Cyclosporine Group Research Articles

Cyclosporine 0.05% Ophthalmic Preparation to Aid Recovery From Loss of Corneal Sensitivity After LASIK

To determine whether cyclosporine (0.05%) can safely and effectively accelerate corneal nerve regeneration after LASIK, thereby facilitating faster recovery of corneal sensitivity. This prospective, randomized, single-center clinical study comprised 44 eyes of 22 patients scheduled to undergo bilateral LASIK. One eye was randomly assigned to receive cyclosporine drops twice daily for 3 months in addition to standard postoperative LASIK medication. Corneal sensitivity was measured using the Cochet-Bonnet esthesiometer in four areas outside and five areas inside the LASIK flap preoperatively and at 1 day, 1 week, 1 month, and 3 months postoperatively. Safety parameters of best spectacle-corrected visual acuity and the incidence of adverse events were also collected. For all four points outside the LASIK flap, normal corneal sensitivity was maintained throughout the study. In addition, no significant difference was found between the cyclosporine-treated eyes and the control eyes at these points. All points within the LASIK flap except the point closest to the hinge demonstrated profound corneal hypoesthesia at 1 day, 1 week, and 1 month postoperatively with no differences noted between the control and cyclosporine-treated eyes. These same points had statistically significantly greater corneal sensitivity in the cyclosporine group relative to the control group (P< or =.011) at 3 months postoperatively. Cyclosporine was shown to significantly improve corneal sensitivity at 3 months after LASIK, which suggests that topical cyclosporine promotes enhanced corneal nerve regeneration.

Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation

Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens. We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival. The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%). A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].).

Chronic Graft-Versus-Host Disease after Tacrolimus Versus Cyclosporine for Graft-Versus-Host Disease Prophylaxis in Pediatric Patients Undergoing Matched Unrelated Donor Hematopoietic Stem Cell Transplantation. A Pediatric Blood and Marrow Transplant Consortium Study..

Chronic graft versus host disease (GVHD) is a significant cause of morbidity and mortality in matched unrelated donor hematopoietic stem cell transplantation. Incidence of acute GVHD is a major risk factor for chronic GVHD. Calcineurin inhibitors form the backbone of graft versus host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation. When comparing cyclosporine to tacrolimus for GVHD prophylaxis, we previously reported a trend toward superiority of cyclosporine as prophylaxis against acute GVHD. We now analyze their effect on the incidence and severity of chronic GVHD. In a multi-institutional trial, we prospectively collected the clinical data on 141 evaluable patients receiving either cyclosporine/methotrexate or tacrolimus/methotrexate based prophylactic regimens for 6/6 matched unrelated donor, transplant. Conditioning regimens were fully ablative; no T-cell depletion was permitted; cord blood donors were excluded. Patients were required to receive either cyclosporine or tacrolimus, but the choice was per investigator preference. The two arms were reasonably balanced: 60.1% of patients received cyclosporine and 39.9% of patients received tacrolimus. Rates for acute GVHD were 60.4% for cyclosporine and 73.8% for tacrolimus (p = 0.086). Rates for chronic GVHD were 44.2% for cyclosporine and 47.3% for tacrolimus (p = 0.7). In the 61 patients with chronic GVHD, extensive disease was present in 82.9% of cyclosporine group and 80.8% of the tacrolimus group (p = 1.0) Those graded as moderate or severe comprised 80% of the cyclosporine group and 56% of the tacrolimus group (p = 0.46) and those both extensive and moderate or severe were 71.4% and 52%, respectively (p = 0.12). In pediatric matched unrelated donor transplantation, the incidence and severity of chronic graft versus host disease in patients receiving either tacrolimus/methotrexate or cyclosporine/methotrexate based regimens for prophylaxis of GVHD are not significantly different.

