small disordering of the lipid acyl chains. Binding of CyA and neutral and positively charged analogs to lipid membranes showed endothermic heats of reaction between +,5.9 and +,11.3 kcal/mol, whereas enthalpy of binding was close to zero for the negatively charged derivative. Binding constants of cyclosporines to liposomal membranes were in the range of KP,=,1650,5560 M,,1 depending on the cholesterol content. 2H-NMR provides evidence that CyA is essentially located in the interior of the bilayer membrane. For the charged analogs an additional interaction occurs at the head group level, placing the polar groups of these CyA analogs in the vicinity of the phosphocholine dipoles. The association of CyA and its analogs is accompanied by a positive enthalpy change, which is overcompensated by positive entropy changes. Binding of CyA to lipid membranes thus follows the classical hydrophobic effect, which is in contrast to many other peptide-lipid binding reactions. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91: 856,867, 2002 [source] Cyclosporin A treatment in severe childhood psoriasisJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2006TM Pereira Abstract Though used occasionally, systemic therapies in severe childhood psoriasis have not been systematically investigated. Cyclosporin A (CysA) is effective in adults with severe psoriasis but there are no extensive data regarding the efficacy and safety of its use in childhood psoriasis. In this paper, we describe six children aged between 11 months and 13 years (average: 7.6 years) treated with CysA microemulsion formulation for severe psoriasis, who had been unresponsive to other treatments. The CysA dose ranged from 2 to 4 mg/kg/day, for periods varying from 8 to 105 weeks (mean: 54 weeks). Dose tapering was gradual after lesion improvement and adjusted according to clinical response. Adjuvant therapy with topical steroids, vitamin D3 ointments, coal tar preparations or anthralin was used in all children. Acitretin was used in three patients for short periods. The children were regularly monitored for serum renal and liver function and blood pressure. Improvement of skin lesions was achieved after between 4 and 30 (mean: 12) weeks of treatment, with complete remission in three children. Relapse of lesions occurred in the other children during CysA reduction, but they responded to a dose increase. The treatment was found to be well tolerated and with no significant side-effects. CysA can be used in carefully selected and monitored patients and may represent an alternative tool for severe episodes of psoriasis in children, when other therapies are unsuccessful. [source] Cyclosporin in psoriasis: how?JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 3 2004SR Feldman [source] Hematopoietic and immune recovery after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation in a pediatric populationPEDIATRIC TRANSPLANTATION, Issue 4 2002Yoshihisa Nagatoshi Abstract: To compare the hematopoietic and immune recoveries after allogeneic transplantation with different cell sources, we analyzed the recovery patterns of blood components after allogeneic peripheral blood stem cell transplantation (PBSCT) in comparison with that after allogeneic bone marrow transplantation (BMT) in a pediatric population. Sixteen patients received PBSCT, and 24 received BMT between January, 1995 and March, 2000. The patients had acute lymphoblastic leukemia (ALL; n = 22), acute myelogenous leukemia (AML; n = 8), myelodysplastic syndrome (MDS; n = 3), or other diseases (n = 7). The median ages of patients in the PBSCT and BMT groups were 9 yr and 6 yr, respectively. Cyclosporin A (CsA) plus methotrexate or methylprednisolone was used as a graft-vs.