CsA Levels Research Articles

Chemotherapy plus cyclosporine A for the treatment of intraocular retinoblastoma: The University of Miami Miller School of Medicine experience

20005 Background: In the past decade chemotherapy and focal control became the standard of care in retinoblastoma. The ideal chemotherapy regimen has not yet been determined. We analyzed the results of treatment at the University of Miami Miller School of Medicine using the regimen carboplatin (20 mg/kg, day 1), vincristine (0.05 mg. /kg, day 1), etoposide (5 mg / kg, days 1 and 2) with or without cyclosporine A (10 mg. /kg over 2 hours followed by 45 mg/kg over 31 hours) every 3–4 weeks. We attempted to maintain peak CSA levels between 2,400 and 6,000 and steady state levels between 2,400 and 4,200 ng/ml. When CSA was given, vincristine was started at 0.0125 mg /kg. The dose was escalated by 25% with each cycle of therapy, as tolerated. Methods: A retrospective analysis was performed in 41 patients diagnosed with bilateral retinoblastoma from Dec 1996 to Jan 2006. Only eyes with intraocular disease (76 eyes) were included in this analysis. Before each cycle of chemotherapy ophthalmologic examination under anesthesia was performed and active tumor and seeding were treated with local ablation using laser therapy. Eyes in which enucleation was planned at diagnosis were excluded from this analysis. Results: Most patients received 9 cycles of chemotherapy. Sixty percent (46/76) of the eyes were treated with chemotherapy and CSA. The eye salvage rate for eyes classified by the International Classification of Retinoblastoma (ICRB) as groups A, B, C and D was 100%. The eye salvage rate for the 21 eyes classified as ICRB group E was 29%. No difference in salvage rate was observed in eyes treated with or without CSA. One patient died from disease progression. Only one patient required radiation therapy to both eyes. To date there have been no reports of development of secondary malignancies. Conclusion: The addition of CSA to the treatment of the eyes classified as ICRB groups A, B, C and D made no difference in the eye salvage rate. Also, we were not able to demonstrate any benefit from the addition of CSA in patients with stage E eyes- although our sample size was quite small. Aggressive focal control and chemotherapy beginning at diagnosis may be the reason for the excellent EFS in group A, B, C and D eyes. No significant financial relationships to disclose.

Cyclosporine monitoring in the early post-transplant period in pediatric liver transplant recipients

Monitoring of CsA blood levels two h post-dose (C2) has shown a higher correlation to drug exposure than monitoring of trough levels (C0) at least in adults, but initial doses and target blood levels of CsA have yet to be established in pediatric transplant patients. The objectives of the study were to describe the pharmacokinetics of CsA administered by NGT in the first days after transplantation and the dose of Sandimmun Neoral required to achieve minimum therapeutic range blood levels. This study included 20 pediatric liver transplant recipients (mean age of 3.2 yr) treated with CsA administered by NGT from day one post-transplant until they were able to ingest oral medication. The study was continued until one yr of post-transplant follow-up. Eight h pharmacokinetic profiles were performed on days one, three, and five post-transplant to determine the minimum dose required to achieve the therapeutic range. All children received an initial dose of 15 mg/kg/day of CsA by NGT. Mean CsA doses administered on days one, three, and five were 16.8, 29.5, and 36.5 mg/kg/day, respectively. Mean C0 levels of 119, 310, and 337 ng/mL and mean C2 levels of 213, 753, and 888 ng/mL were obtained. No correlation was found between C0 and C2 levels and the AUC(0-8 h). Intravenous administration of CsA was required in 55% of patients. The biopsy-confirmed acute rejection rate was 45%, with graft and patient survival rates of 95 and 100%, respectively. Poor absorption of CsA in small children requires a considerable increase in dose. CsA exposure cannot be estimated by single C0 or C2 determinations in the early post-transplant period.

A Pharmacokinetic and Safety Evaluation of an Episcleral Cyclosporine Implant for Potential Use in High-Risk Keratoplasty Rejection

To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection. CsA episcleral implants were made with a high (implant A) or low (implant B) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than 1 year. An ocular toxicity study was performed in dogs older than 1 year. A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 microg/mg at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 microg/mg during the 1-year study. There were no signs of ocular toxicity at 1 year. Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours.