A Randomized Controlled Trial of Tacrolimus Versus Cyclosporine After Lung Transplantation

The optimal maintenance immunosuppressive regimen after lung transplantation is uncertain. We conducted a randomized controlled trial of tacrolimus versus cyclosporine in combination with azathioprine and prednisone after lung transplantation. Ninety adults were randomized to tacrolimus (n = 44) or cyclosporine (n = 46). The primary end point was a composite of a cumulative acute rejection A score of 3 or higher, a cumulative lymphocytic bronchitis B score of 4 or higher, or the onset of bronchiolitis obliterans syndrome (BOS) stage 0-p. Recipients randomized to cyclosporine were significantly more likely to develop the primary end point than those randomized to tacrolimus. During the study period, the primary end point developed in 39 of 46 cyclosporine subjects compared with 24 of 44 tacrolimus subjects (p = 0.002); acute rejection or lymphocytic bronchitis end points developed in 29 of 46 cyclosporine subjects compared with 18 of 44 tacrolimus subjects (p = 0.036). Furthermore, BOS stage 0-p was more likely to develop in the cyclosporine group than in the tacrolimus group, but this was not statistically significant (log-rank p = 0.1). In addition, there was a trend to a higher incidence of diabetes among those in the tacrolimus group, but there was no significant difference in graft survival or the total number of infections, or in the incidence of hypertension, chronic kidney disease, or cancer between the 2 groups. Tacrolimus is associated with a lower burden of acute rejection and lymphocytic bronchitis and a trend to a greater freedom from BOS stage 0-p than cyclosporine after lung transplantation.

Immunosuppression strategies after liver transplantation: a single centre experience in 57 liver transplant recipients

The art of administering immunosuppression lies in the ability to achieve a delicate balance between rejection and infection, thus maximizing patient survival and minimizing morbidity. To analyze the effect of immunosuppression strategies following liver transplant on the incidence of acute rejection, bile leak, renal dysfunction and posttransplant graft unrelated infection. A retrospective analysis of immunosuppression regimens in 57 liver transplant recipients between Jan 1998 to July 2004 at a single institution. For the purpose of study, the patients were divided into two groups: A - Cyclosporine based therapy (n=37), and B - Tacrolimus based therapy (n=20). In addition, both groups received Azathioprine or Mycophenolate mofetil with steroids. There were two subgroups in each Group A and B: Group C - Received induction using IL2Rab (n=5), and D - Where Sirolimus was used instead of Mycophenolate mofetil (N=7). The subgroups were equally distributed among the basic groups. The regimen was started based on one of the standard protocols but changes were made according to the clinical status of each patient. The statistical analysis was done using Chi square test on SPSS12. A lower incidence of rejection was observed in Tacrolimus group compared to Cyclosporine group. There was an unacceptably high incidence of bile leak in patients where Sirolimus was used as an adjunct. IL2Rab enabled us to maintain a lower trough level of Tacrolimus for maintenance and enabled us to discontinue steroids earlier. Based on this study we dropped Sirolimus from our immunosuppression protocol and the encouraging results obtained with tacrolimus based therapy have supported its use as standard therapy in our immunosuppression regimens.

Calcineurin Inhibitor Reduction Based on Maintenance Immunosuppression With Mycophenolate Mofetil in Renal Transplant Patients: POP Study

Since calcineurin inhibitors (CNI) have been introduced, they have become the cornerstone of immunosuppression for renal transplant patients, but their cardiovascular and neurological toxicities, and primarily their renal toxicity, have brought about an increased effort to find combinations of immunosuppressants that are either CNI-free or that use minimum doses of these drugs. The weight of immunosuppression therefore lies with drugs that have a better toxicity profile. The POP observational transverse study including 213 renal transplant patients was designed to study CNI minimization strategies. The mean time of transplant evolution to the time of reduction was 9.9 ± 11.8 months. The acute rejection rate to the start of reduction was 9.4%. Almost all the patients were undergoing treatment with CNI + mycophenolate mofetil (MMF) + steroids in the immediate posttransplantation period. When reduction was chosen, all patients were undergoing treatment with MMF (mean dose at the start of reduction = 1490.7 ± 478.0 mg/d). Among the cohort, 66.7% of patients were being treated with tacrolimus (mean C0 levels 13.3 ± 6.6 ng/mL) and 33.3% with cyclosporine (mean C0 levels 192.2 ± 94.0 ng/mL; mean C2 levels 1097.5 ± 457.6). The main reasons for withdrawal were nephrotoxicity (55.9% of the cases), as well as prevention of adverse effects (21.6%). The mean target CNI dose reduction was 41.4% ± 21.45% in the tacrolimus group and 28.6 ± 10.0% in the cyclosporine group. In conclusion, CNI toxicity, primarily renal toxicity, makes reduction of these drugs based on the use of full MMF doses an alternative to manage renal transplant patients.