-host disease (GvHD) prophylaxis regimen in the PBSCT group, whereas CsA alone or methotrexate alone was used in the BMT group. Circulating lymphocyte numbers and subpopulations determined by flow cytometric analysis were used as markers of immune recovery. In the PBSCT group, the median number of harvested CD34+ cells was 7.25 (range: 1.3,27.6) × 106/kg of the recipient's body weight, while the median number of harvested nucleated cells was 4.7 (range: 3.7,10.5) × 108/kg. All of the patients were engrafted. Myeloid engraftment occurred sooner after PBSCT than after BMT (median number of days to achieve absolute neutrophil counts (ANC) > 0.5 × 109/L; 11 and 15, respectively; p < 0.0001) and similar results were found for platelet engraftment (median number of days to achieve a platelet count of > 20 × 109/L; 12 and 21, respectively; p = 0.004). On the other hand, after PBSCT the absolute numbers of total circulating lymphocytes and lymphocyte subpopulations were not significantly different from those after BMT. The incidence of acute GvHD after PBSCT was the same as that after BMT, while chronic GvHD developed more frequently after PBSCT than after BMT (p = 0.005). In a pediatric population, the indications for PBSCT and BMT should be based on these findings in addition to regard for the donor's safety. [source] Cyclosporin A monitoring and AUC determination , where do we go?PEDIATRIC TRANSPLANTATION, Issue 3 2002Guido Filler MD First page of article [source] Rapamycin and MPA, But Not CsA, Impair Human NK Cell Cytotoxicity Due to Differential Effects on NK Cell PhenotypeAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010D. N. Eissens Cyclosporin A (CsA), rapamycin (Rapa) and mycophenolic acid (MPA) are frequently used for GVHD prophylaxis and treatment after allogeneic stem cell transplantation (SCT). As NK cells have received great interest for immunotherapeutic applications in SCT, we analyzed the effects of these drugs on human cytokine-stimulated NK cells in vitro. Growth-kinetics of CsA-treated cultures were marginally affected, whereas MPA and Rapa severely prevented the outgrowth of CD56bright NK cells. Single-cell analysis of NK cell receptors using 10-color flow cytometry, revealed that CsA-treated NK cells gained a similar expression profile as cytokine-stimulated control NK cells, mostly representing NKG2A+KIR,NCR+ cells. In contrast, MPA and Rapa inhibited the acquisition of NKG2A and NCR expression and NK cells maintained an overall NKG2A,KIR+NCR+/, phenotype. This was reflected in the cytolytic activity, as MPA- and Rapa-treated NK cells, in contrast to CsA-treated NK cells, lost their cytotoxicity against K562 target cells. Upon target encounter, IFN-, production was not only impaired by MPA and Rapa, but also by CsA. Overall, these results demonstrate that CsA, MPA and Rapa each have distinct effects on NK cell phenotype and function, which may have important implications for NK cell function in vivo after transplantation. [source] Randomized Controlled Trial of Tacrolimus Versus Microemulsified Cyclosporin (TMC) in Liver Transplantation: Poststudy Surveillance to 3 YearsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2007J. G. O'Grady The 1-year results of the tacrolimus versus microemulsified cyclosporin (TMC) study found a benefit with tacrolimus immunosuppression after primary liver transplants in adults with respect to freedom from graft loss and immunological failure. The integrity of the randomization process was preserved for a further 2 years for poststudy surveillance. The data after 3 years confirms the significant difference between tacrolimus and cyclosporin with tacrolimus less likely to meet the composite primary endpoint (log rank p = 0.01; relative risk 0.75; 95% CI 0.60,0.95; p = 0.016). However, freedom from death or retransplantation no longer achieves statistical significance (relative risk 0.79; 95% CI 0.62,1.02; p = 0.065). A total of 62.1% of patients randomized to tacrolimus were alive at 3 years with their original graft and still on their allocated study medication, as compared with only 41.6% in the cyclosporin limb (p < 0.001). No difference was detected between tacrolimus and cyclosporin in hepatitis-C-positive patients with the available data. The TMC study confirms after 3 years of follow-up the benefits of tacrolimus-based immunosuppression over cyclosporin using C0 monitoring. [source] Cyclosporin versus Tacrolimus as Primary Immunosuppressant After Liver Transplantation: A Meta-AnalysisAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2006V. C. McAlister A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73,0.99; graft loss: RR 0.73, 95% CI 0.61,0.86). Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75,0.88) and steroid-resistant rejection (RR 0.54, 95% CI 0.47,0.74) in the first year. Lymphoproliferative disorder or dialysis rates were not different but more de novo diabetes (RR 1.38, 95% CI 1.01,1.86) occurred with tacrolimus. More patients stopped cyclosporin than tacrolimus (RR 0.57, 95% CI 0.49,0.66). Treating 100 recipients with tacrolimus instead of cyclosporin would avoid rejection and steroid-resistant rejection in nine and seven patients respectively, graft loss and death in five and two patients respectively, but four additional patients would develop diabetes after liver transplantation. [source] C4d Deposition and Clearance in Cardiac Transplants Correlates With Alloantibody Levels and Rejection in RatsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5p1 2006K. Minami Antibody-mediated rejection of human cardiac transplants is correlated with C4d deposits and macrophage infiltrates in capillaries of endomyocardial biopsies. We produced an antibody to rat C4d to study C4d deposition and clearance in Lewis rats that were sensitized with a blood transfusion from DA rats 7, 14 or 21 days before cardiac transplantation. Cyclosporin A (CsA) immunosuppression was initiated after transplantation at a dose that inhibited graft rejection, antibody production and C4d deposition in unsensitized recipients. Blood transfusion elicited high levels of circulating IgG alloantibodies, predominantly of the complement-activating IgG2b subclass, that peaked 14 days after transplantation. At this time, macrophages accumulated in capillaries, and C4d deposits were diffuse and intense on arteries, capillaries and veins. Grafts that survived 90 days in sensitized recipients still had deposits of C4d that were associated with increased interstitial fibrosis and vasculopathy in arteries. Clearance of C4d was determined by retransplanting DA cardiac allografts from Lewis recipients back to DA recipients. C4d deposits were decreased to minimal levels within 5 days after retransplantation. Thus, C4d deposition is not limited to the capillaries, but extends throughout the arterial tree, and despite formation of a covalent bond, C4d is cleared within days. [source] Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant alleleBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010Jean-Baptiste Woillard WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Mycophenolate mofetil (MMF), the most widely used drug in allograft transplantation, is subject to hepatic and intestinal glucuronidation and entero-hepatic cycling. , Diarrhoea is its most frequent adverse event leading to non-compliance, treatment interruption and ultimately to an increased rate of acute rejection. , Cyclosporin reduces the biliary excretion of mycophenolate metabolites, presumably by inhibiting the efflux transporter MRP2. , When combined with MMF, cyclosporin reduces the incidence of diarrhoea, suggesting the role played by biliary excretion of mycophenolate glucuronides in this adverse event. WHAT THIS STUDY ADDS , In a long-term cohort of renal transplant patients on MMF, the two factors significantly associated with a reduced incidence of diarrhoea were the co-medication with cyclosporin (as opposed to tacrolimus or sirolimus) and the *2 variant allele of the intestinal UGT1A8. , Polymorphisms in the other UDP-glucuronosyl-transferases and MRP2 were not significant. AIM In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites. METHODS Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (,275T>A), UGT2B7 (,840G>A) and ABCC2 (,24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model. RESULTS Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8*2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331). CONCLUSION These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF-induced diarrhoea. [source] The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: a microdialysis studyBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2002T H Tsai Baicalein is a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, a medicinal herb that has been used since ancient times to treat bacterial infections. As little is known concerning its pharmacokinetics, this study focussed on its pharmacokinetics as well as the possible roles of the multidrug transporter P-glycoprotein on its distribution and disposition. Three microdialysis probes were simultaneously inserted into the jugular vein, the hippocampus and the bile duct of male Sprague,Dawley rats for sampling in biological fluids following the administration of baicalein (10, 30 and 60 mg kg,1) through the femoral vein. The P-glycoprotein