Cyclosporine Group Research Articles

Living Related Kidney Transplantation Without Calcineurin Inhibitors: Initial Experience in a Mexican Center

We performed a prospective randomized trial comparing sirolimus/mycophenolate mofetil (MMF)/prednisone to cyclosporine/MMF/prednisone and selected induction therapy with basiliximab. Twenty patients received sirolimus (10 mg loading dose followed by 3 mg/m body surface area/day, keeping 24-hr trough levels at 10-15 ng/mL for six months and 5-10 ng/mL thereafter. Twenty-one patients began cyclosporine (4 to 8 mg/kg/day, keeping 12-hour trough levels at 150-300 ng/mL for 6 months and 100-200 ng/mL afterwards). Mean follow up was 15.8 months. One-year patient and graft survival was similar in both groups (>90%). Acute rejection rate was 16.6% in the sirolimus group and 5.2% in the cyclosporine group (P=NS). There were no differences in mean serum creatinine between groups. No patients who received basiliximab and had sirolimus target levels suffered acute rejection at one year. The sirolimus group had significantly higher cholesterol and triglycerides. A calcineurin inhibitor-free regimen using sirolimus produces comparable one-year transplant outcomes in living related kidney transplants compared to a calcineurin inhibitor regimen.

The effect of budesonide mouthwash on oral chronic graft versus host disease

Oral chronic graft versus host disease (cGVHD) is common and a major cause of morbidity and loss of quality of life in long term survivors. Cyclosporine with prednisone remains the first line therapy for oral manifestations of cGVHD. However, even with routine administration of systemic agents, many patients with oral manifestations of cGVHD do not have resolution of their disease and may benefit from incorporation of local therapy. Budesonide is a highly potent steroid which has minimal systemic side effects and being used for oral cGVHD. We designed a retrospective study to compare treatment results of patients with oral cGVHD who received topical budesonide in addition to systemic therapy that consists of combined prednisone and cyclosporine (Group A, n = 12), with the treatment results of patients who were administered the same systemic therapy alone (Group B, n = 11) to determine whether budesonide mouthwash had any advantage on response rates. Three mg topical budesonide/10 ml saline was used 3-4 times a day for up to 6 months in group A. Diagnosis, clinical staging, and treatment response scoring for cGVHD were performed according to National Institutes of Health (NIH) consensus criteria. At the baseline examination, there were no statistically significant differences in terms of median oral cGVHD examination scores between two groups. After treatment, there was statistically significant decrease in median oral cGVHD examination scores compared to baseline (P < 0.001 and 0.021), and significant differences were found between two groups (P < 0.032). Overall response rate was 83% and 36% for group A and B, respectively (P = 0.036). However, no statistically significant differences were found between median pain scores of two groups before and after treatment (P = 0.740 and P = 0.091). No major systemic side effects and oral candidiasis were observed in two groups of patients. We concluded that topical budesonide might be added to systemic therapy to obtain better response rates in patients with oral cGHVD.

Cyclosporin versus tacrolimus for liver transplanted patients

Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies. Several randomised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients, but it remains unclear which is superior. To evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, and conference proceedings were searched (August 2005) to identify relevant randomised clinical trials. Our search included scanning of reference lists in relevant articles and correspondence with investigators and pharmaceutical companies. All randomised clinical trials where tacrolimus was compared with cyclosporin for the initial treatment of first-time liver transplant recipients. We included randomised trials irrespective of blinding, language, and publication status. The primary outcome measure was all-cause mortality. Data were synthesised (fixed-effect model) and results expressed as relative risk (RR), values less than 1.0 favouring tacrolimus, with 95% confidence intervals (CI). Two authors assessed trials for eligibility, quality, and extracted data independently. We included 16 randomised trials. The number of deaths was 254 in the tacrolimus group (1899 patients) and 302 in the cyclosporin group (1914 patients). At one year, mortality (RR 0.85, 95% CI 0.73 to 0.99) and graft loss (RR 0.73, 95% CI 0.61 to 0.86) were significantly reduced in tacrolimus-treated recipients. Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75 to 0.88), and steroid-resistant rejection (RR 0.54, 95% CI 0.47 to 0.74) in the first year. Differences were not seen with respect to lymphoproliferative disorder or de-novo dialysis rates, but more de-novo insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. More patients were withdrawn from cyclosporin therapy than from tacrolimus (RR 0.57, 95% CI 0.49 to 0.66). Tacrolimus is superior to cyclosporin in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it increases the risk of post-transplant diabetes. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid acute rejection and steroid-resistant rejection in nine and seven patients, respectively, and graft loss and death in five and two patients, respectively, but four additional patients would develop diabetes after liver transplantation.