Limitations of cyclosporine C2 monitoring in pediatric heart transplant recipients

Monitoring CSA levels at two h after dosing (C2) has been shown effective in providing adequate CSA-based immunosuppression in clinical trials in adult transplant recipients, but there is limited data regarding C2 monitoring in pediatric transplant recipients. Given the differences in CSA pharmacokinetics between children and adults, a cohort of stable pediatric transplant recipients was converted from monitoring CSA trough (C0) to C2 levels, to establish the clinical utility and safety of C2 monitoring. After an abbreviated AUC(0-5) to establish baseline exposure, subsequent CSA dosing was adjusted based on C2 levels. Additional evaluation included monitoring for rejection, changes in CSA dose, toxicity, serum chemistries, and infection. Twelve heart transplant recipients were enrolled, with mean age 4.8 yr (range: 0.6-14.0). All patients received microemulsified CSA (Neoral((R)); Novartis Pharmaceuticals, East Hanover, NJ, USA) twice daily. Baseline CSA dose was 5.39 +/- 2.05 mg/kg/day (mean +/- s.d.), with mean C0 = 267 +/- 112, C2 = 1065 +/- 565, and AUC(0-5) = 3817 +/- 1435. Only seven participants showed clear CSA peak levels at two h, with five exhibiting delayed peaks at three to five h post-dose. These seven participants completed 48 wk of study, with mean CSA dose decreasing to 4.55 +/- 3.61 mg/kg/day, maintaining mean C2 599 +/- 211 (vs. target C2 = 800). No significant change in serum creatinine was observed, although GFR increased from 76.9 to 107.6 mL/min/1.73 m(2) (p = 0.11). Five patients failed to achieve target C2 levels (>800) during the first four wk, despite comparable AUC values, and were maintained on trough monitoring (C0). Mean systolic and diastolic blood pressures fell slightly, three minor infections were noted during the study period, and one episode of acute rejection occurred, despite stable CSA dosing. Nearly 50% of stable pediatric transplant recipients failed to achieve adequate peak C2 CSA levels during conversion from C0 to C2 monitoring. Age-dependent differences in CSA absorption and/or clearance pharmacokinetics may explain these findings.

Angioimmunoblastic T cell lymphoma: Treatment experience with cyclosporine

Angioimmunoblastic T cell lymphoma is a distinct entity for which there is no standard therapy. On the basis of the rationale that CsA may represent a novel drug for AITL, a disease with considerable immune dysregulation, and encouraging case reports, the authors have treated 12 patients with this agent. Ten had failed prior steroids and/or chemotherapy and two had no prior therapy. CsA was administered at a dose of 3 – 5 mg/kg PO bid for 6 – 8 weeks and gradually tapered by 50 mg every 1 – 3 weeks. Responding patients received a maintenance dose of 50 – 100 mg, with a gradual taper after a maximal response was achieved as tolerated. Doses were titrated for renal dysfunction or hypertension. CsA levels were not monitored. Eight of 12 patients responded (three complete and five partial remissions). Dose reductions were required in six patients; renal insufficiency (n = 3), fatigue (n = 2), and hypertension (n = 1). Two patients developed acute infections and one patient died shortly after active treatment. These results suggest that CsA deserves further testing as a novel therapy for AITL. By interrupting T-cell activation, CsA may alter the immune dysregulation that characterizes AILT. The efficacy of CsA is being explored in patients with recurrent AILT in a prospective trial (ECOG 2402).