inhibitor cyclosporin A was used to help delineate its roles. The study design consisted of two groups of six rats in parallel: control rats which received baicalein alone and the cyclosporin A treated-group in which the rats were injected cyclosporin A, a P-glycoprotein inhibitor, 10 min prior to baicalein administration. Cyclosporin A treatment resulted in a significant increase in elimination half-life, mean residence time and area under the concentration versus time curve (AUC) of unbound baicalein in the brain. However, AUC in the bile was decreased. The decline of baicalein in the hippocampus, blood and bile suggested that there was rapid exchange and equilibration between the peripheral compartment and the central nervous system. In addition, the results indicated that baicalein was able to penetrate the blood,brain barrier as well as undergoing hepatobiliary excretion. Although no direct transport studies were undertaken and multiple factors may affect BBB penetration and hepatobiliary excretion, strong association of the involvement of P-glycoprotein in these processes is indicated. British Journal of Pharmacology (2002) 137, 1314,1320. doi:10.1038/sj.bjp.0704959 [source] Cyclosporin A inhibits eosinophilic infiltration into the conjunctiva mediated by type IV allergic reactionsCLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 4 2006Atsuki Fukushima MD Abstract Background:, Eosinophils are important effector cells in severe allergic conjunctivitis such as vernal keratoconjunctivitis. Infiltration of eosinophils into the conjunctiva is mediated by type I and type IV allergic reactions. Cyclosporin A (CsA) eye drops are administered therapeutically for severe allergic conjunctivitis, but the mechanism by which CsA acts, that is, by inhibiting type I, type IV or both types of allergic reactions, is not known. We investigated whether CsA eye drops inhibit type I, type IV or both types of allergic reactions in the conjunctiva. Methods:, Experimental immune-mediated blepharoconjunctivitis (EC) was induced in BALB/c mice by either active immunization or passive immunization by transfer of ragweed (RW)-primed splenocytes and RW-specific IgE, followed by RW challenge to the conjunctiva. These mice were treated in eye drops with vehicle, 0.1% CsA, 0.5% CsA or 0.1% betamethasone five times (1 and 2 h before RW challenge and 1, 2 and 3 h after RW challenge). Twenty-four hours after the challenge, the conjunctivas were harvested for histological analysis to evaluate eosinophilic infiltration. To evaluate effects of CsA eye drops on systemic immune responses, sera and spleens were collected from actively immunized mice at the time of sacrifice to examine serum IgE levels and cellular immune responses, respectively. Results:, CsA eye drops significantly inhibited eosinophilic infiltration into the conjunctiva in actively immunized EC-developing mice compared with vehicle-treated mice. The CsA-induced inhibition was similar to inhibition induced by 0.1% betamethasone. Serum IgE levels and splenocyte responses in CsA-treated mice were equivalent to those in vehicle-treated mice. Betamethasone treatment inhibited eosinophilic infiltration into the conjunctiva induced by both splenocyte transfer and IgE transfer, while CsA treatment inhibited infiltration induced by splenocyte transfer. Conclusions:, CsA eye drops inhibited eosinophilic infiltration into the conjunctiva without affecting systemic immune responses. CsA predominantly inhibits eosinophilic infiltration by interfering with the type IV allergic reaction in the conjunctiva. [source] Cost-effectiveness of sirolimus therapy with early cyclosporin withdrawal vs. long-term cyclosporin therapy in AustraliaCLINICAL TRANSPLANTATION, Issue 4 2006Adam Gordois Abstract:, Cyclosporin (CsA) is Australia's most widely used immunosuppressant following renal transplantation. Randomized clinical trials demonstrate that sirolimus use for immunosuppression is associated with significantly lower incidence rates of nephrotoxicity and chronic graft rejection, and lower serum creatinine levels, suggesting long-term benefits if used as a replacement therapy for CsA. The cost-effectiveness of replacing CsA with sirolimus after 2,4 months (as approved by Australian regulatory authorities) was assessed relative to continued CsA plus low-dose sirolimus. A Markov