Renal Function in Patients With Cadaveric Kidney Transplants Treated With Tacrolimus or Cyclosporine

Introduction Renal function predicts graft survival in kidney transplant patients. This study compared the 2-year evolution of renal function in patients treated with cyclosporine or tacrolimus in combination with mycophenolate mofetil (MMF) and prednisone. Methods We studied 1558 cadaveric renal transplant recipients from 14 Spanish hospitals between January 2000 and December 2002. Of these, 1168 were treated with tacrolimus and 390 with cyclosporine. The primary efficacy endpoint was long-term renal function. Renal function was measured by serum creatinine and glomerular filtration rate (GFR) by creatinine clearance calculated from the Cockcroft-Gault formula. This report summarizes the 2-year results. Results At 24 months the tacrolimus group showed significantly better serum creatinine (1.5 ± 0.7 vs 1.8 ± 0.8 mg/dL, P < .001) and GFR (60.5 ± 20.9 mL/min vs 47.9 ± 10.0, P < .001) than the cyclosporine group. Additionally, recipients with ideal graft donors (23.5 ± 2.8 vs 24.0 ± 2.9 years) had a better serum creatinine at 2 years (1.23 ± 0.2 vs 1.5 ± 0.4 mg/dL, P < .05). Multivariate analysis showed that tacrolimus was an independent factor associated with better renal function: odds ratio 1.6, 95% confidence interval (1.2 to 2.2), P < .001. Conclusions Patients with a renal transplant treated with tacrolimus in combination with MMF and prednisone displayed better renal function at 2 years than those who received cyclosporine.

Reduction of Ischemia–Reperfusion Injury in the Rat Kidney by FTY720, a Synthetic Derivative of Sphingosine

The current shortage of organ donors has led many centers to use marginal and nonheart-beating donors (NHBDs). Recent research has implicated the infiltration of lymphocytes as an important mediator of ischemia-reperfusion injury (IRI). FTY720 is an immunosuppressant that promotes lymphocyte sequestration into lymph nodes. The purpose of this study was to examine the potential for FTY720 to abrogate IRI when subjected to increasing ischemic times. Male Sprague-Dawley rats underwent bilateral flank incision with removal of the right kidney and clamping of the left hilum. Groups were divided into ischemia times of 45, 55, and 65min; each group was further divided into a control group (IRI only), IRI+FTY720 (1 mg/kg/d), and IRI+cyclosporine (15 mg/kg/d), n=4 per group. Thre days after 45 min of ischemia, serum creatinine in the ischemia only (477+/-37 micromol/L) and cyclosporine groups (698+/-32 micromol/L) was significantly increased compared with the FTY720-treated animals (194+/-66 micromol/L). The beneficial effect of FTY720 was also observed at 55 and 65 min; indeed, FTY720-treated animals demonstrated signs of recovery from 65 min of ischemia whereas control and cyclosporine-treated animals required sacrifice between days 3 and 5. Treatment with FTY720 reduced renal damage assessed histologically and also reduced apoptosis and increased cell proliferation. Treatment with FTY720 reduced IRI and prevented unrecoverable acute renal failure after significant ischemic injury. This study suggests that FTY720 may help improve the quality of grafts from NHBD and marginal donors by abrogating the IRI insult.

The Dynamics of Glucose Metabolism Under Calcineurin Inhibitors in the First Year After Renal Transplantation in Nonobese Patients

