Stopping Cyclosporine Research Articles

Recovery in Function in Olfactory Escheating Cell Transplanted Rat Spinal Cord After Stopping the Injection of Cyclosporine

The study aimed to check whether animals can retain directed forepaw reaching (DFR) function after stopping cyclosporine which is used to prevent immunorejection in xenotransplant of Olfactory Encheating cells (OECs) in Albino Swiss Strain (AS) rat corticospinal tract lesion. The Hematoxylin & Eosin (H&E) staining and immunohistochemistry techniques have been performed on the cryostat sections of corticospinal tract (CST) lesion post-surgery to check the immunorejection and the existence of OEC transplanted tissue before and after injection of cyclosporine. The DFR function have been checked after each stage to see whether animals retain the DFR tasks after stopping cyclosporine . The results show that the daily injection of 100ml diluted cyclosporine avoids immune attack and reduces inflammatory cells infiltrate in delayed CST ipsilateral rat model and also our study proved that stop of cyclosporine injection would not prevent DFR function and the regenerated fibres can still be visualised after 6 months post-operation period.Despite the fact that so many methods such as animal genetic engineering is used to avoid imminuregection after xenotrasplantation in animal model, daily cyclosporine injection for some period after surgery seems to be effective and effortless method to not only deter immunorejection in host animal but it also preserve function such as DFR for a long period post-surgery

Total Body Irradiation Free Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide for Children with Sickle Cell Disease

Introduction- Allogeneic hematopoietic stem cell transplant (HSCT) is a curative option for children with Sickle cell disease (SCD). Children of ethnic minorities lacking a matched sibling donor were unable to access HSCT as most registries lacked matched unrelated donors for them. However, success of haploidentical related donor HSCT with post-transplant cyclophosphamide (PTCy) in SCD has changed that. Now the next need is to avoid total body irradiation (TBI) during conditioning in infants due to its effects on the developing brain and in children with SCD with prior old infarcts to reduce risk of further brain damage. Another need is to avoid severe acute graft vs. host disease (GVHD). Starting cyclosporine as early as day-1 has shown to reduce it. Here we describe outcomes of 3 children with SCD who underwent haploidentical HSCT with PTCy with TBI free conditioning and had early introduction of cyclosporine. Methods- Three children with SCD (Non-identical-twins both females aged 1-year-old and a 14-year-old male) who had no matched related or unrelated donor available underwent haploidentical HSCT after taking informed consent of the parents. Donor for the first twin was her 6/12 matched mother and for the second twin was 7/12 matched older brother and donor for 3rd patient was his 5/10 matched father. Both twins had never been transfused but has had recurrent swollen painful joints while third patient had recurrent bone pain, chest crisis & had received repeated blood transfusions and his MRI had shown multiple old infarcts. The conditioning was with Rituximab 100 mg/m2 IV on day -7, Busulfan 3.6 mg/kg/dose daily IV for 4 days (Day -6 to -3) for the twins and 3.2 mg kg/dose daily for 3rd patient, Fludarabine 40 mg/m2/dose daily IV for 4 days (Day -6 to -3) and Rabbit anti-thymoglobulin (Thymoglobulin) 1.5 mg/kg/dose daily for 3 days (Day -4 to -2). Peripheral blood stem cells-20 million/kg CD34+ cells each for the the twins and 7 million/kg for the 3rd patient was harvested from the respective haploidentical donors and infused to the patients on Day 0. GVHD prophylaxis was with PTCy 50 mg/kg on Day+3 & 4, intravenous cyclosporine from day-1 and MMF from day+5. Results - All three children engrafted (neutrophils on day+19, day+22, day+22 and platelets on day+12, day+15, day+22 respectively). First twin had uneventful course but second twin developed transplant associated microangiopathy on day+28 so cyclosporine was stopped and switched to sirolimus. She recovered fully with methyprednisone and rituximab therapy. Third patient developed atonic seizures, aphasia and severe drowsiness on day+11 needing mechanical ventilation. No new stroke or infective cause was identified. He recovered fully with conservative management and stopping cyclosporine. Chimerism on day+30 and day+100 was fully donor for the twins however 3rd patient developed mixed chimerism on day+22 - 62% donor cells and rejection by day+40- 4% donor cells. Acute GVHD grade I was seen in second twin. No chronic GVHD was observed. All three children are alive at follow up of 244, 231 and 90 days. Both twins are disease free & off immune suppression and 3rd child has had autologous recovery after rejection. Conclusion- Busulfan & Fludarabine based conditioning is a radiotherapy free option for children with SCD undergoing haploidentical HSCT with PTCy. However, in multi-transfused children it may not be sufficient to prevent rejection. Early introduction of cyclosporine is feasible and can possibly reduce acute GVHD. Disclosures No relevant conflicts of interest to declare.

