Term Cyclosporin Research Articles

Cyclosporine vs. tacrolimus after liver transplantation for primary sclerosing cholangitis – a propensity score-matched intention-to-treat analysis

There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US. From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates. The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p= 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant. Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC. The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation.

20% Autologous serum vs. 0.05% cyclosporine and preservative-free artificial tears in the treatment of Sjögren related dry eye.

To compare the 3-month results of treatment with 20% autologous serum or combination treatment with preservative-free artificial tears and 0.05% cyclosporine in patients with dry eye disease due to primary Sjögren's syndrome. A total of 130 eyes of 65 patients with newly diagnosed dry eye disease due to primary Sjögren's syndrome were included in the study. The patients were divided into two treatment groups: 66 eyes of 33 patients were assigned to the autologous serum treatment group, and 64 eyes of 32 patients were assigned to the combination treatment group. Schirmer test, tear break-up time and Ocular Surface Disease Index (OSDI) scores were recorded at pretreatment and at 3 months of treatment. At 3 months of treatment, the mean Schirmer value and the mean tear break-up time were significantly higher in the combination treatment group (p<0.0001 and p=0.034, respectively). The OSDI score at 3 months was significantly lower in the autologous serum Group (p=0.004). When the two groups were evaluated separately, the improvements in Schirmer, tear break-up time test, and OSDI scores from before to after treatment were statistically significant: p<0.0001, p<0.001, and p<0.0001, respectively, for the authologus serum Group, and p<0.0001, p<0.001, and p<0.0001, respectively, for the combination treatment group. In short-term treatment of dry eye disease due to primary Sjögren's syndrome, treatment with autologous serum was significantly superior to -combination treatment with preservative-free artificial tears and 0.05% cyclosporine in terms of improvement in OSDI scores. Improvements in Schirmer test and tear break-up time scores were significantly superior in the group treated with preservative-free artificial tears and 0.05% cyclosporine.

Efficacy and Safety of Cyclosporine in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis.

There are various studies that have addressed the use of Cyclosporine among patients with acute myocardial infarction (AMI). However, to date there is hardly any concise and systematically structured evidence that debate on the efficacy and safety of Cyclosporine in AMI patients. The aim of this review is to systematically summarize the overall evidence from published trials, and to conduct a meta-analysis in order to determine the efficacy and safety of Cyclosporine vs. placebo or control among patients with AMI. All randomized control trial (RCT) published in English language from January 2000 to August 2017 were included for the systematic review and meta-analysis. A total of six RCTs met the inclusion and were hence included in the systematic review and meta-analysis. Based on the performed meta-analysis, no significant difference was found between Cyclosporine and placebo in terms of left ventricular ejection fraction (LVEF) improvement (mean difference 1.88; 95% CI −0.99 to 4.74; P = 0.2), mortality rate (OR 1.01; 95% Cl 0.60 to 1.67, P = 0.98) and recurrent MI occurrence (OR 0.65; 95% Cl 0.29 to 1.45, P = 0.29), with no evidence of heterogeneity, when given to patients with AMI. Cyclosporine also did not significantly lessen the rate of rehospitalisation in AMI patients when compared to placebo (OR 0.91; 95% Cl 0.58 to 1.42, P = 0.68), with moderate heterogeneity (I2 = 46%). There was also no significant improvement in heart failure events between Cyclosporine and placebo in AMI patients (OR 0.63; 95% Cl 0.31 to 1.29, P = 0.21; I2 = 80%). No serious adverse events were reported in Cyclosporine group across all studies suggesting that Cyclosporine is well tolerated when given to patients with AMI. The use of Cyclosporine in this group of patients, however, did not result in better clinical outcomes vs. placebo at improving LVEF, mortality rate, recurrent MI, rehospitalisation and heart failure event.

Long Term Cyclosporin A Blood Level after Kidney Transplantation, Revisited

Long Term Cyclosporin A Blood Level after Kidney Transplantation, Revisited

Tofacitinib: Janus Bifrons in Ulcerative Colitis Treatment

Tofacitinib: Janus Bifrons in Ulcerative Colitis Treatment

Cyclosporine: A Review

The discovery and use of cyclosporine since its inception into clinical use in the late 1970s has played a major role in the advancement of transplant medicine. While it has improved rates of acute rejection and early graft survival, data on long-term survival of renal allografts is less convincing. The finding of acute reversible nephrotoxicity and nephrotoxicity in nonrenal transplants has since led to the widely accepted view that there is a chronic more irreversible component to this agent as well. Since that time, there has been intense interest in finding protocols which seek to minimize and even avoid the use of calcineurin inhibitors altogether. We seek to review cyclosporine in terms of its mechanism of action, pathophysiologic, and histologic features associated with acute and chronic nephrotoxicity and recent studies looking to avoid its toxic side effects.