The incidence of glucose metabolism disturbances after transplantation often is based on the use of hypoglycemic agents and not on the results of glucose tolerance tests (GTTs), which may camouflage the real incidence. A lack of information also exists regarding the profile of glucose metabolism during the first year after transplant. Oral GTT along with insulin measurements and drugs pharmacokinetics were prospectively performed at days 30, 60, 180, and 360 after transplant to diagnose disturbances of glucose metabolism after renal transplantation, in nonobese patients receiving either tacrolimus (n=55) or cyclosporine (n=29), along with mycophenolate mofetil and steroids. The incidence of impaired glucose tolerance or diabetes mellitus reached a peak at 60 days and decreased at 1 year. It could not be adequately diagnosed using fasting plasma glucose in a decreased abnormal (>99 ng/mL) range. In both groups, insulin secretion, evaluated by the Homeostasis Model Assesment (HoMA-beta), decreased (P<0.005) from the condition of normal GTT (101+/-56%) to impaired glucose tolerance (72+/-35%) and diabetes mellitus (54+/-25%). In the cyclosporine group, insulin secretion was normal and stable throughout the study period, but in the tacrolimus group, insulin secretion recovered over time and was inversely correlated with tacrolimus exposure. Insulin resistance (HoMA-IR) did not change. This study shows the need to perform an oral GTT at 60 days and at the end of the first year of renal transplantation to adequately diagnose impaired glucose metabolism.

ACE Inhibitors and Persistent Left Ventricular Hypertrophy After Renal Transplantation: A Randomized Clinical Trial

Interventional studies of left ventricular hypertrophy (LVH) in renal transplant recipients are scarce and to date evaluated only patients immediately after renal transplantation. Randomized controlled trial that assessed the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in regressing persistent LVH after successful transplantation. 70 renal transplant recipients (47 men; age, 30 to 68 years) without diabetes previously randomly assigned to either cyclosporine or tacrolimus therapy, with LVH persisting 3 to 6 months after transplantation. Subjects were randomly assigned to either lisinopril (ACE-inhibitor group; 36 patients) or no therapy (control group; 34 subjects). Main outcome was change in left ventricular mass index (LVMi) at month 18. A consistent decrease in both systolic (SBP) and diastolic blood pressure (DBP) was observed in both groups (between-group differences, -1.7 +/- 3.3 mm Hg; 95% confidence interval [CI], -4.8 to 8.2; P = 0.6 for SBP; 0.3 +/- 2.2 mm Hg; 95% CI, -4.8 to 4.1; P = 0.9 for DBP), whereas LVMi regressed more in the ACE-inhibitor group (between-group difference, 10.1 +/- 16.3 g/m(2.7); 95% CI, 4.2 to 16.1; P < 0.01). A significant interaction of ACE inhibitors with cyclosporine in affecting LVMi change was shown by means of post hoc multiple regression analysis (P < 0.01; differences between cyclosporine and tacrolimus group, 13.3 +/- 3.9 g/m(2.7); 95% CI, 5.3 to 21.2; P < 0.01 in the ACE-inhibitor group; 3.7 +/- 4.2 g/m(2.7); 95% CI, -4.7 to 12.2; P = 0.4 in the control group). Single-center study with small sample size. Interaction of ACE inhibitors with cyclosporine treatment emerged from post hoc analysis. A prolonged course of ACE-inhibitor therapy is effective in regressing the persistent LVH of renal transplant recipients by mechanisms independent of effects on BP. This regression seems to be at least in part the effect of an interaction between ACE inhibitors and cyclosporine.

Nifedipine and Cyclosporin Affect Fibroblast Calcium and Gingiva

It has been stated that cyclosporin and nifedipine produce gingival overgrowth. However, the specific pathogenic mechanism remains uncertain. We used an experimental rat model to test the hypothesis that changes in collagen metabolism and numbers of gingival blood vessels are not mediated by intracellular calcium concentration (ratiometric Fura-2 AM measurement) in gingival fibroblasts. In the cyclosporin group, both width (364.2 +/- 67.5 mum) and microvessel density (number of vessels/mm(2), stained with anti-CD34 antibody) (41.6 +/- 5.1) of gingiva were statistically different when compared with those in the control group (width = 184.3 +/- 35.2 mum, microvessel density = 19.6 +/- 2.4). The nifedipine group showed the highest content of collagen (proportion of total stroma occupied by collagen, stained with Picro-Mallory) (nifedipine group = 66.3 +/- 9.4, cyclosporin group = 55.2 +/- 7.9, control group = 30.1 +/- 10.2). Freshly cultured fibroblasts from the cyclosporin group exhibited higher ratiometric values of fluorescence than did both the control and nifedipine groups (p = 0.03). Our results support the hypothesis that changes in gingival collagen metabolism are not mediated by calcium intracellular oscillations.