Long-term increase of serum cholesterol level in ulcerative colitis patients treated with cyclosporine: An underdiagnosed side effect frequently associated with other drug-related complications

Introduction: Cyclosporine is one of the recommended therapeutic choices in severe ulcerative colitis (UC) refractory to steroid therapy, although several serious side-effects may limit the use of the drug. Cyclosporine has been reported to increase the total cholesterol level; however the change in the serum cholesterol levels before and after cyclosporine therapy has not been examined in UC patients. The aim of this study was to compare the serum cholesterol levels before and after the cyclosporine therapy in patients with refractory UC and to examine the association between serum cholesterol level and other common side-effects. Patients and methods: We retrospectively assessed the serum cholesterol levels of UC patients who had been treated with cyclosporine. Data of 72 patients (39 female, 33 male, mean age at diagnosis 31.8 years, mean disease duration: 13.5 years) were analyzed statistically. Results: The mean age of UC patients at the start of cyclosporine therapy was 40.3 years, and the mean disease duration at the beginning of the therapy was 8.6 years. The median duration of cyclosporine therapy was 9.6 months, and side effects developed in 52 patients. 65% of them developed increased cholesterol levels. The mean levels of serum cholesterol were 4.48, 6.1 and 5.08 mmol/l at the beginning, during and at the end of the therapy. Elevated serum cholesterol levels were detected in 47.2% of the patients. Serum cholesterol level was significantly increased during and after stopping cyclosporine therapy compared the time before the use of the drug (p

P450 Long-term impacts of colectomy surgery among ulcerative colitis patients study (LOCUS): the final analysis

to steroid therapy, although several serious side-effects may limit the use of the drug. Cyclosporine has been reported to increase the total cholesterol level; however the change in the serum cholesterol levels before and after cyclosporine therapy has not been examined in UC patients. The aim of this study was to compare the serum cholesterol levels before and after the cyclosporine therapy in patients with refractory UC and to examine the association between serum cholesterol level and other common side-effects. Methods: We retrospectively assessed the serum cholesterol levels of UC patients who had been treated with cyclosporine. Data of 72 patients (39 female, 33 male, mean age at diagnosis 31.7 years, mean disease duration: 13.5 years) were analyzed statistically. Results: The mean age of UC patients at the start of cyclosporine therapy was 40.3 years, and the mean disease duration at the beginning of the therapy was 8.6 years. The median duration of cyclosporine therapy was 9.6 months, and side effects developed in 52 patients. 65% of them developed increased cholesterol levels. The mean levels of serum cholesterol were 4.48, 6.1 and 5.08mmol/l at the beginning, during and at the end of the therapy. Elevated serum cholesterol levels were detected in 27% of the patients. Serum cholesterol level was significantly increased during and after stopping cyclosporine therapy compared the time before the use of the drug (p < 0.001, p < 0.004). However, cholesterol levels measured during the therapy was significantly higher compared to the time after stopping cyclosporine (p < 0.001). Significant association was found between the increased serum cholesterol levels and side effects developing during cyclosporine therapy. Conclusions: Our findings suggest that cyclosporine therapy may result in increased serum cholesterol levels even in longterm after stopping the therapy. Considering that cholesterol level were significantly more common in patients developing drug-related complications, routine measurement of serum cholesterol can increase the safety of the drug.

