Cyclosporine Group Research Articles

A comparative study of Tacrolimus versus Cyclosporine as immunosuppression for kidney transplant recipients

Kidney transplantation is the most common transplantation in the world. Annually, a large number of patients that have chronic renal failure are undergoing renal transplantation and the major subject about these patients is the rejection of graft that should be controlled by immunosuppressive agents. The aim of this study is investigation of the effect of Cyclosporin against Tacrolimus in patients with kidney transplantation. This study was performing between 2010 and 2012 on all patients who had kidney transplantation and refer to Imam Reza hospital from Kermanshah University of Medical Sciences. 100 patients, aged 18–60 years, with end-stage renal disease were administered either Tacrolimus (n=49) or Cyclosporine (n=51). In both groups, Cellept could be discontinued from day 92 onwards. Corticosteroid treatment comprised methylprednisolone boluses followed by a rapid prednisone taper from 20 mg (day 2) to 5 mg (day 43 and thereafter). Patients followed up 12 months. In the Tacrolimus treatment group, 7 grafts (14%) were lost and 8 (16%) grafts were lost in the Cyclosporine treatment group between months 0 and 12 and there is no significant different between these groups ( P= 0.845 ). No cases were diagnosed with biopsy-proven chronic rejection at months 0 and 12. Mean serum creatinine concentrations were 1.8 ± 1.5 mg/dl in the Tacrolimus group and 2.3 ±2.9 in the Cyclosporine group by month 12 ( P= 0.348 ). these data are consistent with previously published observations and confirm that Tacrolim us is a highly efficacious baseline immunosuppressant for patients undergoing kidney transplantation. Tacrolimus-based immunosuppression may promote long-term benefits with regard to graft functio n and graft survival.

Cyclosporine in Stevens Johnson syndrome and toxic epidermal necrolysis and retrospective comparison with systemic corticosteroid

Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening dermatological emergencies. Many immunosuppressive modalities have been tried with variable results. To determine the efficacy of cyclosporine in cases of SJS and TEN and compare the efficacy with systemic corticosteroid in the same condition. Study was conducted at a tertiary hospital during 01 July 2011 to 30 June 2012. SCORTEN was assessed at the time of admission. Total body surface area (TBSA) assessment was like any burn patients. Cyclosporine was administered in the dose of 3 mg/kg body weight in three divided dosage for 07 days and then tapered over another 07 days. Data were compared to a historical series of SJS/TEN patients, managed by systemic steroids a year ago. A total of 11 consecutive patients with a mean age of 32.09 and standard deviation (SD 16.17) were enrolled in to cyclosporine group, which were retrospectively compared to 6 patients with a mean age of 27.87 (SD 13.97) years in the corticosteroid group. The mean duration of re-epithelialization was 14.54 (SD 4.08) and 23 days (SD 6.68) in cyclosporine and corticosteroid group respectively (P = 0.009956). Mean hospital stay was 18.09 (SD 5.02) and 26 (SD 6.48) days in cyclosporine and corticosteroid group respectively (P = 0.02597). A total of 1.11 and 0.51 patients were expected to die against no death and two deaths in cyclosporine and corticosteroid group respectively (Standardized mortality ratio = 3.92) (P = 0.04321). This study definitely suggests that cyclosporine has encouraging role in the management of uncomplicated cases of SJS, SJS-TEN overlap or TEN.

Multicenter, Prospective Study of Tacrolimus Plus Methotrexate As Graft-Versus-Host Disease Prophylaxis in HLA-Matched Sibling Peripheral Blood Stem Cell Transplantation: Comparison with Cyclosporine Group As Control