Hepatitis C Virus Recurrence After Liver Transplantation: Influence of Immunosuppressive Regimens on Viral Load and Liver Histology

Cyclosporine has recently been reported to produce in vitro suppression of hepatitis C virus replication driven by blockade of cyclophilins, an effect not shown for tacrolimus. However, the clinical consequence of this in vitro finding have not been well studied in vivo. We compared viral load and fibrosis in transplanted patients receiving monotherapy with tacrolimus or cyclosporine. Patients with recurrent hepatitis C after transplantation were selected from two tertiary centers with the following inclusion criteria: monotherapy with tacrolimus or cyclosporine for more than 12 months before viral load measurement, no antiviral treatment, corticosteroids stopped within 12 months after transplantation. HIV, hepatitis B, and active infection by cytomegalovirus were excluded. Patient characteristics, viral load, and fibrosis were compared by univariate analysis between the cyclosporine and tacrolimus groups. Significant variables, viral load, and fibrosis were included in a multivariate model. Sixty-six patients were included, 46 on tacrolimus and 20 on cyclosporine. Fifty-six were male, and the mean age was 55.3 ± 10.1 years. Fibrosis (Ishak score) was 3.9 ± 1.9 in the cyclosporine group and 2.7 ± 1.9 in the tacrolimus group ( P = .019). Viral load (log 10IU/mL) was 5.8 ± 0.5 and 5.9 ± 0.5, respectively ( P = .7) and time since liver transplantation was 95.3 ± 47.7 and 41.1 ± 16.8 months ( P = .0001). In the multivariate model, viral load ( P = .65) and fibrosis ( P = .24) were not significantly different and only time since transplantation remained significant ( P = .0001). In conclusion, viral load was not different in patients with tacrolimus as compared with cyclosporine, and the lower fibrosis observed in the cyclosporine group lacked significance when considered together with time since liver transplantation.

Pharmacokinetics of Mycophenolic Acid and Its Glucuronidated Metabolites in Stable Lung Transplant Recipients

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil, an immunosuppressive agent commonly used in solid organ transplantation. MPA is metabolized to the inactive metabolite 7-O-mycophenolic acid glucuronide (MPAG) and the active metabolite acyl glucuronide (AcMPAG). Pharmacokinetic profiling of MPA by determining AUC is a tool for determining drug exposure. Many studies, conducted primarily in kidney and some heart and liver transplant recipients, have shown wide interpatient variability in MPA's pharmacokinetic parameters. There have been few studies in the lung transplant group and, even though the lung is not involved in drug elimination, these patients may have different MPA pharmacokinetic characteristics. To characterize the pharmacokinetic parameters and metabolic ratios of MPA in stable adult lung transplant recipients. In an open-label manner, lung transplant recipients were recruited. Blood samples were obtained at 0, 0.3, 0.6, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours postdose. Plasma was separated and acidified for drug concentration analysis (MPA, MPAG, AcMPAG) by an HPLC-ultraviolet detection method. Conventional pharmacokinetic parameters were determined via noncompartmental methods. There was large interpatient variability in all pharmacokinetic parameters of MPA, MPAG, and AcMPAG. Similar variability was observed after stratifying patients into concomitant medication groups: cyclosporine and tacrolimus. There was a trend for the tacrolimus group to have a higher dose-normalized AUC, higher AUC, lower apparent clearance, and lower AUC ratio of AcMPAG/MPA compared with the cyclosporine group. In addition, the cyclosporine group had a lower minimum concentration and higher AUC ratio of MPAG/MPA than did the tacrolimus group (p < 0.05). Because of the large interpatient variability in the pharmacokinetic parameters of MPA, MPAG, and AcMPAG, therapeutic drug monitoring of MPA and its metabolites in lung transplant recipients may be beneficial.