Lycopene, a Carotenoid, Attenuates Cyclosporine‐Induced Renal Dysfunction and Oxidative Stress in Rats

The aim of this study was to investigate the possible protective role of antioxidant treatment with lycopene on cyclosporine A-induced nephrotoxicity using biochemical and histopatological approaches. Adult male Sprague-Dawley rats were randomly divided into four groups. The control group received physiological saline; animals in the lycopene group received only lycopene (10 mg/kg); animals in the cyclosporine A group received only cyclosporine A (15 mg/kg) and animals in cyclosporine plus lycopene group received cyclosporine and lycopene for 21 days. The effects of lycopene on cyclosporine A-induced nephrotoxicity were evaluated by plasma creatinine, urea, sodium and calcium concentrations; kidney tissue thiobarbituric acid reactive species, reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and catalase activities and histopatological examinations. Administration of cyclosporine A to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. Cyclosporine A also induced oxidative stress as indicated by increased kidney tissue concentrations of thiobarbituric acid reactive species and GSH, and reduced activities of GSH-Px and catalase. Moreover, the kidneys of cyclosporine A-treated rats showed tubular necrosis, degeneration, dilatation, thickened basement membranes, luminal cast formation and inter-tubular fibrosis. Lycopene markedly reduced elevated plasma creatinine, urea levels and counteracted the deleterious effects of cyclosporine A on oxidative stress markers. In addition, lycopene ameliorated cyclosporine A-induced pathological changes including tubular necrosis, degeneration, thickened basement membranes and inter-tubular fibrosis when compared to the alone cyclosporine A group. These data indicate that the natural antioxidant lycopene might have protective effect against cyclosporine-induced nephrotoxicity and oxidative stress in rat.

A randomized‐controlled trial to compare topical cyclosporin with triamcinolone acetonide for the treatment of oral lichen planus

Various treatments have been employed to treat symptomatic oral lichen planus (OLP), but a complete cure is very difficult to achieve because of its recalcitrant nature. Topical cyclosporin therapy of OLP has shown conflicting results in many reports. The purpose of this study was to compare the effectiveness of cyclosporin solution with triamcinolone acetonide 0.1% in orabase in the treatment of Thai patients with OLP. Thirteen Thai patients with symptomatic OLP and proven by biopsy were randomly assigned treatment with cyclosporin (six) or triamcinolone acetonide 0.1% (seven). The patients were instructed to apply cyclosporin or triamcinolone acetonide 0.1% three times daily at the marker lesions and affected areas. The assessments were at weeks 0, 2, 4, 8 by clinical scoring and grid measurement of the target lesions. Cyclosporin levels were assessed at weeks 2 and 8 of treatment. Pain and burning sensation were evaluated by linear visual analogue scale (0-10). OLP patients in the triamcinolone acetonide group showed equal cases of clinical complete and partial remission (50%). Whereas, in the cyclosporin group, there was partial remission in only two cases (33.5%) and no response in four cases (66.7%). However, our study showed that there were no statistical differences in pain, burning sensation and clinical response in OLP patients between the two groups (P > 0.01). Moreover, five of six cases in the cyclosporin group developed side-effects such as transient burning sensation, itching, swelling lips, petechial haemorrhages and others. Our results indicated that topical cyclosporin did not provide any beneficial effect and was not more effective than triamcinolone acetonide 0.1% in the treatment of Thai patients with symptomatic OLP.

Concentrations of Mycophenolic Acid and Glucuronide Metabolites Under Concomitant Therapy With Cyclosporine or Tacrolimus