Sirolimus Attenuates the Rate of Progression of Early Chronic Allograft Nephropathy

Optimal treatment for patients with chronic allograft nephropathy (CAN) is not known. Early intervention is preferred. We examined the benefit of adding sirolimus (SRL; C 0 5–12 ng/mL: HPLC) on the rate of progression of early CAN. We identified patients with biopsy-confirmed Banff grade 1 CAN. After biopsy, patients were switched to SRL + CsA + prednisolone (SRL), MMF + CsA + prednisolone (MMF), or CsA + AZA + prednisolone (AZA). GFR was estimated by Cockcroft-Gault and MDRD formulae. The rate of GFR decline (delta GFR) was determined by calculating the slope of the regression line of estimated GFR (MDRD and Cockcroft-Gault method) at different times. Statistical analysis was performed by the Wilcoxon test. The 41 patients with CAN grade 1 were assigned to SRL: MMF: AZA = 12: 20: 9. Before biopsy; the graft age for SRL: MMF: AZA were 56 ± 27: 70 ± 48: 51 ± 36 months; and the GFR (MDRD method), 38 ± 8: 42 ± 15: 36 ± 14 mL/min; GFR (C-G method) 45 ± 13, 42 ± 12, 41 ± 15 mL/min; trough CsA levels 152 ± 36: 145 ± 46: 177 ± 61 ng/dL; delta GFR (MDRD method) −0.18 ± 0.20: −0.15 ± 0.59: −0.20 ± 1.08; delta GFR (C-G method) −0.13 ± 0.37: −0.19 ± 0.24: −0.65 ± 0.99. Follow-up time for SRL: MMF: AZA was 19 ± 4: 35 ± 32: 59 ± 54 months. At last follow-up; GFR (MDRD method) for SRL: MMF: AZA were 39 ± 13: 35 ± 21: 40 ± 24 mL/min; GFR (C-G method) 46 ± 17, 37 ± 18, 46 ± 25 mL/min; BP 128 ± 11/79 ± 7: 131 ± 22/80 ± 14: 132 ± 20/82 ± 11 mm Hg; and CsA level 52 ± 25: 122 ± 41: 155 ± 49. After biopsy, statin was prescribed in nine SRL, 10 MMF, and three AZA. ACEI was prescribed in two SRL, three MMF, and two AZA. Compared with the prebiopsy values, the delta GFR (MDRD method) changed to −0.04 ± 0.31 (SRL; P = .04), −0.17 ± 0.40 (MMF; P = .60), and −0.97 ± 1.52 (AZA: P = .16). Delta GFR (C-G method) was also significantly improved in the SRL group (−0.02 ± 0.47; P = .05) but not in the MMF (−0.13 ± 0.51; P = .53) or AZA (−0.54 ± 1.78; P = .44). We concluded that patients with early CAN who are switched to SRL and low-dose CsA have a significant attenuation of the rate of GFR declination when compared with patients who receive MMF or AZA addition.

Tacrolimus for the treatment of focal segmental glomerulosclerosis resistant to cyclosporine A

Sir,We read with great interest the article by Loeffler et al. [1]referring to the efficacy of tacrolimus (TL) in children withrefractory nephrotic syndrome (NS). However, there is littlepublished information on TL treatment of childhood focalsegmental glomerulosclerosis (FSGS) [1, 2]. In this letter,we report on two pediatric patients with cyclosporine A(CsA)-resistant FSGS in whom successful and rapid clinicalremission and reduction in the dose of prednisolone (PSL)were achieved following TL treatment.Case 1 A 9-year-old Japanese boy was referred to ourhospital with a 2-month history of unremitting steroid-resistant proteinuria. A percutaneous renal biopsy revealedlesions characteristic of FSGS. Despite aggressive immu-nosuppressive therapy, such as methylprednisolone pulsetherapy (MPT), and therapy with cyclophosphamide(CPM), mizoribine (MZR) and CsA at the dose of5.0 mg/kg daily [3], the heavy proteinuria persisted forthe next 6 months. The trough blood level of CsA remainedbetween 111 and 316 ng/ml. Intermittent low-densitylipoprotein (LDL) apheresis, followed by oral PSL at thedose of 1.0 mg/kg daily in combination with CsA, provedto be partially effective. However, the patient developedsevere steroid toxicity, including obesity, short stature,cataract, and osteoporosis.Case 2 An 11-year-old Japanese girl was brought to aregional hospital with an 8-day history of generalizededema. Urinalysis revealed a urinary protein excretion levelof 1,153 mg/dl without hematuria. A percutaneous renalbiopsy revealed lesions characteristic of FSGS. AlthoughMPT was administered followed by oral PSL combinedwith CsA at the dose of 3.0 mg/kg daily, heavy proteinuriapersisted for the next 4 months. The trough blood level ofCsA remained between 120 and 257 ng/ml. The patient wasthereafter referred to our hospital for further examinations.A second renal biopsy revealed lesions of mild CsA-relatednephrotoxicity in about 5% of the interstitium. Therefore,CsA was stopped and replaced by high-dose intermittentMZR [4]. LDL-apheresis was also initiated, which provedto be partially effective. However, another relapse of heavyproteinuria occurred 6 months after the admission. Thepatient subsequently developed severe steroid-inducedosteoporosis.TL treatment After obtaining approval from the ethicscommittee at our institution, both patients were treatedwith TL. The initial TL dose was 4 mg daily, administeredin two divided dose (0.1 mg/kg in case 1 and 0.08 mg/kg incase 2). Timing of the commencement of TL from the onsetof NS was 3 years in case 1 and 18 months in case 2. Thetrough blood level of TL remained in the range of between4.6 and 13.3 ng/ml in case 1, while in case 2, the troughblood level of TL remained in the range of between 4.3 and6.5 ng/ml, despite the TL dose was subsequently increasedto 6 mg (0.12 mg/kg).