Calcineurin inhibitors in chronic urticaria

The purpose of the review is to review the pathophysiology, available data, and our current recommendations for calcineurin inhibitor (cyclosporine and tacrolimus) treatment in antihistamine refractory chronic idiopathic urticaria (CIU) patients. Low-dose cyclosporine (<5 mg/kg per day) may have unique immunological modulating properties beyond mast cell and basophil stabilization in CIU. Starting CIU treatment with very low cyclosporine dosages (1 mg/kg per day) and titrating based on response and side-effects may decrease adverse events while preserving efficacy. In cyclosporine responsive patients failing cyclosporine taper, case series data support the safety and efficacy of long-term (5-10 years), very low dose (1-2 mg/kg per day) cyclosporine treatment with appropriate clinical monitoring. For CIU patients refractory to antihistamines, low-dose cyclosporine therapy (<3 mg/kg per day) with appropriate laboratory monitoring provides an alternative with an acceptable side-effect profile. Long-term (>12 months) moderate-dose (2.5-5 mg/kg per day) cyclosporine treatment may cause longitudinal increases in serum creatinine. However, decreasing or stopping cyclosporine dosing reverses measured nephrotoxicity in the vast majority of patients, and some patients with careful monitoring can tolerate very low-dose cyclosporine (<2 mg/kg per day) for longer periods. Tacrolimus is an alternative to cyclosporine with a slightly different adverse effect profile. Minimal data are available on its use in chronic urticaria.

Mycophenolic Acid Exposure after Administration of Mycophenolate Mofetil in the Presence and Absence of Ciclosporin in Renal Transplant Recipients

The pharmacokinetics of mycophenolic acid (MPA) are complex, with large interindividual variability over time. There are also well documented interactions with cyclosporin, and assessment of MPA exposure is therefore necessary when reducing or stopping cyclosporin therapy. Here we report on the pharmacokinetic and pharmacodynamic behaviour of MPA in renal transplant patients on standard dose, reduced dose and no cyclosporin. The CAESAR study, a prospective 12-month study in primary renal allograft recipients, was designed to determine whether mycophenolate mofetil-based regimens containing either low-dose cyclosporin or low-dose cyclosporin withdrawn by 6 months could minimize nephrotoxicity and improve renal function without an increase in acute rejection compared with a mycophenolate mofetil-based regimen containing standard-dose cyclosporin. A subset of patients from the CAESAR study contributed to this pharmacokinetic analysis of MPA exposure. Blood samples were taken over one dosing interval on day 7 and at months 3, 7 and 12 post-transplantation. The sampling time points were predose, 20, 40 and 75 minutes and 2, 3, 4, 6, 8 and 12 hours after mycophenolate mofetil dosing. Assessments included plasma concentrations of MPA and mycophenolic acid glucuronide (MPAG) and cyclosporin trough concentrations. The area under the plasma concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) for MPA was the primary pharmacokinetic parameter, and the AUC(12) for MPAG was the secondary parameter. In total, 536 de novo renal allograft recipients were randomized in the CAESAR study. Of these, 114 patients were entered into the pharmacokinetic substudy and 110 patients contributed to the pharmacokinetic analysis. There was a rapid rise in MPA concentrations (median time to peak concentration 0.72-1.25 hours). At day 7 and month 3, the MPA AUC(12) values were similar in the cyclosporin withdrawal and low-dose cyclosporin groups (patients with the same cyclosporin target concentrations to month 6), while at 7 and 12 months, the values in the cyclosporin withdrawal group were higher than in the low-dose group (19.9% and 30.2% higher, respectively). MPA AUC(12) values in the standard-dose cyclosporin group were lower than in the other groups at all time points and increased over time. At all time points, the MPA peak plasma concentration was similar in all groups, and the MPAG concentrations rose more slowly than MPA concentrations. The ratio of the AUC from 6 to 12 hours/AUC(12) suggests that an increasing AUC in the cyclosporin withdrawal group is due to an increase in the enterohepatic recirculation. These findings are consistent with the hypothesis that cyclosporin inhibits the biliary secretion and/or hepatic extraction of MPAG, leading to a reduced rate of enterohepatic recirculation of MPA. Several concurrent mechanisms, such as cyclosporin-induced changes in renal tubular MPAG excretion and enhanced elimination of free MPA through competitive albumin binding with MPAG, can also contribute to the altered MPAG pharmacokinetics observed in the presence and absence of cyclosporin.