Targeting JAK3 in kidney transplantation

This review will discuss the mechanism of action and important clinical trial data in renal transplantation for the small molecule Janus kinase (JAK) 3 inhibitor tofacitinib, formerly known as CP-690,550 and tasocitinib. JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors, particularly members of the cytokine receptor common gamma (cγ) chain family. JAK3 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis. Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared with vehicle control. Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival. There was also a lower rate of new-onset diabetes after transplant. However, there was a trend toward more infections, including cytomegalovirus and BK virus nephritis. Tofacitinib may be a promising alternative to calcineurin inhibitors. The optimal therapeutic window is still being determined.

The role of tacrolimus in renal transplantation

Tacrolimus gained FDA approval for use in liver transplantation in 1994 and, approximately 3 years later, was approved for the prevention of acute rejection in kidney transplantation. Over the last decade tacrolimus has become the calcineurin inhibitor of choice for the prevention of rejection in renal transplantation. The objective of this study was to provide a review and update of the literature on the use of tacrolimus in renal transplantation. Numerous clinical trials have shown tacrolimus to be superior to cyclosporine in the prevention of acute rejection and recent trials have demonstrated superiority of tacrolimus over cyclosporine in terms of allograft survival. Post-transplant diabetes remains more common with tacrolimus than cyclosporine, despite lower doses of both tacrolimus and corticosteroids. A novel once-daily dosage form of tacrolimus has recently been developed and is approved for use in Europe. Tacrolimus remains an important immunosuppressant for the prevention of acute rejection. The prolonged-release formulation may improve compliance and possibly long-term outcomes.

Tacrolimus in Heart Transplant Recipients

The development of cyclosporine was pivotal in allowing cardiac transplantation to become an accepted treatment for patients with end-stage heart disease. More recently, tacrolimus has become available as a useful alternative to cyclosporine, and has been successfully combined with either azathioprine or the newer anti-proliferative agents, mycophenolate mofetil or sirolimus. Numerous randomized clinical trials have demonstrated that tacrolimus is comparable to cyclosporine in terms of overall patient survival and at least equally effective in preventing acute rejection. In addition, tacrolimus has been particularly effective as a rescue treatment in cases where recurrent rejection has occurred with cyclosporine. The adverse effects of tacrolimus differ from those of cyclosporine, and the drug particularly shows an improved profile with respect to hypertension, dyslipidemia, and long-term renal function. These data have recently led to the regulatory approval of tacrolimus for primary immunosuppression in patients undergoing cardiac transplantation in the US.

48 YEAR OLD MALE WITH SUDDEN ONSET OF RIGHT SIDED WEAKNESS

This 48 year-old male presented with sudden right sided weakness and hypertension, and on CT was found to have a deep left hemispheric intracerebral hematoma. There were accompanying bilateral hypointensities in the occipital lobes, unchanged 1 day later, when expansion of the hematoma and uncal herniation resulted in death. The past medical history included liver transplantation followed by long term cyclosporin, features of thrombotic thrombocytopenic purpura (TTP) attributed to cyclosporin, type 1 diabetes mellitus and acute renal failure attributed to diabetic nephropathy. There was a 2-month history of hypertension poorly responsive to therapy. The occipital lobes at autopsy showed focal cortical hemorrhages with bilateral discoloration of white matter sparing subcortical zones. Microscopy showed white matter pallor with parenchymal cysts, enlarged perivascular spaces and focal acute hemorrhages consistent with edema secondary to acute hypertension. Cortical hemorrhages were associated with intravascular thrombi and fibrin exudates, as well as an accompanying microinfarct, attributed to TTP. The occipital pathology reflects the posterior leukoencephalopathy syndrome (PLS) combined with cortical lesions of TTP. PLS is usually diagnosed radiologically by occipital hypointensities, and is reversible, so that autopsy pathology is rarely examined. TTP may predispose to the development of the PLS in certain cases.