Single-dose daily treatment with cyclosporin A for relapsing nephrotic syndrome: report of a case showing poor response

Sir, – We have previously reported on the potential usefulness and safety of single-dose daily preprandial administration of low-dose cyclosporin A(CsA, Neoral) for the treatment of childhood nephrotic syndrome (NS) [Kudo et al. 2005, Nakahata et al. 2005, Tanaka et al. 2004]. Our treatment protocol yielded higher peak blood levels of CsA without associated elevation of the trough blood levels, therefore, promising better treatment results and safer use of the drug, and also a better costbenefit ratio as compared to the conventional twice-daily dosing used in the treatment of NS [Nakahata et al. 2005, Tanaka et al. 2004, 2006]. However, we recently encountered a young boy with long-standing minimalchange NS (MCNS) who showed a poor response to our current CsA treatment protocol for relapsing NS. The patient was successfully treated by twice-daily preprandial administration of CsA with peak blood level monitoring. In this letter, we would like to discuss this discrepancy of the treatment results.

Comparison of Generic Cyclosporine Microemulsion versus Neoral in de Novo Renal Transplant Recipients Managed By 2-Hour Postdose Monitoring

Introduction The bioequivalence of generic formulations is established by measuring pharmacokinetic parameters in healthy volunteers. Cyclosporine (CsA) absorption and exposure is known to differ between healthy volunteers and transplant recipients. Therefore bioequivalence testing may be inadequate to ensure therapeutic equivalence. We sought to compare the efficacy of generic cyclosporine (ArpimuneME, RPG Life Sciences) versus Sandimmune Neoral in de novo renal transplant recipients. Methods A prospective single-center, open-label study enrolled 20 de novo renal transplant patients (group 1: mean age 30.55 ± 9.81 years, M:F 19:1, mean donor age 43.4 ± 10.8). All patients received ArpimuneME along with azathioprine and prednisolone. The results were compared with 17 matched controls (group 2: mean age 28.1 ± 9.5 years, M:F 13:4, mean donor age 47.8 ± 6.8) who received Neoral and were transplanted during the same period. C 2 levels were monitored by the cloned enzyme donor immunoassay (CEDIA). Results Patient and graft survivals were 100% and 100% and 100% and 92.8% in groups 1 and 2, respectively ( P = NS). Six patients (30%) experienced rejection in group 1 as compared eight patients (47.1%) in group 2. Mean CsA levels (ng/mL) during the first month were 1419.1 ± 213.6 and 1460.5 ± 290.7 and at 3 months, 1296.3 ± 227.8 and 1342.4 ± 303.4 in the two groups, respectively ( P = NS). The mean serum creatinine levels (mg%) in group 1 and group 2 were 1.6 ± 0.8 and 2.0 ± 1.4 at discharge and 1.5 ± 0.4 and 1.5 ± 0.8 at 6 months, respectively ( P = NS). Conclusion Use of a generic microemulsion form of CsA provided safe and effective immunosuppression compared with Sandimmune Neoral when drug monitoring was performed by C 2 levels.