Hematopoietic chimerism induces renal and skin allograft tolerance in DLA-identical dogs

Hematopoietic chimerism, a state where donor and recipient bone marrow cells coexist, is associated with donor-specific tolerance. Nonmyeloablative bone marrow transplantation (BMT) has been shown to induce stable mixed hematopoietic chimerism in dog leukocyte antigen (DLA)-matched dogs. The potential for inducing renal and skin allograft tolerance with nonmyeloablative BMT was investigated in DLA-identical and DLA-haploidentical dogs in this study. Renal allografts were performed in 8 DLA-identical and 4 DLA-haploidentical dogs with nonmyeloablative conditioning (200 cGy TBI) and transient immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) with (n = 8) and without (n = 4) simultaneous BMT. Skin allografts were performed in 2 DLA-identical and 4 DLA-haploidentical dogs after stopping CSP and MMF. Two DLA-identical control dogs received renal allografts without TBI, BMT, or immunosuppression with CSP and MMF. Molecular chimerism was determined with a PCR-based DNA microsatellite assay. Serum creatinine (Cr) concentration, urine specific gravity, and sequential renal biopsies were monitored to assess renal allograft function. Donor-type blood cells were first detected 4 weeks posttransplantation in both the myeloid and lymphoid lineages. Donor chimerism was present for at least 76 weeks in the DLA-identical dogs. Mixed chimerism was not observed in the DLA-haploidentical dogs or DLA-identical dogs that did not undergo BMT. The renal allografts were acutely rejected within 14 days in the 2 DLA-identical control dogs. There was long-term (> 5 yrs) renal allograft survival as evidenced by a normal (< 2.0 mg/dL) serum Cr concentration in both the DLA-identical and DLA-haploidentical dogs that underwent 200 cGy TBI and transient immunosuppression with CSP and MMF either with or without simultaneous BMT. Renal allograft inflammation was severe in the control dogs, mild to moderate in the DLA-haploidentical dogs, and minimal in the DLA-identical dogs. Donor-specific skin grafts were accepted in the DLA-identical dogs but rejected in the DLA-haploidentical dogs. Nonmyeloablative conditioning (200 cGy TBI) and transient immunosuppression with CSP and MMF induce renal and skin allograft tolerance in DLA-identical and permit long-term renal allograft survival in DLA-haploidentical dogs. These findings suggest it may possible to obtain long-term allograft survival in DLA-identical and -haploidentical dogs without the need for chronic immunosuppressive therapy.

Treatment of Herpes Simplex Virus Stromal Keratitis Unresponsive to Topical Prednisolone 1% With Topical Cyclosporine 0.05%

To assess the efficacy of topical cyclosporine 0.05% (Restasis) in patients with herpes simplex virus nonnecrotizing stromal keratitis unresponsive to topical prednisolone. Prospective case series. Patients with herpes simplex virus stromal keratitis (n = 12) that was unresponsive to topical prednisolone acetate 1% for at least four weeks were evaluated at a single site. Eyes were treated with topical cyclosporine twice a day and begun on a rapid prednisolone taper. Visual acuity, slit-lamp appearance, intraocular pressure, and corneal sensitivity were evaluated every two weeks for at least three months. Stromal keratitis resolved with cyclosporine in 10 of 12 patients after one month. The mean lesion area decreased more with cyclosporine than with prednisolone (2.0 mm with cyclosporine compared with 0.25 mm with prednisolone). After stopping cyclosporine therapy, four patients had recurrence of stromal keratitis. This series suggests that herpes simplex virus stromal keratitis can be treated effectively with topical cyclosporine, particularly in cases that are not responsive to topical prednisolone.