model simulated outcomes over a patient's lifetime from initial transplant. Costs, measured in Australian dollars from the perspective of the Australian healthcare system, included immunosuppressants, dialysis, and inpatient and outpatient treatment. In a cohort with a mean age of 45 yr, the mean lifetime cost per patient is $39 052 greater with the study therapy. However, an average of 272 chronic graft rejections and 91 regrafts are prevented per 1000 patients. The mean predicted survival benefit is 2.086 life-years, or 0.938 quality-adjusted life-years (QALYs) when utility weights and discounting are incorporated. The incremental cost per QALY gained with the study therapy was $41 613. Cost-effectiveness was most sensitive to model duration and dialysis cost. Sirolimus is a cost-effective alternative to CsA for the long-term treatment of patients undergoing renal transplantation. [source] Contraction-induced changes in skeletal muscle Na+,K+ pump mRNA expression , importance of exercise intensity and Ca2+ -mediated signallingACTA PHYSIOLOGICA, Issue 4 2010N. B. Nordsborg Abstract Aim:, To investigate if exercise intensity and Ca2+ signalling regulate Na+,K+ pump mRNA expression in skeletal muscle. Methods:, The importance of exercise intensity was evaluated by having trained and untrained humans perform intense intermittent and prolonged exercise. The importance of Ca2+ signalling was investigated by electrical stimulation of rat soleus and extensor digitorum longus (EDL) muscles in combination with studies of cell cultures. Results:, Intermittent cycling exercise at ,85% of VO2peak increased (P < 0.05) ,1 and ,1 mRNA expression ,2-fold in untrained and trained subjects. In trained subjects, intermittent exercise at ,70% of VO2peak resulted in a less (P < 0.05) pronounced increase (,1.4-fold; P < 0.05) for ,1 and no change in ,1 mRNA. Prolonged low intensity exercise increased (P < 0.05) mRNA expression of ,1 ,3.0-fold and ,2 ,1.8-fold in untrained but not in trained subjects. Electrical stimulation of rat soleus, but not EDL, muscle increased (P < 0.05) ,1 mRNA expression, but not when combined with KN62 and cyclosporin A incubation. Ionomycin incubation of cultured primary rat skeletal muscle cells increased (P < 0.05) ,1 and reduced (P < 0.001) ,2 mRNA expression and these responses were abolished (P < 0.05) by co-incubation with cyclosporin A or KN62. Conclusion:, (1) Exercise-induced increases in Na+,K+ pump ,1 and ,1 mRNA expression in trained subjects are more pronounced after high- than after moderate- and low-intensity exercise. (2) Both prolonged low and short-duration high-intensity exercise increase ,1 mRNA expression in untrained subjects. (3) Ca2+i regulates ,1 mRNA expression in oxidative muscles via Ca2+/calmodulin-dependent protein kinase (CaMK) and calcineurin signalling pathways. [source] Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channelDIABETES OBESITY & METABOLISM, Issue 6 2001D. K. Fuhrer Summary Aim By focusing on the pancreatic , cell response to tacrolimus, cyclosporin A (CsA) and rapamycin we hoped to identify immunophilin, calcineurin and/or novel mechanism involvement and advance the understanding of immunosuppressant regulated insulin control. Methods A glucose responsive , cell model was established in which the glucose response was blocked by immunosuppressant treatment and this model was used to further characterise this effect. Quantification of insulin release to immunosuppressants and specific inhibitors was used to identify the mechanism involved. Results It was found that upon the addition of tacrolimus, rapamycin, or CsA, rapid and significant exocytosis of cellular insulin was seen. A dose response study of this effect revealed optimal concentration windows of 50, 80 nm for tacrolimus, 100,300 nm for rapamycin, and 7,12 mm for CsA in RIN-5F cells. Optimal insulin release for HIT-T15 cells was similar. Additional experiments demonstrate that immunosuppressant pretreatment blocked the subsequent immunosuppressant induced insulin release but not that of a thapsigargin control, suggesting that suppression and release are non-toxic, specific and in the same pathway. Further experiments showed that this insulin release was a calcium dependent process, which was blocked by inhibitors of l -type calcium channels. Continued studies showed that the specific