Frequency of hyperuricemia and effect of calcineurin inhibitors on serum uric acid levels in liver transplanted children

Hyperuricemia is common after renal and cardiac transplantations, but it is rarely reported after liver transplantations. The aim of this study is to determine the frequency of hyperuricemia in children following orthotopic liver transplantation and the effects of calcineurin inhibitors tacrolimus and cyclosporine) on blood uric acid levels. Between September 1997 to January 2004, 76 liver transplantations were performed in 70 children (male/female; 39/31) at Ege University, Organ Transplantation Center (37 deceased donation and 39 live donors). Patients who had been transplanted within the last three months and patients who died within six months after liver transplantation were excluded from the study. Finally 59 patients were included in this study. Uric acid levels were measured before transplantation and after transplantation within six months intervals for two yr. In these series 17 cases had increased uric acid levels after liver transplantation (28.8%). Serum uric acid levels in both groups (tacrolimus or cyclosporine) were detected to be significantly higher than initial values at 12th months (p < 0.05). Hyperuricemia developed in eight patients receiving cyclosporine (eight of 11; 72%) whereas nine patients receiving tacrolimus developed hyperuricemia (nine of 48; 18%). However, the rate of having high uric acid levels was significantly higher in cyclosporine group compared tacrolimus group (p = 0.001, OR: 11.5, CI 95% 2.5-52.4). Uric acid levels were also significantly higher in cyclosporine group in 12th and 18th months (respectively, p = 0.003 and p = 0.003). Serum creatinine levels at 12th, 18th and 24th months were significantly higher in cyclosporine group than tacrolimus group (respectively, p = 0.009, p = 0.04 and p = 0.02). Hyperuricemia is a common complication after liver transplantation in children. Cyclosporine may cause hyperuricemia more often in respect to tacrolimus and this may be related to the impairment of renal functions. Complications developing because of hyperuricemia such as gout disease or renal calculi are quite rare in children.

A Randomized Pilot Trial Comparing Cyclosporine and Azathioprine for Maintenance Therapy in Diffuse Lupus Nephritis over Four Years

There is not agreement about the best maintenance treatment for patients with diffuse lupus nephritis. This multicenter, randomized trial compared the safety and efficacy of cyclosporine and azathioprine. Seventy-five patients with diffuse proliferative lupus were given three intravenous methylprednisolone pulses followed by prednisone and oral cyclophosphamide for a median of 90 d. Subsequently, patients were randomly assigned either to cyclosporine or to azathioprine for 2 yr (core study). Treatment continued for up to 4 yr (follow-up study). The primary outcome measure was the incidence of disease flares. Secondary end points were proteinuria per day, creatinine clearance, and adverse effects. Seven flares occurred in the cyclosporine group, and eight occurred in the azathioprine group. At the end of the core study, mean proteinuria decreased from 2.8 +/- 3.57 to 0.4 +/- 0.85 g/d (P < 0.0001) in the cyclosporine group and from 2.2 +/- 1.94 to 0.5 +/- 0.78 g/d (P < 0.0002) in the azathioprine group. After 4 yr, mean proteinuria was 0.2 +/- 0.24 and 0.3 +/- 0.33 g/d, respectively. At the core study end and at the follow-up completion, creatinine clearance and BP levels did not change significantly from baseline in either group. Five of 36 patients who were receiving cyclosporine and four of the 33 who were receiving azathioprine stopped the treatment because of adverse effects. For patients with diffuse proliferative lupus nephritis, azathioprine or cyclosporine combined with corticosteroids demonstrated equal efficacy in the prevention of flares.

Extending Postgrafting Cyclosporine Decreases the Risk of Severe Graft-versus-Host Disease after Nonmyeloablative Hematopoietic Cell Transplantation