AbstractAbstract 4177 BackgroundGraft-versus-host disease (GVHD) is an immunologic complication after allogeneic hematopoietic stem cell transplantation (HSCT) with significant mortality and morbidities. Allogeneic peripheral blood stem cell transplantation (PBSCT) has high risk of GVHD, especially chronic GVHD compared to bone marrow transplantation. Only limited data are available comparing the efficacy of FK506 with that of cyclosporine (CsA) in human leukocyte antigen (HLA)-matched sibling PBSCT. MethodsThirty-nine patients with various hematologic disease received PBSCT with FK506+methotrexate (MTX) as GVHD prophylaxis were compared to ninety-four historical control with CsA+MTX GVHD prophylaxis. ResultsThe 1-year cumulative incidence of grade II-IV acute GVHD was significantly lower in patients who received FK506 than those in the CsA group (10.3% vs 28.2%, p=0.036). The female donor-male recipient pair (hazard ratio; 4.828, 95% CI; 17.84-13.06, p=0.002) and CsA prophylaxis (hazard ratio; 3.279, 95% CI; 1.14–9.43, p=0.027) were significant risk factor of acute GVHD in multivariate analysis. But, there was no difference in the 3-year cumulative incidence of chronic GVHD between the FK506 and the CsA group (77.6% vs 69.6%, p=0.793). The 3-year cumulative incidence of relapse (33.9% vs 23.1%, p=0.505) and 3-year treatment-related mortality (18.9% vs 28.4%, p=0.187) of the two groups were similar. The patients in the FK506 arm had a similar event-free survival (EFS) and overall survival (OS) with patients in the CsA arm (3-year EFS; 53.2% vs 55.1%, p=0.706, 3-year OS; 60.7 vs 61.5%, p=0.610). The age over 35 years (hazard ratio; 4.12, 95% CI; 1.95–8.70, p=0.001), female donor-male recipient pair (hazard ratio; 2.66, 95% CI; 1.52–4.65, p=0.001) and advanced pre-HSCT disease status (hazard ratio; 3.13, 95% CI; 1.72–5.71, p=0.001) were significant prognostic factors associated with OS in multivariate analysis. ConclusionThese results demonstrated that the FK506+MTX can significantly reduce grade II-IV acute GVHD compared to CsA+MTX in sibling PBSCT with similar incidence of chronic GVHD, and comparable outcome in EFS, OS, relapse rate and TRM rate between two groups. Disclosures:No relevant conflicts of interest to declare.

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

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

Role of Rejection on Renal Tumours after Transplantation: A Rodent Tumour Transplant Model

Introduction: Evasion from immune system is one of the many steps required for tumour development and progression. In allografts tumour can either be transplanted inadvertently or develop de novo. Transplanted tumour being “nonself” to host is expected to be rejected by the immune system in the absence of any immunosuppression. Thus acute rejection could be employed as a therapeutic strategy should a tumour recur by stopping the immunosuppression. This study looks at the influence of matching and role of rejection on transplanted tumours. Methods: Luciferase labelled kidney tumour cells of Wistar origin were injected subcutaneously into either Wistar or Lewis strains mimicking a well and a poorly matched combination respectively. Animals were divided into controls with no immunosuppression and experimental group receiving one of the 3 agents (Cyclosporine, Sirolimus, leflunomide) for 2 weeks followed by treatment withdrawal to mimic acute rejection. Weekly IVIS spectrum imaging was performed to monitor the tumour behaviour.Figure: [Control animals]Results: With no immunosuppression, the transplanted tumour cells were rejected in two weeks in well matched and within one week in poorly matched animals (p < 0.001). In Cyclosporine group, only 4/8 Wistar animals rejected the tumour, while all the Lewis animals rejected the tumour within 2 weeks of treatment withdrawal (p < 0.001). In Sirolimus group, both the Wistars and Lewis rats rejected the tumour within one week of treatment withdrawal as opposed to the treatment continue group which took a total of 4 weeks of treatment to destroy the tumour (p < 0.05). In Leflunomide group, 5/7 animals rejected tumour after treatment withdrawal (Only Wistar rats were studied in this group). Control animals Conclusions: In both the controls and treatment withdrawal groups the tumour rejection was significantly stronger among poorly matched animals. Clinically, patients receiving high risk organs (eg; kidneys from patients with small RCC after ex vivo resection) could benefit from a less well HLA matching, to enable rejection “therapy” should a tumour recur in allograft.