Alefacept in combination with tapering doses of cyclosporine in patients with psoriasis

The systemic agent cyclosporine has inhibitory effects on T-cell activation, which likely account for its efficacy in the treatment of moderate to severe psoriasis. However, the use of cyclosporine is limited because of dose-related toxicities (eg, hypertension, nephrotoxicity), which necessitate routine monitoring of its safety. Cyclosporine also causes generalized immunosuppression, which may increase the risk for infections and malignancies. For these reasons, continuous treatment with cyclosporine is not recommended for >1 year. Complete relapse of psoriasis generally occurs within 1 month after stopping cyclosporine therapy. Alefacept is the first biologic agent to be approved in the US for the treatment of moderate to severe chronic plaque psoriasis. This agent has a remittive mechanism of action—it selectively reduces the T-cell population implicated in the pathogenesis of psoriasis. In clinical studies, the safety profile of alefacept has been comparable to placebo and there has been no evidence of an increased risk for infections or malignancies. In clinical practice, patients receiving cyclosporine need a safe and effective strategy for stopping cyclosporine and starting alefacept. An open-label study is underway in adult patients with chronic plaque psoriasis who are well controlled on cyclosporine and who need or desire to transition to alefacept therapy. In phase 1 (weeks 1–12), alefacept 7.5 mg will be administered by IV bolus once weekly, while cyclosporine will be tapered from 4 mg/kg/day (weeks 1–4), to 3 mg/kg/day (weeks 5–8), and then to 2.5 mg/kg/day (weeks 9–12). Topical therapy will also be permitted. After the 12th alefacept dose, both alefacept and cyclosporine will be discontinued. In phase 2 (weeks 12–24), patients will be off both alefacept and cyclosporine, but may receive topical therapy and UVB phototherapy as per physician’s standard of care. In phase 3 (weeks 24–48), patients can receive a repeat course of IV alefacept 7.5 mg once weekly for 12 weeks if clinically indicated followed by 12 weeks of observation. Topical therapy will be permitted throughout phase 3, and UVB phototherapy will be allowed during the observation period. Cyclosporine will not be administered in phase 3. Assessments will include a Physician Global Assessment, the Dermatology Life Quality Index, adverse events, physical examinations, and laboratory tests as specified in the package inserts for alefacept and cyclosporine.

Subclinical Renal Injury Induced by Transient Cyclosporine Exposure is Associated with Salt-Sensitive Hypertension

Cyclosporine use is highly associated with the development of salt-sensitive hypertension. We hypothesized that subtle renal injury induced by cyclosporine could lead to salt sensitivity. Cyclosporine nephropathy was induced by treatment for 4 weeks with cyclosporine (15 mg/kg/day) on a low sodium (0.05%) diet, followed by stopping cyclosporine and placement on a high sodium (4%) diet for 4 additional weeks. Control groups included a group treated with cyclosporine (15 mg/kg/day) on a normal salt diet in which nephropathy does not develop, and a vehicle-treated group. A fourth group received half-dose of cyclosporine (8 mg/kg/day) on a low sodium diet, which results in mild nephropathy. Biopsies were obtained at the end of the cyclosporine administration (4 week) and at sacrifice (8 week), and blood pressure and renal function were measured. Rats treated with cyclosporine for 4 weeks on a low sodium diet developed classic features of tubulointerstitial disease and arteriolopathy; these changes were absent in the cyclosporine/normal salt group and in the vehicle group. At 4 weeks, all groups were switched to a high salt diet; only the rats with nephropathy developed hypertension. The degree of hypertension correlated closely with the degree of tubulointerstitial injury (r=0.85) and with the severity of the arteriolopathy (r=0.9) (p<0.0.1). Importantly, renal function (creatinine clearance) was normal in all groups at 8 weeks, documenting that the hypertension could not be attributed to cyclosporine-mediated alterations in glomerular filtration rate (GFR). One mechanism by which cyclosporine induces hypertension is the induction of subtle renal microvascular and tubulointerstitial disease. This mechanism is not dependent on GFR and may persist even after the cyclosporine is discontinued.