Mycophenolate mofetil [MMF, the prodrug of mycophenolic acid (MPA)] is usually administered at double doses with cyclosporine than with tacrolimus because it is believed that MPA exposure is lower during cyclosporine therapy. This study aimed to compare 12 hour, steady-state concentration-time profiles of MPA and its phenol- and acyl-glucuronide metabolites (MPAG and AcMPAG, respectively) in stable kidney transplant recipients maintained either on cyclosporine (n = 12) or tacrolimus (n = 12). During the absorption phase in the cyclosporine group, dose-normalized concentrations of total and free MPA were significantly higher but the overall area under the concentration-time curve (AUC0-12) was not significantly different. Additionally, exposure to AcMPAG was higher in the cyclosporine group (P < 0.05). Ten of 12 patients in the cyclosporine group were on ketoconazole therapy; however, the exposure to MPA or MPAG was not different when MMF was given orally to Sprague-Dawley rats with or without ketoconazole. In conclusion, cyclosporine modulates the disposition of MPA and metabolites differently from tacrolimus; however, patients on cyclosporine may not require double doses of MMF to achieve the same exposure.

Efficacy and Safety of Cyclophosphamide, Azathioprine, and Cyclosporine (Ciclosporin) as Adjuvant Drugs in Pemphigus Vulgaris

Pemphigus vulgaris is a potentially life-threatening, autoimmune bullous disease of the skin and mucous membranes. Most commonly, the disease is treated with prednisone in combination with an immunosuppressant agent, frequently referred to as adjuvant drug. However, there is no consensus regarding the first-choice adjuvant drug for the treatment of pemphigus vulgaris or the recommended dosage. To evaluate the efficacy and safety of prednisone as monotherapy and in combination with the three most popular adjuvant agents - azathioprine, cyclosporine (ciclosporin), and cyclophosphamide - in the treatment of pemphigus vulgaris. This was a retrospective study with a follow-up of 7-21 years. The study was conducted in an academic hospital with an outpatient division for patients with bullous diseases. A total of 101 patients with moderate-to-severe mucocutaneous pemphigus vulgaris were included in the study. For assessment of disease severity a 'pemphigus score,' based on the percentage of involved skin or oral mucous membranes, was developed. At treatment initiation the average pemphigus score was comparable in all treated groups of patients. Four treatment regimens were evaluated: oral prednisone at an initial dose of 100mg (1.1-1.5 mg/kg) per day as monotherapy, and prednisone combined with adjuvant drugs, i.e. oral azathioprine at a dose of 100mg (1.1-1.5 mg/kg) per day; cyclosporine (ciclosporin) at a dose of 2.5-3 mg/kg/day; or cyclophosphamide at a dose of 100mg (1.1-1.5 mg/kg) per day. The main outcome measures were average time to clinical remission, average time to immunologic remission (non-detectable circulating pemphigus vulgaris antibodies), proportion of patients who remained free of clinical relapse within 5 years after discontinuation of therapy, time from treatment discontinuation until first relapse, and incidence of adverse effects. The average (+/- SD) time to clinical remission was 7.2 +/- 13.1 months in patients who received prednisone monotherapy, 6.8 +/- 10.5 months in patients receiving additional azathioprine, 8.1 +/- 11.8 months in the cyclosporine group, and 4.9 +/- 6.9 months (which was significantly shorter than all other treatment groups, p < 0.05) in patients receiving cyclophosphamide. The average (+/- SD) times to immunologic remission were 33 +/- 27 months, 28 +/- 24 months, 30 +/- 21 months, and 23 +/- 17 months for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively. The proportions of patients who remained free of clinical relapse within 5 years after discontinuation of therapy were 55%, 50%, 43%, and 69% for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively. In patents who experienced relapse, the average (+/- SD) time from treatment discontinuation to clinical relapse was 10.50 +/- 6.86 months in patients receiving prednisone monotherapy, 16.40 +/- 17.36 months in the azathioprine group, 12.44 +/- 6.48 months in the cyclosporine group, and 21.16 +/- 20.13 months in the cyclophosphamide group. The safety profiles of all treatment regimens were comparable. Oral prednisone with cyclophosphamide is the most effective treatment for pemphigus vulgaris. All therapy regimens had a similar safety profile. In our opinion, cyclophosphamide at a dose of 1.1-1.5 mg/kg/day should be the adjuvant drug of choice in the treatment of moderate-to-severe pemphigus vulgaris.