It is unknown whether the duration of systemic immunosuppressive treatment after allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) might influence the incidence, severity, timing, and/or corticosteroid-responsiveness of graft-versus-host disease (GVHD). We retrospectively analyzed outcomes among 185 patients with hematologic malignancies who were given grafts from HLA-matched related donors following conditioning with 2 Gy total body irradiation alone or in combination with fludarabine between December 1998 and March 2003. Postgrafting immunosuppression consisted of mycophenolate mofetil (days 0-27) in combination with 3 different cyclosporine (CSP) regimens: taper from (A) days 35 to 56 (n=107), (B) days 56 to 77 (n=35), and (C) days 56 to 180 (n=43). The overall incidences of grades II-IV and III-IV acute GVHD, and extensive chronic GVHD were 52%, 13%, and 56%, respectively. The duration of CSP prophylaxis did not significantly influence the overall rate of acute GVHD (grade II-IV), extensive chronic GVHD, or non-relapse mortality. However, prolonged administration of CSP (group C) was associated with a significantly decreased hazard of grades III-IV acute GVHD (HR 0.2, 95% CI [0.04, 0.9]) and with an increased likelihood of discontinuing all systemic immunosuppression (HR 2.4, 95% CI [1.1, 5.2]) when compared to the shortest course of CSP (group A). Longer CSP duration decreased the risk of severe GVHD and increased the likelihood of discontinuing all systemic immunosuppression after nonmyeloablative HCT with HLA-matched related grafts.

Hypertension, metabolic derangements and renal dysfunction in renal transplant patients using cyclosporine or tacrolimus

Purpose: To assess metabolical and hypertension adverse events and renal function outcomes in patients with renal transplant receiving neoral cyclosporin or tacrolimus in an outpatient service in Brazil. Methods: All consecutive patients with renal transplant performed at Hospital Alemão Oswaldo Cruz between March 2000 and December 2003 were enrolled. Patients were divided in groups I with 24 patients taking tacrolimus and II with 23 patients taking neoral cyclosporin. It was compared their metabolical and hypertension adverse events and renal function outcomes. Results: Both groups presented comparable outcomes at baseline related to age, gender, race, end-stage renal disease and weight. Serum total cholesterol (186.6 ± 42 x 244.1 ± 48.1 p= 0.002; mg/dl), low-density lipoprotein (LDL) cholesterol (98.01± 23.3 x 153.2 ± 41.5 p= 0.011; mg/dl) and triglyceride (181.2 ± 91.1 x 292.5 ± 258.1 – p= 0.012; mg/dl) were significantly lower in patients receiving tacrolimus than those on cyclosporin. The antihyperlipidaemic medication to control lipid levels required by the cyclosporin group was strongly greater (70 vs 26%, p=0.04). Significantly more patients on cyclosporin than on tacrolimus presented hypertension (60 vs17%, p= 0.009). Post-transplant diabetes mellitus frequency showed no difference between groups (24.1 vs 16.6%). The serum creatinine level at the third month of tacrolimus treated patients was significantly lower than the cyclosporin treated patients (1.15  0.21 vs 1.40  0.38; p=0,009). Conclusion: Patients receiving maintenance immunosuppression with tacrolimus as opposed to ciclosporin present better renal function and reduced cardiovascular risk factors.

A Randomized Trial of Inhaled Cyclosporine in Lung-Transplant Recipients

Conventional regimens of immunosuppressive drugs often do not prevent chronic rejection after lung transplantation. Topical delivery of cyclosporine in addition to conventional systemic immunosuppression might help prevent acute and chronic rejection events. We conducted a single-center, randomized, double-blind, placebo-controlled trial of inhaled cyclosporine initiated within six weeks after transplantation and given in addition to systemic immunosuppression. A total of 58 patients were randomly assigned to inhale either 300 mg of aerosol cyclosporine (28 patients) or aerosol placebo (30 patients) three days a week for the first two years after transplantation. The primary end point was the rate of histologic acute rejection. The rates of acute rejection of grade 2 or higher were similar in the cyclosporine and placebo groups: 0.44 episode (95 percent confidence interval, 0.31 to 0.62) vs. 0.46 episode (95 percent confidence interval, 0.33 to 0.64) per patient per year, respectively (P=0.87 by Poisson regression). Survival was improved with aerosolized cyclosporine, with 3 deaths among patients receiving cyclosporine and 14 deaths among patients receiving placebo (relative risk of death, 0.20; 95 percent confidence interval, 0.06 to 0.70; P=0.01). Chronic rejection-free survival also improved with cyclosporine, as determined by spirometric analysis (10 events in the cyclosporine group and 20 events in the placebo group; relative risk of chronic rejection, 0.38; 95 percent confidence interval, 0.18 to 0.82; P=0.01) and histologic analysis (6 vs. 19 events, respectively; relative risk, 0.27; 95 percent confidence interval, 0.11 to 0.67; P=0.005). The risks of nephrotoxic effects and opportunistic infection were similar for patients in the cyclosporine group and the placebo group. Inhaled cyclosporine did not improve the rate of acute rejection, but it did improve survival and extend periods of chronic rejection-free survival. (ClinicalTrials.gov number, NCT00268515.).