10 Yearsʼ Experience with Belatacept (Nulojix®)

Introduction: Belatacept was approved in 2011 as novel immunosuppressive agent for prevention of acute rejection in adult patients undergoing kidney transplantation on the basis of two open-label, randomized, multicenter, controlled phase 3 studies. From these studies meanwhile 3 years' data are published but longer term results are of particular interest. Patients and methods: From March 2001 November 2002 a total of 218 patients were enrolled in an open-label, randomized, multicenter, controlled phase 2 study. Patients were randomly assigned to 3 treatment groups: “less intensive” belatacept, “more intensive” belatacept, and standard cyclosporine A (Sandimun Optoral/ Neoral®). 5 year data from this phase II study were published. In our department 20 patients (15 receiving belatacept, 5 cyclosporine A) were included, 6 patients meanwhile completed the long term extension of the study. Five are still receiving belatacept. We analyzed reasons for drop out, renal function, acute rejection, development of malignancies and survival. Results: From a total of 14 drop outs most occurred in the first month after transplant: 8 (53%) in the belatacept group and 2 (40%) in the cyclosporine group. From year 5 on only 1 further drop out was observed. Reasons for early drop out were rejections in 4 patients (all belatacept), in 3 patients CMV infections (2 cyclosporine, 1 belatacept), in 2 patients side effects (gastrointestinal disorder and agranulocytosis) and in 1 patient withdrawal of consent. Graft function of the belatacept patients declined from a median clearance of 102ml/min at year 1 to 59ml/min (range 44-79ml/min) at year 10. The 3 patients of the cyclosporine group, which completed the first year, had a median clearance of 58ml/min (range 49-95ml/min). Only the patient with the best graft function completed the long term extension. Clearance declined over the time from 95ml/ min to 59ml/min. Rejections were observed in 6 patients (40%) receiving belatacept and in 2 patients (40%) receiving cyclosporine. Overall, 3 of the 20 patients developed malignancies. Two male patients suffered from bronchial cancer (both smokers; one 2 years after transplantation and withdrawn IC on day 5, the other 8 years after transplantation and under treatment of belatacept), one female patient developed a cervical intraepithelial neoplasia 7 years after transplantation and under treatment of belatacept. Five of the 20 patients died. Four of them after or while receiving belatacept at month 18 after transplantation (sepsis due to pleural empyema after mitral valve replacement), year 2 after transplantation (one patient with unknown reason; one patient due to bronchial cancer, withdrawn IC with switch to cyclosporine A on day 5) and year 8 after transplantation due to bronchial cancer. The patient from the cyclosporine A group died 8 years after transplantation due to a aortic valve stenosis. Conclusion: This is the first report on long term use of Belatacept. Regarding our Patients Belatacept seems to be effective and safe in renal transplant patients. No graft loss due to chronic allograft nephropathy was observed; i.v. administration was well tolerated with less side effects and was well accepted in most patients.

Immunosuppressant utilization and cardiovascular complications among Chinese patients after kidney transplantation: a systematic review and analysis

Data on the utilization of immunosuppressants and incidences of cardiovascular complications after kidney transplantation are generally lacking in China. The objectives of this systematic review and analysis were to investigate the hypothesis that tacrolimus and cyclosporine have different effects on the incidences of cardiovascular complications among Chinese patients after kidney transplantation. A comprehensive database research was performed in PubMed and CMB-disc. Random effect models and meta-regression were used for data analysis. Eleven eligible studies were retrieved (7 comparative studies and 4 conversion studies). There were 838 participants from the eligible studies. The incidences of drug-related hypertension, dyslipidemia and hyperglycemia were compared between tacrolimus and cyclosporine groups. Significant different odds ratios for dyslipidemia (40 vs. 20 %, OR 2.72) and hypertension (63 vs. 37 %, OR 2.93), but not for hyperglycemia (11 vs. 15 %, OR 0.705) were noted between patients receiving cyclosporine and tacrolimus containing regimens. The secondary analysis including comparative studies revealed a similar acute rejection rate, but significantly improved renal functions, lipid profiles and lower liver toxicity associated with tacrolimus. Significant reversal of hypertension and dyslipidemia was also noted in the analysis of the conversion studies. A significant association between immunosuppressant use and cardiovascular complications was identified among Chinese patients after kidney transplantation. Patients receiving cyclosporine-containing regimens and/or with chronic allograft nephropathy should be closely monitored for potential cardiovascular complications.