Cyclosporin Maintenance Monotherapy After Renal Transplantation

The use of cyclosporin monotherapy as maintenance immunosuppression in primary cadaveric renal transplant recipients is not popular except in a few European centres. Corticosteroid withdrawal is becoming more popular, and is usually attempted with the newer immunosuppressants which have a more corticosteroid-sparing effect than cyclosporin. The adverse effects and morbidity associated with maintenance regimens consisting of 2 or 3 immunosuppressive drugs are well known, but the potential benefits of cyclosporin monotherapy must be balanced against an increased risk of graft loss by rejection. We selected patients for a trial of corticosteroid withdrawal and subsequent cyclosporin monotherapy. These patients received an individually designed immunosuppressive regimen with careful control of cyclosporin trough concentrations. The cyclosporin formulations used were its original oil-based solution or gelatin capsule (Sandimmun, Sandimmune )until mid-1996 and then the microemulsion formulation (Neoral). Corticosteroid withdrawal was attempted in 89% of patients with a graft functioning at 3 months after transplantation and was effective in 88% of them. At a mean follow-up time of 98 +/- 23 months, 69% of grafts were functioning and 92% of patients were alive. 50% of patients with a functioning graft were receiving long term cyclosporin monotherapy. Mild rejection episodes occurred in 6% of patients receiving cyclosporin monotherapy per year of treatment, and chronic rejection caused graft loss in 1.4% of patients per year of treatment. Comparison of successful and unsuccessful outcomes allows us to define favourable predictive factors. For corticosteroid withdrawal these are: older recipient age, lower creatininaemia at months 6 and 8 and higher trough cyclosporin concentrations at month 6. For cyclosporin monotherapy these are: later timing of azathioprine withdrawal, recipient age >25 years, donor age <or=40 years, creatininaemia <or=125 micromol/L at initiation of monotherapy and no rejection episode before initiation of monotherapy. We have observed a low incidence of nonmelanoma skin cancers and of squamous-cell carcinoma in our series. This is perhaps the result of the azathioprine-sparing effects of the regimen (7 azathioprine-free years per patient with successful cyclosporin monotherapy, and 4 azathioprine-free years per patient with unsuccessful monotherapy). This important point will need further studies but is encouraging. Maintenance cyclosporin monotherapy is feasible and probably useful in selected primary graft recipients without deleterious effects on overall results in terms of graft and patient survival. Careful patient selection using the predictive factors we have defined should make cyclosporin monotherapy more effective, allowing the present 57% success rate at 5 years post-transplantation to be increased by 15 or 20%.

Use of HMG-CoA Reductase Inhibitors after Kidney and Heart Transplantation

Hypercholesterolaemia is common in patients treated with cyclosporin after kidney and heart transplantation; coronary vasculopathy, graft atherosclerosis or cardiovascular complications are the most frequent causes of mortality. Coronary heart disease has been attributed to hypercholesterolaemia and has been identified as a major risk factor of long term graft outcome in patients after kidney transplantation. HMG-CoA reductase inhibitors have been proven to be effective in lowering serum cholesterol concentrations in kidney and heart graft recipients receiving long term cyclosporin immunosuppression, and are therefore the drugs of choice in patients requiring treatment for hypercholesterolaemia after organ transplantation. The hydrophilic HMG-CoA reductase inhibitors, such as pravastatin and fluvastatin, should be distinguished from the lipophilic agents, lovastatin and simvastatin, with regard to toxicity and accumulation. Maximal doses of drugs in the latter group should be avoided, whereas the former have been administered at high dosages over prolonged periods of time without adverse effects. Recent preliminary data indicate that treatment with pravastatin not only decreases serum cholesterol but may have beneficial effects on the incidence, recurrence and severity of rejection episodes after kidney and heart transplantation.

Short Term Cyclosporin Treatment in Hyper-IgE-like Syndrome

Short Term Cyclosporin Treatment in Hyper-IgE-like Syndrome

The Place of Cyclosporin in the Treatment of Severe Psoriasis

The degree of efficacy of cyclosporin in psoriasis is dose related. While doses of 2.5 to 5 mg/kg/day result in significant clearing of psoriasis within 4 to 8 weeks, response to treatment is more rapid and dramatic with higher doses (> 5 mg/kg/day). A gradual recurrence of psoriasis, without rebound, usually occurs within weeks to months after discontinuation of therapy. Tachyphylaxis has not been reported. An initial dose of 3 to 5 mg/kg/day is recommended for the treatment of severe psoriasis and 5 mg/kg/day for the treatment of erythrodermic psoriasis, because it maximises the probability of therapeutic efficacy while minimising the likelihood of significant adverse effects. Although there appears to be no correlation between cyclosporin whole blood trough concentrations and clinical response, the drug concentrations in skin appear to approximate the peak plasma concentrations. Cyclosporin has been shown to be more effective than systemic retinoids in the treatment of psoriasis vulgaris. Psoriatic erythroderma may respond extremely rapidly to oral cyclosporin. Psoriatic arthropathy and nail disease also improve during cyclosporin therapy. Patients on cyclosporin treatment must be carefully selected and monitored for renal function, with due consideration given to drug interactions. The currently available formulation of cyclosporin does not ensure constant and predictable drug exposure because its gastrointestinal absorption is affected by biliary secretion, ingested food and gastrointestinal motility. A new microemulsion-based formulation (Neoral®)1 capable of guaranteeing more consistent bioavailability has been developed, and is under investigation. There is no significant cyclosporin-sparing effect when etretinate and UVB are used adjunctively. Furthermore, the combination of cyclosporin-UVB should be used with caution because of an increased risk of nonmelanoma skin cancer. The addition of topical corticosteroids results in more rapid clearing of psoriasis plaques, although relapse rates remain unchanged. The combination with calcipotriol has been evaluated in a placebo-controlled study, and it seems to have a cyclosporin-sparing effect. Cyclosporin is useful in short term intermittent therapy to control acute psoriatic flares and/or to induce a remission. Alternative agents can then be used for maintenance treatment, thus reducing the risk of toxicity associated with long term cyclosporin therapy.