Effect of calcineurin inhibitors on survival and histologic disease severity in HCV-infected liver transplant recipients

The severity of recurrent hepatitis C virus (HCV) is likely related to several factors. Controversial results have been reported regarding the effect of specific calcineurin-inhibitors. The aim of this research was to determine whether there are differences on posttransplantation outcome in HCV-infected patients based on initial immunosuppression. Prospective randomized trial comparing tacrolimus vs. cyclosporine-based immunosuppression in a cohort of patients undergoing primary orthotopic liver transplantation between 2001 and 2003 was used. Yearly biopsies were performed. Patients with at least 1 protocol biopsy and those with very severe recurrence despite a follow-up of less than 1 yr (cholestatic hepatitis, progression to bridging fibrosis/cirrhosis) were included. Baseline characteristics (demographics, liver function at transplantation, genotype distribution, donor, surgery, immunosuppression except for the type of calcineurin inhibitor) did not differ between the 2 groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, and/or death due to recurrent disease in the first year) was present in 27 in 90 (30%), and was equally distributed in the cyclosporine and tacrolimus groups (15/46 vs. 12/44, respectively). A total of 33 in 90 (37%) patients had no fibrosis in the first year biopsy with no difference between the cyclosporine and tacrolimus groups (36.5 vs. 37%). The percentage of patients developing recurrent acute hepatitis was also similar (32% vs 35%); time to acute hepatitis though was shorter in the tacrolimus group (59 days [35-185] vs. 92 days [39-343] in the cyclosporin group; P = 0.02). Cholestatic hepatitis was observed in 4 of 44 and 5 of 46 patients under cyclosporine and tacrolimus, respectively (P = not significant). In conclusions, the short-term posttransplantation course of hepatitis C is not related to the calcineurin inhibitor used.

Cyclosporineversustacrolimus in patients with HCV infection after liver transplantation: Effects on virus replication and recurrent hepatitis

To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus (HCV) replication and activity of recurrent hepatitis C in patients post liver transplantation. The data of a cohort of 107 patients who received liver transplantation for HCV-associated liver cirrhosis between 1999 and 2003 in our center were retrospectively analyzed. The level of serum HCV-RNA and the activity of recurrent hepatitis were compared between 47 patients who received either cyclosporine or tacrolimus as the primary immunosuppressive agent and an otherwise similar immunosuppressive regimen which did not lead to biliary complications within the first 12 mo after transplantation. HCV-RNA increased within 3 mo after transplantation but the differences between the cyclosporine group and the tacrolimus group were insignificant (P=0.49 at 12 mo). In addition, recurrent hepatitis as determined by serum transaminases and histological grading of portal inflammation and fibrosis showed no significant difference after 12 mo (P=0.34). Cyclosporine or tacrolimus as a primary immunosuppressive agent does not influence the induction or severity of recurrent hepatitis in HCV-infected patients after liver transplantation.

Unrelated Donor Marrow Transplantation for Acute Lymphoblastic Leukemia in Japan. A Japan Marrow Donor Program Experience between 1993 and 2003.