Differential Effects of Cyclosporin and Etanercept Treatment on Various Pathologic Parameters in a Murine Model of Irradiation-Induced Mucositis

BackgroundRadiation therapy is the most prescribed treatment for many oncologic indications. One of its common side effects is mucositis with hallmark apoptosis in the intestinal crypt and diarrhea. ObjectiveWe investigated the potential beneficial effects of etanercept and cyclosporin treatment during radiation exposure. The effects of these drugs on intestinal apoptosis, long-term weight loss, diarrhea severity, and survival were examined. MethodsFor acute observation studies, animals pretreated with phosphate buffer saline (PBS) vehicle, either etanercept, or cyclosporin were challenged with either 1 Gy or 13 Gy irradiation and sacrificed 6 hours later. The animals' small intestines were then harvested for histologic analysis. For chronic survival studies, 14.5 Gy irradiation was applied. Etanercept or cyclosporin treatments were given 15 minutes before the irradiation, followed by daily administration. ResultsAt 6 hours postirradiation the maximum apoptotic index observed in the small intestine was ∼25% for both 1 Gy and 13 Gy irradiation. Etanercept and cyclosporin pretreatment had no effect on the irradiation-induced apoptosis. During chronic observation, the rate of weight loss was similar in all test groups. At 7 days postirradiation, the weight loss in phosphate buffered saline-treated control, etanercept, and cyclosporin groups reached a maximum at 19%, 24%, and 31.8%, respectively. The weight lost in the cyclosporin group was significantly higher than in the control group. Neither treatment reduced the severity of diarrhea, but cyclosporin increased the survival rate. Sixty percent of cyclosporin-treated animals survived compared with 27% in the PBS-treated control group and 47% in the etanercept-treated group. Serum tumor necrosis factor-α levels, a biomarker for both etanercept's mechanism of action and treatment efficacy, was inhibited by etanercept throughout the study, but cyclosporin only showed an inhibitory effect at 48 hours postirradiation. ConclusionsOur study demonstrates that cyclosporin increases the survival rate of irradiated animals without affecting parameters such as intestinal histology, weight loss, and diarrhea severity.

Renoprotective Effects of Cotransplanted Allogeneic Testicular Sertoli Cells in a Renal Acute Rejection Model in Rats

We sought to study the renoprotective effect of cotransplanted allogeneic testicular Sertoli cells on renal acute rejection in rats. A renal acute rejection model using kidneys from Sprague-Dawley (n=30) transplanted into Wistar rats (n=30) was constructed. The rats were randomly divided into 3 groups: (1) the cyclosporine group, which was treated with daily hypodermic injections of cyclosporine (15 mg/kg) after transplant, (2) the Sertoli cells group with cell suspension (n = 2 × 10⁶ cells) into the subcapsular space of the renal graft, and (3) the control group, which received no posttransplant intervention. Graft function was measured based on serial serum creatinine. Graft histology was examined at 10 days posttransplant, and survival duration was recorded. Serum creatinine was significantly higher in the Sertoli cells and cyclosporine groups than in the controls. Survival duration was significantly longer in the Sertoli cells (19.50 ± 4.3 d) and cyclosporine groups (21.50 ± 5.9 d) than in the controls (14 ± 3.1 d). Allografts in the control group exhibited typical severe acute rejection, including widespread interstitial infiltration with tubulous, patchy necrosis and hemorrhage, severe glomerulitis with extensive capillary occlusion caused by endothelial swelling, and intimal arteritis in the cortex. Findings of acute rejection were less in the Sertoli cells and cyclosporine groups. Sertoli cell implantation is an effective method for increasing survival duration in rat renal transplant, and it has potential as a new alternative to cyclosporine immunosuppression.