Immunosuppressive therapy for ulcerative colitis: results of a nation‐wide survey among consultant physician members of the British Society of Gastroenterology

The role of immunosuppressive therapy in ulcerative colitis remains controversial. There is little information available on how frequently immunosuppressives are used, the circumstances, dose and duration of use and perceived benefit. A postal survey was sent to consultant gastroenterologist members of the British Society of Gastroenterology. Questionnaires were returned by 81% of the 496 UK consultants approached. Azathioprine use was frequent, with 93% reporting previous use and 86% use within the past year. Although 95% usually prescribed a < or =2 mg/kg dose, only 39% were prepared to prescribe higher doses. There was marked variation in duration of use, with 46% using azathioprine for <2 years and 17% continuing it for 4 years or longer. Consultants with more experience of azathioprine in ulcerative colitis used it at higher maintenance doses for longer periods, and in patients with less extensive disease. Cyclosporin use was reported by 47% of those caring for ulcerative colitis patients, with 36% having used it at least once in the past year. However, 65% of users estimated that fewer than 50% of patients subsequently avoided colectomy. On stopping cyclosporin only 21% always introduced an alternative immunosuppressive, while 23% never did so. Potentially serious side-effects attributable to azathioprine and cyclosporin were reported by 36% and 45% of users of each drug, respectively. This survey reveals considerable variation in the amount and pattern of immunosuppressive use in ulcerative colitis, with serious side-effects commonly seen. There is a pressing need for further randomized controlled trials to provide reliable evidence as to how immunosuppressive therapy should be used in ulcerative colitis.

Long-term results after stopping cyclosporine at 6 months following renal transplantation

Long-term results after stopping cyclosporine at 6 months following renal transplantation

Failure of cyclosporine to induce graft-vs-host disease or graft-vs-leukemia after syngeneic bone marrow transplantation in mice

Cyclosporine administration can result in graft-vs-host disease (GVHD) after syngeneic or autologous bone marrow transplantation (BMT). However, data on its anti-tumor effects are limited. We have tried to produce cyclosporine-induced GVHD or graft-vs-leukemia (GVL) against two la-bearing murine leukemias. BALB/c mice undergoing syngeneic BMT after total-body irradiation received 1 mg/kg or 10 mg/kg cyclosporine or dextrose intraperitoneally for 30 days post-transplant, followed by 5 × 10 3 BCL1 murine leukemia cells 1 or 3 weeks after stopping cyclosporine. Similarly, SJL/J mice undergoing syngeneic BMT received 10 mg/kg cyclosporine or dextrose intraperitoneally for 30 days post-transplant, and were inoculated with 5 × 10 3 or 10 5 murine acute myeloid leukemia (mAML) cells 3 weeks after stopping cyclosporine. No clinical or histological evidence of GVHD was seen, and leukemia-free and overall survival was similar with cyclosporine and dextrose. We conclude that under the experimental conditions used, it is not possible to induce syngeneic GVHD with cyclosporine in BALB/c or SJL/J mice. In the absence of GVHD, this approach is also not associated with any GVL effect against murine leukemias BCL1 and mAML.

Hepatotoxicity of intravenous cyclosporin A in patients with acute ulcerative colitis on total parenteral nutrition.

A group of 24 patients underwent a 7-14-day course of continuously infused Cyclosporin A (2 mg.kg-1.day-1) to treat a severe attack of ulcerative colitis. In 19 of them, including eight treated with total parenteral nutrition, we retrospectively analyzed the serum aminotransferase (AST/ALT) levels at the beginning and at the end of Cyclosporin infusion. The baseline levels of AST/ALT in the group were 19.9 +/- 3.2 and 31.4 +/- 6.4; on stopping Cyclosporin infusion, they were 43 +/- 15.8 and 119 +/- 56, respectively. Six patients showed an ALT change above 1.5 times the upper limit of reference. They included five of the eight patients treated with total parenteral nutrition (62.5%). In one of six, ALT rose to 1000 U/l and was accompanied by full-blown febrile cholangitis (proven by liver biopsy). This episode was preceded by excessive accumulation of Cyclosporin in blood. The development of liver toxicity was independent of the length of Cyclosporin treatment, nor did it impair drug efficacy. Thus, in these patients total parenteral nutrition and Cyclosporin were synergistic, causing twice the frequency of liver damage (62.5%) reported for ulcerative colitis patients on total parenteral nutrition alone (37%). Total parenteral nutrition should not be used to support patients needing Cyclosporin for autoimmune disease. However, too high a dose of Cyclosporin may cause liver disease per se.