Cyclosporin A Has a Protective Effect with Induced Upregulation of Hsp70 and nNOS on Severe Spinal Cord Ischemic Injury in Rabbits

The purpose of this study is to ascertain the neuroprotective effect of cyclosporin A on the 25-min surgical ischemia model in the spinal cords of rabbits with neuropathological correlation and histoimmunochemical analyses measuring HSP70 and neuronal NOS (nNOS). New Zealand white rabbits were randomly divided into four groups (each n = 8): the C2, C7, Cs2, and Cs7 groups. The C2 and C7 groups underwent a 25-min surgical aortic cross-clamp without intervention and were sacrificed respectively on day 2 and on day 7 postoperatively. The Cs2 and Cs7 groups received cyclosporin A (25 mg/kg) intravenously 15 min after the 25-min cross-clamp and were sacrificed respectively on day 2 and day 7 postoperatively. Neurologic functions were evaluated on postoperative days 2 and 7 using the Tarlov scoring system. Then the rabbits were sacrificed for histopathologic observation. HSP 70 and nNOS stains with TUNEL assay were done for the C2 and Cs2 groups. All rabbits survived the experimental procedure. Tarlov's score for the Cs7 group (2.75 ± 0.89) was significantly higher than that of the C7 group (1.25 ± 1.39) (p <. 05). Tarlov's score of the Cs7 group was also statistically higher on day 7 than on day 2 (p <. 05). Strong correlation between the neurological and histological scorings was found. The TUNEL assay showed that the mean number of positive cells in the C2 group was 17.5 ± 22.6 and in the Cs2 group was 12.5 ± 11.1, but there was no statistically significant difference between the groups. There was more expression of HSP70 and nNOS in the cyclosporin groups than in the ischemia groups. In conclusion, this study demonstrates that cyclosporin A reduces neurological injury in the rabbit model of 25-min spinal cord ischemia. The neuroprotective effect of cyclosporin A against ischemia seems to be related to overexpressions of nNOS and HSP70.

Calcineurin Inhibitors in Pediatric Renal Transplant Recipients

The calcineurin inhibitors, cyclosporine (ciclosporin) [microemulsion] and tacrolimus, are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. For pediatric patients, both drugs should be dosed per body surface area, and pharmacokinetic monitoring is mandatory. While monitoring of the trough levels may suffice for tacrolimus, cyclosporine therapy that utilizes the microemulsion formulation requires additional monitoring (e.g. determination of 2-hour post-dose levels). In a well designed randomized study in children, as in studies in adults, there was no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However, tacrolimus was significantly more effective than cyclosporine microemulsion in preventing acute rejection after renal transplantation when used in conjunction with azathioprine and corticosteroids. With regard to long-term outcome, the difference in acute rejection episodes resulted in a better glomerular filtration rate at 1 year after transplantation and eventually in better graft survival 4 years after renal transplantation. Whether this difference persists when calcineurin inhibitors are used in combination with mycophenolate mofetil has not been determined. The prevalence of hypomagnesemia was higher in the tacrolimus group whereas hypertrichosis and gingival hyperplasia occurred more frequently in the cyclosporine group. In contrast with adults, the incidence of post-transplantation diabetes mellitus was not significantly different between tacrolimus- and cyclosporine-treated patients. There was also no difference with regard to post-transplantation lymphoproliferative disorder. Medication costs were similar, but in view of the lower rejection episodes and better long-term graft survival as well as the more favorable cosmetic side effect profile, tacrolimus may be preferable. The recommendation drawn from the available data is that both cyclosporine and tacrolimus can be used safely and effectively in children. We recommend that cyclosporine should be chosen when patients experience tacrolimus-related adverse events.

Effect of Hyperbaric Oxygen on Cyclosporine-Induced Nephrotoxicity and Oxidative Stress in Rats