From 1993 to 2003, 1223 patients, 0 to 61 year old, with high risk acute lymphoblastic leukemia underwent their first bone marrow transplantation through Japan Marrow Donor Program. Most transplants were performed between HLA serologically matched Japanese pairs with a few exceptions.Of all, 520 patients underwent transplantation in the first complete remission (1CR: median follow up 488 days), and their probability of 5 year overall survival (OS) by Kaplan Meier analysis was 58.4(standard error; SE 2.8) %. The 281 patients in the 2CR (452 days) showed OS 49.4(3.7) %, 75 at the third or further CR (249 days), OS 29.5(5.9) %, and 333 at relapse or non CR(162 days), OS 16.4(2.6) %. The outcome of the younger tended to be the better except that the oldest group 51–61 year of age did fair. The GVHD prophylaxes were cyclosporine and short term methotrexate (sMTX) in 681 patients, and tacrolimus plus sMTX in 461. Among the 1CR patients, the 5 year OS of 276 patients in cyclosporine group was 52.0% (SE.3.7%) and 217 tacrolimus group showed significantly better OS, 66.5% (SE 5.7%, P=0.03). The grade II to IV, or III to IV acute GVHD developed in 47.3% or 19.1% respectively without any age difference. Acute GVHD grade I might solely favor the patients in 1CR at 5 years or earlier post-transplant, and the survival of those in 2CR was minimally affected by grade 0 to III acute GVHD. On the other hand, the presence of chronic GVHD did not improve the survival rate of the patients in 1CR, whereas the patients in 2CR achieved better survival if they had limited or extensive chronic GVHD. The importance of HLA class I DNA type matching in Japanese population has been published (N Engl J Med. 1998 Oct 22). Patients with ALL did poorly between the pairs with DNA A-locus mismatch in 1CR and 2CR, B-locus mismatch in 2CR, DRB1-locus mismatch in 2CR.We concluded that, the unrelated donor marrow transplantation in Japan provided as good chance of survival for the patients with ALL as related donors did, despite poorer risk group they belong to. GVHD prophylaxis with tacrolimus might attain better outcome in 1CR patients, and chronic GVHD seemed to improve the OS for the patients in 2CR, but not for 1CR patients.

Comparison between effects of cyclosporine and tacrolimus on glomerular filtration rate in pediatric post‐orthotopic liver transplant patients

Tacrolimus (FK506) and cyclosporine, synonymous with immunosuppressive therapy in organ transplantation, are not spared of potential adverse effects such as nephrotoxicity. We retrospectively compared their effects on cGFR in a post-OLT pediatric population. cGFRs of 32 patients from the LTUNUHS either on tacrolimus (group 1) or cyclosporine (group 2) from pretransplantation, transplantation and 3, 6, 9, 12, 18, 24, 30 and 36 months post-transplantation were compared. 95% CI and p-values were calculated for comparison with p < 0.05 considered significant. Longitudinal data analysis revealed no significant cGFR difference between groups 1 and 2 (p = 0.154). However, there was a significant difference in cGFR with time after transplantation (p < 0.0001). The mean difference score between both treatment groups was 277.92 (95% CI = 88.13-643.97). The survival rate post-OLT was 84.4%. In this retrospective sex-matched case controlled study of LTUNUHS patients, there was no difference between tacrolimus and cyclosporine on renal function. However, there was significant difference in cGFR with time post-OLT (p < 0.0001). The reason for this observation could be multifactorial.

Effects of Mycophenolate Mofetil on Cardiac Allograft Survival and Cardiac Allograft Vasculopathy in Miniature Swine

Chronic rejection, as manifested by cardiac allograft vasculopathy, remains the leading cause of late graft failure in heart transplant recipients. Despite recent clinical trials, the efficacy of mycophenolate mofetil in preventing human cardiac allograft vasculopathy remains controversial. We investigated whether mycophenolate mofetil would prevent cardiac allograft vasculopathy and prolong cardiac allograft survival in our well-established miniature swine model of heart transplantation. Hearts disparate at the major histocompatibility complex class I locus were heterotopically transplanted into miniature swine recipients treated with a 12-day course of mycophenolate mofetil (n = 3) or cyclosporine A (n = 3). Allograft survival, acute rejection, and chronic rejection were monitored in the two groups. Hearts transplanted with 12 days of cyclosporine were rejected between 46 and 61 days, whereas two of the three hearts transplanted with mycophenolate mofetil remained beating beyond 120 days (p = 0.02). At necropsy, there was a 4.9% mean prevalence of cardiac allograft vasculopathy in the mycophenolate mofetil group as compared with 16.6% in the cyclosporine group (p = 0.03). Cardiac allograft rejection and vasculopathy in the cyclosporine-treated group was associated with prominent myocardial interferon-gamma gene expression, a finding absent in two thirds of the mycophenolate mofetil-treated swine. Moreover, the mycophenolate mofetil-treated swine failed to develop IgM or IgG alloantibodies. A short course of mycophenolate mofetil resulted in a longer allograft survival than a similar course of cyclosporine. Moreover, mycophenolate mofetil reduced the prevalence of cardiac allograft vasculopathy as compared with cyclosporine-treated controls. The salutary effect of mycophenolate mofetil may be related to its ability to decrease interferon-gamma expression in the myocardium and prevent the generation of alloantibodies.