The Effect of Glutathion S-Transferase Polymoprhisms and Anti-GSST1 Antibodies on Allograft Functions in Recipients of Renal Transplant

The balance between oxidative stress and anti-oxidant defense systems after renal transplantation may explain the development and progression of allograft dysfunction. Glutathione S-transferase (GST) decreases the damage from oxidative stress. In contrast, recipient antibodies against GSTT1 expressed on the graft are believed to cause its dysfunction. The aim of our research was to study the probable relationship to rejection between GST gene polymorphisms and anti-GSTT1 antibodies. We included 122 patients transplantations from living donors and 51 healthy individuals as controls group in our study. The patient groups were comprised of 57 patients who did and 65 who did not experienced rejection episode. Polymerase chain reactions were used to detect GSTM1 and GSTT1 polymorphisms, whereas PCR-RFLP (restriction fragment length polymorphism), for GSTP1 polymorphism. An enzyme-linked immunosorbent assay method was used for anti-GSTT1 antibody scans. There was no significant difference between the groups for allele and genotype frequencies of GSTT1, GSTM1, GSTP1 polymorphisms of the recipients, donors, and controls. Within the rejection group the frequency of patients with the GSTM1 null genotype was higher among subjects prescribed cyclosporine A versus tacrolimus (P = .029). Among the entire patient group, 46 subjects with GSTT1 null genotype were scanned for anti-GSTT1 antibody which was detected in 5 of 8 patients with an acute rejection episode (P = .04). Anti-GSTT1 antibody was observed more frequently albeit not significantly, among the cyclosporine versus tacrolimus patient group (P = .16). This study suggested that GSTM1 genotype may be important for cyclosporine detoxification and for allograft outcomes due to drug nephrotoxicity. After transplantation, antigens distinct from the HLA system such as GSTT1 protein may also be targets for alloimmune responses.

Genetic and Clinical Determinants of Early, Acute Calcineurin Inhibitor-Related Nephrotoxicity

Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity. We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip. Cox models, unadjusted and adjusted for clinical factors, examined the association between SNPs and time to early CNI-related acute nephrotoxicity in the first 6 months posttransplant. Cyclosporine was associated with a 1.49 hazard (95% confidence interval, 1.04-2.14) of acute nephrotoxicity relative to tacrolimus. Acute nephrotoxicity occurred in 22.6% of cyclosporine and 19.8% of tacrolimus recipients. The median (interquartile range) daily dose and trough concentration at time of nephrotoxicity were 400 mg (400-500 mg) and 228 ng/mL (190-272 ng/mL) in the cyclosporine group, and 6 mg (4-8 mg) and 12.6 ng/mL (10.2-15.9 ng/mL) in the tacrolimus group, respectively. In single-SNP adjusted analysis, nine SNPs in the XPC, CYP2C9, PAX4, MTRR, and GAN genes were associated with cyclosporine nephrotoxicity. In a multi-SNP analysis, SNPs from the same genes remained significant after adjusting for the clinical factors, showing that the SNPs are jointly and independently predictive of cyclosporine nephrotoxicity. No SNPs were associated with tacrolimus nephrotoxicity. We identified SNPs that were potentially associated with early, acute cyclosporine-related nephrotoxicity. Identifying risk SNPs before transplantation provides an opportunity for personalization of immunosuppression by identifying those who may benefit from CNI-avoidance or minimization, or assist in selecting CNI type. These SNPs require independent validation.

Infliximab or cyclosporine for acute severe ulcerative colitis: A retrospective analysis

Medical treatment of steroid-refractory ulcerative colitis (UC) is limited to either cyclosporine or infliximab. Studies comparing cyclosporine with either placebo or intravenous methylprednisone showed promise for cyclosporine, but associated it with significant toxicity. There is conflicting, but increasingly positive evidence for using infliximab. There are no studies directly comparing these two treatments. Our aim was to compare the outcomes of patients with steroid-refractory UC treated with either intravenous cyclosporine or infliximab. We carried out a retrospective review of inpatients with steroid-refractory UC, treated with either intravenous cyclosporine or infliximab, at Waitemata District Health Board, between January 2001 and February 2010. The primary end-points were time to colectomy, and colectomy rates at 3 and 12 months. Secondary end-points were time to discharge from initiation of treatment, steroid dependence at 12 months, and reported adverse events. The total study population was 38, with 19 in the infliximab group. Follow up to 12 months was complete in all patients. At 3 months, the colectomy rate was 63% for cyclosporine, compared to 21% (P = 0.0094). By 12 months the rate was 68% and 37% for cyclosporine and infliximab, respectively (P = 0.06). Patients in the cyclosporine group required an additional 5 days in hospital (P = 0.0086). Steroid dependence at 12 months was 50% for cyclosporine versus 25% for infliximab (P = 0.36). Cyclosporine caused more adverse events (P = 0.17). Infliximab improved clinical outcomes compared to the previous use of intravenous cyclosporine in patients admitted with steroid-refractory acute severe UC.