Safety aspects of the long term cyclosporin A therapy.

The long term safety issues of cyclosporin A therapy of rheumatoid arthritis can be classified into two categories: side effects typical for the cyclosporin group of drugs and side effects due to the immunosuppression. A decrease in the renal function and elevation of the blood pressure are the main cyclosporin-related side effects. Blood pressure can be controlled in most cases by dose reduction or by antihypertensive therapy. With the current low dose strategy, a mild decrease of renal function is common but the incidence of permanent renal damage is low and the prognosis is good. Immunosuppression as such may predispose for malignancies and infections. Cyclosporin A is not mutagenic. However, it may impair the immunosurveillance for transformed cells. Data from organ transplantation suggest that immunosuppressive regimens including cyclosporin A increase the incidence of lymphoproliferative disorders and skin cancers. It is not clear whether cyclosporin A can increase the incidence of these tumors in patients with rheumatoid arthritis due to a relatively small number of patients studied thus far. Monitoring of cyclosporin A therapy of rheumatoid arthritis is simple but mandatory.

血管柄付同種骨移植の実験的研究 （第３報） 免疫抑制剤長期投与群と短期投与群の比較

A study of vascularized massive bone allograft was performed, using the devised model of inbred rat with cyclosporin A as immunosuppressive drug. This model was designed for making it easy to observe callus formation on both proximal and distal sites of massive interaclary bone allograft and the montitoring of the viability of osteocytes by the bone scan. Cyclosporin A was used postopertively both continuously and short term (14 days after transplant) at 10mg/kg/day (i. m.) as recipient treatment.Bone scintigram indicated remakable difference between continuous cyclosporin group and short term cyclosporin group. High uptake was continuously observed in the continuous cyclosporin groups. In the short term cyclosporin group, howevever, the high uptake was observed during the 3 to 4 weeks. and it changed into the weak or mottled uptake until 6 weeks after transplantation.In the continuous cyclosporin group periosteal new bone formation was observed on both donor and recipient bone, and each of them united until 4 weeks postoperatively at the proximal side and it took one more week to get a union at the distal side. These results were very similar to those of the vascularized bone isograft. On the other hand, in the short term cyclosporin group, the union was remarkably delayed and it took 8 weeks to obtain the union at the proximal side, and failure of the bone union developed in few of models at the distal side.In conculsion, under immunosuppression, viability of he allogratted bone was maintaind and the union of both osteosynthetic side occurred surely as soon as the vasucularized bone isograft. However, in the short term (14 days) cyclosporin group, vascularized allografted bone was rejected after stopping cyclosporin. The union delayed than the continuous cyclosporin group when the cyclosporin was stopped 14 days after transplantation and before union.

Low dose, short term Cyclosporin A does not protect the Schwann cells of allogeneic nerve grafts

The question of whether Cyclosporin A, at the low doses reported to allow survival of nerve allografts, allows the allogeneic Schwann cells to survive has been investigated. Nerve allografts were inserted by microsurgical techniques into trembler mice treated with 10 mg/kg or 15 mg/kg Cyclosporin A, daily for 12 weeks post-operatively. Electrophysiological recordings were made one week prior to surgery, and at the end of the immunosuppression period, after which the grafts were processed for electron microscopy. All grafts showed signs of rejection and donor Schwann cells had been replaced by host cells. The results suggest that Cyclosporin A in these doses is insufficient to overcome rejection problems or to induce tolerance to donor Schwann cells.

Long term cyclosporin therapy has its penalties

Long term cyclosporin therapy has its penalties

FK506

WARTY, VIJAY; DIVEN, WARREN; CADOFF, EVAN; TPDO, SATORU; STARZL, THOMAS; SANGHVI, AJIT Author Information

Short Term Cyclosporin Therapy Appears Helpful

Short Term Cyclosporin Therapy Appears Helpful