Higher exposure to mycophenolic acid with sirolimus than with cyclosporine cotreatment

Therapeutic drug monitoring of mycophenolate mofetil is recommended because of the interindividual variability in the exposition to its active moiety, mycophenolic acid. However, most of the pharmacokinetic studies involved patients cotreated with cyclosporine (INN, ciclosporin). We analyzed the pharmacokinetics of mycophenolic acid in 13 renal graft recipients treated with sirolimus in an anticalcineurin-free regimen and compared it with that of 17 patients cotreated with cyclosporine. The area under the concentration versus time curve over a 12-hour period (AUC 0-12 ) of mycophenolic acid was estimated at 2 weeks, 1 month, 2 months, and 3 months after transplantation. At the first 3 time points, patients cotreated with sirolimus had significantly higher mycophenolic acid AUC 0-12 values compared with patients cotreated with cyclosporine, as follows: 81 mg . h/L (SD, 39 mg . h/L) versus 43 mg . h/L (SD, 11 mg . h/L) (P < .001), 72 mg . h/L (SD, 17 mg . h/L) versus 48 mg . h/L (SD, 13 mg . h/L) (P < .001), and 70 mg . h/L (SD, 25 mg . h/L) versus 47 mg . h/L (SD, 17 mg . h/L) (P < .01) at week 2, month 1, and month 2, respectively. At all time points, patients cotreated with sirolimus had significantly higher dose-normalized mycophenolic acid AUC 0-12 values. At months 1 and 2, white blood cell counts were lower in the sirolimus group than in the cyclosporine group, as follows: 4.8 x 10(3)/mL (SD, 1.1 x 10(3)/mL) versus 6.5 x 10(3)/mL (SD, 2.2 x 10(3)/mL) (P < .01) at month 1 and 4.6 x 10(3)/mL (SD, 1.1 x 10(3)/mL) versus 5.9 x 10(3)/mL (SD, 2.0 x 10(3)/mL) (P < .05) at month 2. These data show that exposure to mycophenolic acid is higher in patients cotreated with sirolimus than in those cotreated with cyclosporine.

Cyclosporine-Induced Coronary Endothelial Dysfunction: Is Tetrahydrobiopterin the Solution?

Background Coronary endothelial dysfunction after heart transplantation is predictive of cardiac allograft vasculopathy. Immunosuppressive drugs, particularly cyclosporine may contribute to this dysfunction by a direct effect. Tetrahydrobiopterin (BH 4) is a potent antioxidant and an essential cofactor of nitric oxide biosynthesis. The purpose of this study was to investigate whether BH 4 could reverse the endothelial dysfunction induced by cyclosporine. Methods A previously described in vitro model of drug incubation in Krebs-bicarbonate solution (4°C, 48 hours) of porcine epicardial coronary arteries was used. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10 −4 mol/L) in the presence or absence of 6-methyltetrahydropterin (MH 4 [0.1 mol/L], a BH 4 analog) to assess its effect on the cylcosporine-induced endothelial dysfunction. Results The average doses of PGF2 α required to attain 50% of the maximal contraction to KCl was significantly lower ( P < .001) in the cyclosporine group (8.6 ± 1.94 × 10 −6 mol/L) compared to the control group (24.8 ± 5.2 × 10 −6 mol/L). Exposure to cyclosporine induced a significant decrease in endothelium-dependent relaxations to serotonin (5HT) (% E max [5HT]: 77% ± 4%; P < .05). Addition of MH 4 significantly reversed this impaired response (% E max [5HT]: 62% ± 4%; P < .05). No alterations of relaxation were observed with bradykinin in both groups. Endothelium-independent relaxations to sodium nitroprussiate were fully preserved. Conclusions These results suggest a significant protective role of BH 4 on coronary endothelial function following exposure to cyclosporine, which could reduce the incidence of endothelial dysfunction and cardiac allograft vasculopathy following cardiac transplantation.