Cyclosporine or infliximab as rescue therapy in severe refractory ulcerative colitis: Early and long-term data from a retrospective observational study

IntroductionAbout 30-40% of patients with acute severe ulcerative colitis (UC) fail to respond to intensive intravenous (iv) corticosteroid treatment. Iv cyclosporine and infliximab are an effective rescue therapy in steroid-refractory UC patients but up to now it is still unclear which is the best therapeutic choice. MethodsWe reviewed our series of severe steroid-refractory colitis admitted consecutively since 1994 comparing two historical cohort treated with iv cyclosporine (2mg/kg) or iv infliximab (5mg/kg). The main outcome was the colectomy rate at 3 months, 12 months and at the end of the follow-up. ResultsA total of 65 patients were included: 35 in the cyclosporine group and 30 in the infliximab one. At 3 months the colectomy rate was 28.5% in the cyclosporine group and 17% in the infliximab group (p=0.25), while 48% versus 17% at 12 months (p=0.007, OR 4.7; 95% CI: 1.47-15.16). The 1-2-3 year cumulative colectomy rates were 48%, 54%, 57% in the cyclosporine group, and 17%, 23%, 27% in the infliximab group. At the end of the follow-up the colectomy rate was 60% versus 30% (p=0.04, HR 2.2; 95% CI: 1.11-4.86). High level of C reactive protein (p=0.04), extensive disease (p=0.01) and no azathioprine treatment (p<0.001) were related to the risk of colectomy. ConclusionThis study, despite being retrospective, indicates that both cyclosporine and infliximab are effective in avoiding a colectomy in steroid-refractory UC patients. During the follow-up the risk of a colectomy is higher in patients treated with cyclosporine than with infliximab.

The effects of immunosuppressants on vascular function, systemic oxidative stress and inflammation in rats

Immunosuppressants have been associated with increased cardiovascular disease risk. We determined the effects of calcineurin and mammalian target of rapamycin (mTOR) inhibitor administration on endothelial dysfunction and associated inflammation and oxidative stress in adult rats. Cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus and placebo were administered to 8-week-old male Wistar rats for 10 consecutive days. Aortic vascular endothelial and smooth muscle function were assessed ex vivo in organ baths. Maximal aortic contraction to noradrenaline in sirolimus-treated rats was significantly greater than cyclosporine groups, everolimus and placebo, whereas endothelial-dependent relaxation was significantly impaired with cyclosporine and tacrolimus compared with everolimus. Endothelial-independent relaxation was impaired in tacrolimus-treated rats compared with low dose cyclosporine, everolimus and sirolimus. Sirolimus was associated with a reduction in plasma interleukin (IL)-1β and tumour necrosis factor (TNF)-α and higher levels of catalase and total antioxidant status. In nontransplanted rats, vascular dysfunction was evident following administration of cyclosporine A, sirolimus and tacrolimus, whereas everolimus did not compromise aortic endothelial or smooth muscle function. At the doses administered in this model, the immunosuppressants exerted varying effects on vascular function.

Estimation of tissue osteopontin levels before and after different traditional therapeutic modalities in psoriatic patients

Several lines of evidences support a major role for Th1 cells in psoriasis. Treatment of psoriasis with cyclosporine, methotrexate and psoralen plus ultraviolet A (PUVA) is associated with clinical improvement and decrease in epidermal hyperplasia. Osteopontin (OPN) exerts a T-helper type 1 (Th1) cytokine function, regulating inflammatory cell accumulation and function. To detect the effects of methotrexate, cyclosporine and PUVA on OPN expression in psoriatic plaques, and whether these changes correlate with clinical response. For three groups of psoriatic patients (each including 12 patients), the Psoriasis Area Severity Index (PASI) and levels of lesional skin OPN were determined using enzyme-linked immunosorbent assays before and after treatment with methotrexate, cyclosporine or PUVA. Skin biopsies from 20 healthy volunteers served as control for OPN levels in normal skin. Baseline lesional skin of psoriatic patients showed a statistically significant elevation of OPN levels in comparison to controls. Three months after therapy, the three therapeutic modalities were associated with a significant decrease in the mean levels of PASI and tissue OPN, with the PUVA group showing the highest level of reduction in OPN levels and cyclosporine group showing the highest level of reduction in PASI. Our study points to the possible role played by OPN in the pathogenesis of psoriasis and in reflecting disease severity. These standard therapeutic modalities used in the current study were associated with a significant decrease in PASI and OPN levels. They constitute highly effective therapeutic modalities for psoriasis, which might exert their anti-psoriatic activity partially through altering the expression of OPN.