Cyclosporin A and vitamin D metabolism: studies in patients with psoriasis and in rats.

1. Cyclosporin A, an immunosuppressive drug used to treat psoriasis, stimulates renal synthesis of 1,25-dihydroxyvitamin D in rats. 1,25-Dihydroxyvitamin D can also reduce the activity of psoriasis, and in the present study we have examined the possibility that cyclosporin A mediates some of its actions in psoriasis by renal or extra-renal production of 1,25-dihydroxyvitamin D. 2. Treatment of 12 psoriatic patients with cyclosporin A (5 mg day-1 kg-1) for 3 months significantly improved the psoriasis activity and severity index and reduced glomerular filtration rate, but serum 1,25-dihydroxyvitamin D levels were not changed. However, 1-3 months after stopping cyclosporin A treatment, an increase in the psoriasis activity and severity index score was accompanied by a small, but significant, increase in serum 1,25-dihydroxyvitamin D concentration. Plasma 1,25-dihydroxyvitamin D levels in rats gavaged with cyclosporin A (15 mg day-1 kg-1 for 2 weeks) were significantly increased compared with controls, but a lower dose of cyclosporin A (2.4 mg day-1 kg-1) had no effect. Renal 25-hydroxyvitamin D-24-hydroxylase activity in rat kidney homogenates was not different between control and cyclosporin A-treated rats. Renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity was not detectable in these homogenates. Extra-renal production of 1,25-dihydroxyvitamin D by activated macrophages isolated from the synovial fluid of patients with inflammatory arthritis was reduced after incubation with cyclosporin A (0.1-10 mumol/l) for 30 h or 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of cyclosporine in treatment of fistula of crohn's disease

Sixteen Crohn's disease patients with active fistula who had failed standard medical therapy were treated with intravenous cyclosporine. Ten patients had perirectal disease, four had enterocutaneous fistula, and two had rectovaginal fistula. Patients were initially treated with intravenous cyclosporine, 4 mg/kg/day, and then switched to oral cyclosporine, 6-8 mg/kg/day. Improvement was graded using the Present-Korelitz criteria, and success was defined as moderate to total closure of the fistula. Fourteen of 16 patients (88%) responded in the acute phase to parenteral cyclosporine. Closure of fistula occurred in seven (44%) with moderate improvement in the remaining seven (44%). Subsequently, five patients (36%) relapsed to some degree on oral cyclosporine (three severe and two mild relapses). Nine (64%) patients maintained their improvement in the chronic phase. Chronic steroids could be discontinued in 6/8 (75%) of patients. Mild side effects were common [paresthesias (75%) and hirsutism (19%)]. A single patient had severe paresthesias requiring discontinuation of therapy. Mild hypertension was noted in four (25%) and one patient (6%) had to be withdrawn because of nephrotoxicity, which reversed after stopping cyclosporine. We conclude that intravenous cyclosporine is effective therapy for perianal, rectovaginal, and enterocutaneous fistula in Crohn's disease. Its future role awaits controlled trials as well as determination of the risk-benefit ratio.

Changes in numbers of epidermal cell adhesion molecules caused by oral cyclosporin in psoriasis.

To determine the effects of a three month course of low dose cyclosporin on the expression of epidermal cell adhesion molecules. Eighteen patients with psoriasis were treated for 12 weeks with either 2.5 or 5 mg/kg/day of oral cyclosporin. Biopsy specimens taken from skin before, during, and after cyclosporin treatment were stained immunohistochemically for CD 54 (ICAM-1), CD 29 (beta-1 integrins), and CD18 (beta-2 integrins). There was a highly significant (p < 0.01) clinical response after 12 weeks of cyclosporin as assessed by the Psoriasis Area and Severity Index (PASI) score. The staining of CD 29 on keratinocytes of affected and unaffected psoriatic skin was not affected by cyclosporin. Epidermal CD54 was variably expressed in active psoriatic plaques and changed unpredictably after cyclosporin (p = NS). Staining for CD18 on large epidermal dendritic cells was reduced after cyclosporin (p < 0.02). The expression of CD18 by large epidermal dendritic cells during treatment correlated strongly with the PASI score at that time and one month after stopping cyclosporin (p < 0.02). Persistence of epidermal staining for CD 54 in psoriasis is compatible with a good clinical response to cyclosporin. Residual staining for CD 18 on large epidermal dendritic cells may be a useful marker for early clinical relapse.