Reactive oxygen species have been suggested to be involved in cyclosporine nephrotoxicity. Hyperbaric oxygen is known to induce the generation of reactive oxygen species in tissues. The aim of this study was to investigate whether the use of hyperbaric oxygen concurrently with cyclosporine potentiates cyclosporine nephrotoxicity by inducing oxidative stress in kidneys. The study consisted of four groups of rats: a control group, a cyclosporine group (15 mg/kg/day intraperitoneally for 14 days), a hyperbaric oxygen group (60 min. every day for five days at 2.5 atmosphere absolute), and a cyclosporine + hyperbaric oxygen group (cyclosporine 15 mg/kg/day intraperitoneally for 14 days + hyperbaric oxygen for 60 min at 2.5 atmosphere absolute every day for five days on the last five days of cyclosporine treatment). Oxidative stress was determined by measuring renal thiobarbituric acid-reactive substances content, renal superoxide dismutase, and glutathione peroxidase activities. Cyclosporine increased serum urea and creatinine levels, indicating the development of nephrotoxicity, and induced significant oxidative stress in rat kidneys. Hyperbaric oxygen alone did not alter any of the biochemical and oxidative stress parameters compared to the control group. When used concurrently with cyclosporine, hyperbaric oxygen significantly reduced cyclosporine-induced oxidative stress, but it neither attenuated nor aggravated cyclosporine-induced nephrotoxicity. These results suggest that reactive oxygen species are involved in cyclosporine nephrotoxicity, but are not the direct cause of the toxicity. Although concurrent use of cyclosporine and hyperbaric oxygen did not exacerbate cyclosporine nephrotoxicity in this model, we recommend that the renal functions of patients be monitored periodically when these treatments are used concurrently.

Effect of cyclosporine on weight and crown-rump length of mice embryo

Cyclosporine A is an immunosuppressive agent, which is widely used for organ transplantation, autoimmune and other diseases. Cyclosporine inhibits the calcineurin and thereby causes inhibition of chondrogenesis. Cyclosporine crosses the placenta and reaches to the embryo, and thereby may affect them. Many females, that should receive cyclosporine, are in childbearing age. The objective of this study was to determine whether cyclosporine administration has any effect on weight and crown-rump length of mouse embryos. Many out bred adult mice were selected. Female mice were mated overnight with males, checked in the morning for vaginal plug. Pregnant mice were randomly assigned into experimental and control groups. The experimental group received cyclosporine and control group received an equivalent amount of olive oil on days 7, 8, and 9 of gestation. Pregnant mice were killed and embryos were removed on days 13, 16, and 18 of gestation. The weight and crown-rump length of embryos were recorded. Comparison between two groups was made using t. test. There were highly significant differences between crown-rump length of experimental and control groups on days 16 and 18 ( P <0.05), but on day 13, crown-rump length difference was not significant. In all ages of gestation, the experimental group had less weight than the control group ( P <0.05). Results of this study indicate that cyclosporine causes low weight and low crown-rump length in mice embryos.

Limited Sampling Strategy for Mycophenolic Acid in Japanese Heart Transplant Recipients

The purpose of the study was to characterize the pharmacokinetics of mycophenolic acid (MPA) in Japanese heart transplant recipients and to find the time point that has the best correlation with the MPA area under the plasma concentration curve (AUC). Twenty-two Japanese recipients treated with mycophenolate mofetil were evaluated in the study. Approximately 9 months after transplantation, the area under the MPA serum concentration-time curve from 0 to 12 h (AUC(0-12 h)) was evaluated. The MPA AUC(0-12 h) h values in the cyclosporine (CsA) and tacrolimus (FK) groups ranged from 13.11 to 50.98 mug . h/ml and from 39.19 to 93.18 mug . h/ml, respectively. Fourteen models were developed and analyzed for their ability to estimate the MPA AUC(0-12 h) based on a limited number of samples in the CsA group. Sixteen models were developed in the FK group. The best model for predicting the full MPA AUC(0-12 h) in the CsA group was a 3-time-point model that included C(0 h), C(1 h) and C(2 h) (r(2), 0.96; mean prediction error, 0.15+/-7.85%); a 2-time-point model that included C(0 h), and C(2 h) (r(2), 0.94; mean prediction error, 0.495+/-10.35%) was also reliable. In the FK group, a 3-time-point model that included C(1 h), C(2 h) and C(4h) (r(2), 0.73; mean prediction error, 2.73+/-17.09%) was the best model for predicting the full MPA AUC(0-12 h), but it was not reliable in clinical practice. A 3-(C(0 h), C(1 h) and C(2 h)) and a 2-time-point model (C(0 h) and C(2 h)) are useful for predicting the full MPA AUC(0-12 h) in Japanese heart transplant recipients treated with CsA but not with FK.