Post-Transplant Hypomagnesemia in Turkish Renal Transplant Recipients: The Frequency and Related Factors

Aim: Hypomagnesemia is a frequent complication in RTRs, particularly in the early post-transplant period. Hypomagnesemia is usually associated with the use of calcineurin inhibitors. The relationship between cyclosporine use and hypomagnesemia is well known. However, it has been reported in several studies that hypomagnesemia was seen more in RTRs treated with tacrolimus compared to those treated with cyclosporine. In this study, we aimed to investigate the frequency and risk factors of post-transplant hypomagnesemia and effects of calcineurin inhibitors on hypomagnesemia among Turkish patients. Patients and method: The study included 68 adult renal transplantation recipients. Hypomagnesemia was defined as serum magnesium level <1.4 mEq/L. Result: Hypomagnesemia were found in 26 (38.2%) of the 68 patients. Levels of serum calcium and glucose were significantly higher in hypomagnesemic group compared to normomagnesemic group (9.7 ± 0.5 mg/dL vs. 8.4 ± 0.5, p: 0.029 and 107.3 ± 19.1 mg/dL vs. 95.8 ± 16.1, p: 0.010, respectively). Post-transplant duration was meaningfully longer in normomagnesemic group (9.5 months vs. 46.5, p: 0.001). Serum magnesium level was meaningfully higher in patients with cyclosporine compared to patients treated with tacrolimus (1.44 ± 0.5 mEq/L vs. 1.52 ± 0.2, p: 0.002, respectively). Post-transplant duration was significantly longer in cyclosporine group (12 months vs. 98.5, p: 0.001). Frequency of hypomagnesemia was significantly higher tacrolimus group (58% vs. 10%, p: 0.001). Conclusion: The frequency of hypomagnesemia was high among Turkish renal transplant recipients, especially those treated with tacrolimus. Increased concentrations of serum calcium and glucose and the shorter post-transplant duration were risk factors for post-transplant hypomagnesemia.

In Vivo Effects of Immunomodulators in a Murine Model of Fluorouracil-Induced Mucositis

BackgroundFluorouracil (5-FU) is a pyrimidine analogue used as a cancer treatment. Its toxic side effects, including mucositis, are reported to occur in 40% of the treated patients. Because of the inflammatory component of mucositis, we explored the possibility of modulating this condition with an immunomodulatory agent and a tumor necrosis factor-α inhibitor. ObjectiveThe aim of this study was to evaluate the effect of 2 immunosuppressive agents, etanercept and cyclosporine, in a murine model of 5-FU–induced mucositis. MethodsTo study the short-term effects of 5-FU on mucositis, cyclosporine and etanercept were administered to mice after an injection of 5-FU. The animals (n = 8) were euthanized at 6 hours post-challenge. Hematoxylin and eosin–stained histologic sections of the small intestine were examined for signs of apoptosis. To further examine the potential of cyclosporine in the treatment of 5-FU–induced mucositis in a longer duration, the animals (N = 15) were given 2 challenges of 5-FU within 6 hours. All mice were dosed daily until day 9 with either cyclosporine (100 mg/kg) or phosphate-buffered saline (PBS). ResultsSix hours after 5-FU challenge, 25 mg/kg etanercept and 50 mg/kg cyclosporine had no effect on 5-FU–induced apoptosis (P > 0.05). However, 100 mg/kg cyclosporine significantly reduced the cumulative level of apoptosis >41.6% of the intestinal crypt surface (P < 0.05). During long-term observation, all mice began to lose weight at a rate of approximately 0.8 g/day after 5-FU exposure. The rates of weight loss and survival were not affected by cyclosporine treatment. The diarrhea onset began on day 4 with 46.7% of the PBS-treated mice showing signs of diarrhea compared with 53.3% in the cyclosporine group. The diarrhea score for both groups plateaued on day 7, with a cumulative score of 41 for the PBS group and 50 for the cyclosporine group. Cyclosporine treatment did not affect the diarrhea onset day or severity compared with the PBS-treated group (P > 0.05). ConclusionsOur data indicated that etanercept is not a suitable treatment for 5-FU–induced mucositis. Despite decreased apoptosis in the gut, cyclosporine did not affect the severity of the diarrhea or survival. Therefore, we concluded that cyclosporine treatment was only effective in mediating the short-term apoptotic events in the intestines but has no long-term effect on the animals' survival and diarrhea.