Clinical trial evaluating the efficacy and safety of cyclosporine in dogs with atopic dermatitis

To determine efficacy and safety of cyclosporine in the treatment of atopic dermatitis among dogs in North America. Randomized controlled (phase 1) and open-label (phase 2) trials. 268 dogs with atopic dermatitis. In phase 1, dogs were randomly assigned to be treated with cyclosporine (5 mg/kg [2.3 mg/Ib], PO, q 24 h) or a placebo. In phase 2, all dogs were treated with cyclosporine for 16 weeks. Frequency of cyclosporine administration was decreased if dogs improved clinically. At the end of phase 1, canine atopic dermatitis extent and severity index (CADESI) scores for dogs treated with cyclosporine were significantly lower than scores for control dogs. Percentage of dogs with severe pruritus decreased from 67% to 16% for the cyclosporine group but from 66% to only 61% for the control group. During phase 2, cyclosporine dosage was decreased to every-other-day administration in 39% of the dogs after 4 weeks. After 12 weeks, 22% of the dogs were treated twice weekly and 36% were treated every other day. After 16 weeks, CADESI score had decreased > 50% in 68% of the dogs and 47% of dogs had no or mild pruritus. The most frequent adverse reactions were gastrointestinal tract signs. Results suggest that cyclosporine is efficacious for the treatment of atopic dermatitis in dogs and that frequency of cyclosporine administration can be reduced following an initial induction period. The drug was well tolerated.

Liver Transplantation for Primary Biliary Cirrhosis: Influence of Primary Immunosuppression on Survival

Introduction Liver transplantation is the only established curative therapy for end-stage primary biliary cirrhosis (PBC). However, the influence of primary immunosuppression on long-term patient and graft survival is still controversial. Patients and methods Among 1372 patients who underwent liver transplantation from April 1989 to January 2001, 95 (6.9%) suffered from PBC. The primary immunosuppression consisted of cyclosporine (CyA; n = 56) and tacrolimus (FK; n = 39). Results The median survival of all PBC patients at 5 years was 92% and at 10 years, 90%. There was no difference between the two primary immunosuppression agents. Seven patients died, including five in the cyclosporine group (median = 25 months) and two in the tacrolimus cohort (median = 37 months). One CyA patient group died due to PBC recurrence. Seven patients underwent retransplantation without any difference in primary immunosuppression (CyA 7%; FK 10%). Fifty patients developed an acute rejection episode (CyA 57%; FK 46%); 2 patients, chronic rejection (CyA 2%; FK 4%). Fifty-five patients developed AMA titers after liver transplantation (CyA 66%; FK 46%). Patients presented cyclosporine-based regimens showed significantly ( P = .001) more side effects. Conclusion Long-term follow-up after liver transplantation for PBC shows excellent organ and patient survival. The choice of the primary immunsuppressant had no significant influence on patient survival, PBC-related graft loss, or development of acute or chronic rejection episodes.

Magnesium Supplementation Prevents Chronic Cyclosporine Nephrotoxicity via Adjusting Nitric Oxide Synthase Activity

Introduction Nitric oxide synthase (NOS) is a protective factor for chronic cyclosporine nephrotoxicity by virtue of adjusting the production of nitric oxide (NO). The aim of this study was to explore the role of NOS in the effect of magnesium supplementation to prevent chronic cyclosporine nephrotoxicity. Methods Rats maintained on a low-salt diet were divided into three groups: normal controls, cyclosporine group (CsA 15 mg · kg −1 · d −1 subcutaneously) and CsA + Mg 2+ group (CsA subcutaneously and dietary supplementation with 0.6% Mg enriched by MgCl 2). On day 28, plasma Mg 2+, plasma creatinine, NOS activity, and NO content in renal tissue were examined. The renal expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in kidneys was determined by an immunohistochemistry technique. The lesions of chronic cyclosporine nephrotoxicity were identified by HE and PAS stains as well as electron microscope. Results After 28 days of CsA administration, characteristic histological lesions of chronic cyclosporine nephotoxicity were observed, including arteriolopathy, tubular atrophy and interstitial fibrosis. Giant mitochondria and microcalcifications were observed by electron microscopy. Simultaneously, constitutive nitric oxide synthase (cNOS) activity in kidneys was increased, but NO content did not increase correspondingly ( P < .05) compared with normal controls. Dietary supplementation with Mg 2+ ameliorated the CsA-induced histological lesions. cNOS activity was decreased to normal levels and NOS was increased ( P < .05) compared with animals that only received CsA. CsA and magnesium supplementation did not change iNOS activity. Conclusions Dietary supplementation with Mg 2+ seems to improve renal function and almost abolish CsA-induced histological lesions via altering the abnormal activation of cNOS in this model.