Effects of cyclosporin A on glomerular barrier function in the nephrotic syndrome.

1. To elucidate the mechanisms by which cyclosporin A diminishes proteinuria, we studied 20 patients with severe nephrotic syndrome. Biopsy-established pathologies included minimal change disease (n = 5), membranous glomerulopathy (n = 6), membranoproliferative glomerulonephritis (n = 5) and focal segmental glomerulosclerosis (n = 4). Before, at the end of a 90 day course of cyclosporin A, and finally 1 month after stopping cyclosporin A we determined 24 h protein excretion. Measurements of glomerular filtration rate, effective renal plasma flow, fractional clearance rates of albumin and immunoglobulins with different charges and the transglomerular sieving of uncharged dextrans of broad size distribution were used to study the effects of cyclosporin A on renal perfusion and the glomerular filtration barrier. The findings were analysed with a theoretical model of solute transport. 2. Among the different forms of glomerulopathy the response to low-dose cyclosporin A (trough levels 32.0-36.9 ng/ml) varied markedly. In minimal change disease, proteinuria decreased from 9.5 +/- 3.1 to 1.3 +/- 0.2 g/24 h (mean +/- SEM, P less than 0.01). This response was due to restoration of the charge selectivity of the glomerular barrier. The depressed value of the glomerular permeability coefficient also returned to normal. Glomerular filtration rate, effective renal plasma flow and renal vascular resistance did not change. Proteinuria returned after stopping cyclosporin A, although it did not reach pretreatment levels. In membranous glomerulopathy, proteinuria fell from 9.9 +/- 1.5 to 1.8 +/- 0.3 g/24 h (P less than 0.01). Changes in protein excretion and dextran sieving were compatible with an increase in glomerular permselectivity and a decrease in filtrate flow through the 'shunt' pathway. Glomerular filtration rate was maintained, although effective renal plasma flow fell significantly. Proteinuria relapsed after stopping cyclosporin A. In membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis proteinuria did not respond to cyclosporin A, although cyclosporin A exerted important haemodynamic effects. 3. In minimal change disease and membranous glomerulopathy cyclosporin A exerts its beneficial effects on proteinuria through changes in the properties of the glomerular barrier, resulting in increased charge and size selectivity, respectively.

Cyclosporin reduces renal prostanoid excretion in type 1 diabetic patients.

Prostacyclin and thromboxane A2 are important regulators of kidney blood flow. To examine whether changes in their metabolism could be involved in the nephrotoxicity of cyclosporin, we determined urinary excretion of 6-keto PGF1a and dinor-6-keto PGF1a (prostacyclin metabolites) and dinor-TxB2 (thromboxane metabolite) in five newly diagnosed type 1 diabetic patients during and after stopping cyclosporin therapy. In the resting state, cyclosporin had no effect on prostanoid excretion. In response to exercise, urinary excretion of 6-keto PGF1a was reduced by 50% (P less than 0.02), dinor-6-keto PGF1a by 15% (P less than 0.05) and dinor-TxB2 by 45% (P less than 0.02), while albumin excretion increased 4.5-fold (P less than 0.05) during cyclosporin therapy. Simultaneously, there was a rise in serum creatinine concentration, and renal biopsy specimens obtained from three patients showed periglomerular and interstitial fibrosis and tubular atrophy. After the discontinuation of cyclosporin therapy, serum creatinine concentrations returned to normal, histological changes improved and there was an associated rise in urinary prostanoid excretion. These data suggest that a reduction in renal prostanoid synthesis by cyclosporin may diminish renal blood flow and function, and lead to histological changes in the kidney.

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.