ATP-sensitive potassium channel agonist diazoxide (150 mm) also blocked immunosuppressant-induced insulin release. Conclusions A model that fits this data is a novel calcineurin-independent immunophilin mediated partial closing of the ATP-sensitive potassium channel, which would lead to an initial insulin release but would reduce subsequent responses through this pathway. [source] Acetate inhibits NFAT activation in T cells via importin ,1 interferenceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2007Kazuhiro Ishiguro Dr. Abstract Acetate is a principal short chain fatty acid produced by bacterial fermentation in the colon and a major end product of alcohol metabolism. In the present study, we assessed the effects of acetate on T cell activation and found that acetate inhibited NFAT activation but not NF-,B activation. Moreover, acetate impaired the nuclear translocation of NFAT but not that of NF-,B. Unlike cyclosporin A (CsA), acetate did not affect the dephosphorylation of NFAT and calcineurin activity. Acetate impaired the binding of NFAT to importin ,1, which is involved in NFAT nuclear translocation. NFAT is a critical transcription factor in cytokine and early response gene expression in activated T cells. Agents targeting NFAT such as CsA are used to suppress harmful immune responses in inflammatory diseases. Therefore, we also evaluated the efficacy of acetate in murine models of inflammatory diseases, and found that acetate administration (as well as administration of dexamethasone) attenuated trinitrobenzenesulfonic acid-induced colitis and dinitrofluorobenzene-induced dermatitis. These findings indicate for the first time that acetate inhibits NFAT activation by interfering with the interaction between NFAT and importin ,1 in T cells and that acetate can potentially act as an anti-inflammatory agent. [source] Pemphigus mouse model as a tool to evaluate various immunosuppressive therapiesEXPERIMENTAL DERMATOLOGY, Issue 3 2009Yujiro Takae Abstract:, Pemphigus vulgaris (PV) is an autoimmune bullous disease caused by immunoglobulin G (IgG) autoantibodies against desmoglein 3 (Dsg3). We have generated an active disease mouse model for PV by adoptive transfer of Dsg3,/, lymphocytes. In this study, we investigated the benefits and limitations of this model as a tool to evaluate various immunosuppressive therapeutic strategies. We used the following three measurements to evaluate the effects of the drugs during the time course: Dsg3 enzyme-linked immunosorbent assay scores that represent the level of production of anti-Dsg3 IgG, body weight loss that reflects the severity of oral erosions and PV score that reflects the extent of skin lesions. We examined various immunosuppressive agents currently used to treat patients with PV model mice in preventive protocol. Cyclophosphamide almost completely suppressed the production of anti-Dsg3 IgG, development of body weight loss and the appearance of the PV phenotype in contrast with the control group without the drug. Azathioprine, cyclosporin A and tacrolimus hydrate also showed suppressive effects to various degrees. However, methylprednisolone and dexamethasone failed to show significant effects in contrast to the findings reported in humans. Knowing the advantages and limitations of this model will provide an important foundation for the future evaluation and development of novel therapeutic strategies. [source] Treatment of neutral glycosphingolipid lysosomal storage diseases via inhibition of the ABC drug transporter, MDR1FEBS JOURNAL, Issue 9 2006Cyclosporin A can lower serum, liver globotriaosyl ceramide levels in the Fabry mouse model We have shown that the ABC transporter, multiple drug resistance protein 1 (MDR1, P-glycoprotein) translocates glucosyl ceramide from the cytosolic to the luminal Golgi surface for neutral, but not acidic, glycosphingolipid (GSL) synthesis. Here we show that the MDR1 inhibitor, cyclosporin A (CsA) can deplete Gaucher lymphoid cell lines of accumulated glucosyl ceramide and Fabry cell lines of globotriaosyl ceramide (Gb3), by preventing de novo synthesis. In the Fabry mouse model, Gb3 is increased in the heart, liver, spleen, brain and kidney. The lack of renal glomerular Gb3 is retained, but the number of verotoxin 1 (VT1)-staining renal tubules, and VT1 tubular targeting in vivo, is markedly increased in Fabry