Anti-Arthritic Effects of Immunomodulatory Peptide Injected in Joints

To examine the clinical and histological outcomes following intra-articular injection of an immunomodulatory peptide (CP) during an acute attack of adjuvant induced arthritis in rats. Arthritis in rats was induced by injecting 0.1 mL of Mycobacterium Tuberculosis (MTB; 10mg/ml) intra-dermally at the base of the tail. After the onset of arthritis, affected ankle joints were injected with either 20 μl of water, dexamethasone (4 mg/ml), cyclosporine (0.38 mg; equivalent to 3mg/kg in humans), CP (60 mg/ml; 12.5 mg/ml; 6.25 mg/ml; 3.125 mg/ml) or a CP analogue (CPD; 6.25mg/ml). There were a minimum of 5 rats/group and intra-articular injection was given on two separate occasions following the onset of arthritis. Rat weight, paw thickness, paw-width, ankle width and arthritic joint count were measured. Affected joints were X-rayed and joint tissue taken for histology. Rats given dexamethasone and cyclosporine had a significant improvement in clinical outcomes compared to the control group. CP at the highest dose was significantly better compared to the water group and the clinical effects were dose dependent. Histology of the joints showed severe inflammation and destruction in the water treated group with minimal inflammatory effects in the dexamethasone and cyclosporine group. Joints injected with cyclosporine were characterized by extensive fibrosis. The joints from CP treated rats showed mild to moderate inflammation with histological features somewhere between the cyclosporine and water injected groups. This study demonstrates that CP given intra-articularly has antiarthritic effects and raises new possibilities for treatment.

Protective effect of folic acid on cyclosporine-induced bone loss in rats

Hyperhomocysteinemia is seen in patients with decreased bone mineral density. Cyclosporine can cause alveolar bone loss and osteopenia. It is also associated with elevated serum homocysteine levels. We aimed to investigate the effect of cyclosporine on serum homocysteine level, bone volume, and bone density, and determine whether folic acid had a protective effect against bone loss. In an experimental study, 40 male Sprague-Dawley rats were randomly assigned to five groups and received dietary supplementation for 6 weeks with olive oil (Group A), cyclosporine (Group B), folic acid (Group C), and cyclosporine plus folic acid (Group D), or no supplementation (Group F, control). Serum homocysteine, calcium, alkaline phosphatase, total bone volume, periodontal ligament volume, and volume density of bone were compared between groups. Mean serum homocysteine level (10.84 ± 0.93 μmol/l) was significantly higher in group B (cyclosporine supplementation) compared with the other groups (P = 0.001). Mean total mandibular volume was 46.3 ± 13.6 mm(3) in rats treated with cyclosporine, 80.4 ± 15.70 mm(3) in rats treated with folic acid (P = 0.004), and 73.9 ± 21.3 mm(3) in rats treated with cyclosporine plus folic acid (P = 0.028). In our experimental model, cyclosporine increased serum homocysteine levels and decreased bone volume and density. Folic acid may have a preventive role against bone loss in rats treated with cyclosporine.

Alterations in QTc and PR intervals in renal transplant patients receiving immunosuppressive drugs

IntroductionKidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD). Strategies to increase donor organ availability and to prolong the transplanted kidney's survival have become...