mice. Adult Fabry mice were treated with ,-galactosidase (enzyme-replacement therapy, ERT) to eliminate serum Gb3 and lower Gb3 levels in some tissues. Serum Gb3 was monitored using a VT1 ELISA during a post-ERT recovery phase ± biweekly intra peritoneal CsA. After 9 weeks, tissue Gb3 content and localization were determined using VT1/TLC overlay and histochemistry. Serum Gb3 recovered to lower levels after CsA treatment. Gb3 was undetected in wild-type liver, and the levels of Gb3 (but not gangliosides) in Fabry mouse liver were significantly depleted by CsA treatment. VT1 liver histochemistry showed Gb3 accumulated in Kupffer cells, endothelial cell subsets within the central and portal vein and within the portal triad. Hepatic venule endothelial and Kupffer cell VT1 staining was considerably reduced by in vivo CsA treatment. We conclude that MDR1 inhibition warrants consideration as a novel adjunct treatment for neutral GSL storage diseases. [source] Characterization of depolarization and repolarization phases of mitochondrial membrane potential fluctuations induced by tetramethylrhodamine methyl ester photoactivationFEBS JOURNAL, Issue 7 2005Angela M. Falchi Depolarization and repolarization phases (D and R phases, respectively) of mitochondrial potential fluctuations induced by photoactivation of the fluorescent probe tetramethylrhodamine methyl ester (TMRM) were analyzed separately and investigated using specific inhibitors and substrates. The frequency of R phases was significantly inhibited by oligomycin and aurovertin (mitochondrial ATP synthase inhibitors), rotenone (mitochondrial complex I inhibitor) and iodoacetic acid (inhibitor of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase). Succinic acid (mitochondrial complex II substrate, given in the permeable form of dimethyl ester) abolished the rotenone-induced inhibition of R phases. Taken together, these findings indicate that the activity of both respiratory chain and ATP synthase were required for the recovery of the mitochondrial potential. The frequency of D phases prevailed over that of R phases in all experimental conditions, resulting in a progressive depolarization of mitochondria accompanied by NAD(P)H oxidation and Ca2+ influx. D phases were not blocked by cyclosporin A (inhibitor of the permeability transition pore) or o -phenyl-EGTA (a Ca2+ chelator), suggesting that the permeability transition pore was not involved in mitochondrial potential fluctuations. [source] A folding variant of human ,-lactalbumin induces mitochondrial permeability transition in isolated mitochondriaFEBS JOURNAL, Issue 1 2001Camilla Köhler A human milk fraction containing multimeric ,-lactalbumin (MAL) is able to kill cells via apoptosis. MAL is a protein complex of a folding variant of ,-lactalbumin and lipids. Previous results have shown that upon treatment of transformed cells, MAL localizes to the mitochondria and cytochrome c is released into the cytosol. This is followed by activation of the caspase cascade. In this study, we further investigated the involvement of mitochondria in apoptosis induced by the folding variant of ,-lactalbumin. Addition of MAL to isolated rat liver mitochondria induced a loss of the mitochondrial membrane potential (,,m), mitochondrial swelling and the release of cytochrome c. These changes were Ca2+ -dependent and were prevented by cyclosporin A, an inhibitor of mitochondrial permeability transition. MAL also increased the rate of state 4 respiration in isolated mitochondria by exerting an uncoupling effect. This effect was due to the presence of fatty acids in the MAL complex because it was abolished completely by BSA. BSA delayed, but failed to prevent, mitochondrial swelling as well as dissipation of ,,m, indicating that the fatty acid content of MAL facilitated, rather than caused, these effects. Similar results were obtained with HAMLET (human ,-lactalbumin made lethal to tumour cells), which is native ,-lactalbumin converted in vitro to the apoptosis-inducing folding variant of the protein in complex with oleic acid. Our findings demonstrate that a folding variant of ,-lactalbumin induces mitochondrial permeability transition with subsequent cytochrome c release, which in transformed cells may lead to activation of the caspase cascade and apoptotic death. [source] | ||||||||||||||||||||||||||||||||||||||||