Bone Mineral Density in Long-Term Chinese Heart Transplant Recipients: A Cross-Sectional Study

Osteoporosis, which usually peaks during 6 to 12 months after transplantation, remains an important concern after heart transplantation. Immunosuppresants contribute to this phenomenon. Glucocorticoids are well documented to cause bone loss, but the role of cyclosporine (CsA) remains controversial, especially among long-term recipients on low doses of steroid. We herein report a cross-sectional study of bone mineral density (BMD) among long-term Chinese heart transplant recipients. We enrolled 41 patients of mean age 50.15 ± 13.58 years with a mean follow-up of 57.02 months. Lumbar spine and femoral neck BMD were measured by dual energy x-ray absorptiometry. Trough CsA levels (C 0) and markers of mineral metabolism, including bone-specific alkaline phosphatase and urinary N-telopeptide, were determined by immunoassay. Sixty six percent of subjects showed bone loss at the femoral neck, significantly more than those in the lumbar spine. Those receiving a higher CsA dosage (<2.5 mg/kg/d) showed greater femoral neck BMD, but lower serum creatinine values. Our results demonstrated that bone loss remains long after transplantation, though bone markers are within normal limits.

Spirulina attenuates cyclosporine‐induced nephrotoxicity in rats

Cyclosporine (CsA) causes a dose-related decrease in renal function in experimental animals and humans. The generation of reactive oxygen species (ROS) has been implicated in CsA-induced nephrotoxicity. It was previously shown that Spirulina, a blue-green algae, with antioxidant properties effectively attenuated the doxorubicin-induced cardiotoxicity in mice and cisplatin-induced nephrotoxicity in rat. The present study investigated the nephroprotective role of Spirulina against CsA-induced nephrotoxicity in rats. Spirulina (500 mg kg(-1) b.w.) was administered orally for 3 days before and 14 days concurrently with CsA (50 mg kg-1 b.w.). Rats treated with CsA showed nephrotoxicity as evidenced from a significant elevation in plasma urea, creatinine, urinary N-acetyl-beta-D-glucosaminidase (beta-NAG) and a decrease in creatinine and lithium clearance. Pretreatment with Spirulina protected the rats from CsA-induced nephrotoxicity. The CsA-induced rise in plasma urea and creatinine and the decrease in creatinine and lithium clearance were attenuated by Spirulina. There was a significant increase in plasma and kidney tissue MDA with CsA. Spirulina prevented the rise in plasma and kidney tissue MDA. Histopathology of the kidney from CsA-treated rats showed severe isometric vacuolization and widening of the interstitium. However, pretreatment with Spirulina prevented such changes, and the kidney morphology was comparable to that of the control. Spirulina treatment did not alter the blood CsA levels. These results suggest that Spirulina has a protective effect against nephrotoxicity induced by CsA. This study further supports the crucial role of the antioxidant nature of Spirulina in protecting against CsA-induced oxidative stress.

A Novel Bioerodible Deep Scleral Lamellar Cyclosporine Implant for Uveitis

To determine the feasibility, safety, and effectiveness of an episcleral or deep scleral lamellar sustained release cyclosporine (CsA) device in a naturally occurring animal model of uveitis. A two-compartment perfusion chamber was used to assess in vitro human and equine scleral permeability of fluorescein, dexamethasone-fluorescein, or CsA. A biodegradable, matrix-reservoir CsA implant was designed, and release rates of CsA were determined in vitro. Tissue CsA levels were measured in eyes with the implant. Horses with equine recurrent uveitis (ERU) received episcleral or deep scleral lamellar CsA implants and were monitored for up to 3 years. Dexamethasone-fluorescein and CsA penetrated the in vitro equine sclera poorly; however, low but detectable levels of CsA were detected intraocularly in vivo. The implant placed episclerally failed to control inflammatory episodes in ERU. CsA implants placed in the deep sclera adjacent to the suprachoroidal space resulted in high levels of CsA in most ocular tissues. In clinical equine patients with ERU, frequency of uveitic flare-ups was significantly decreased after implantation of a deep scleral lamellar CsA implant. Diffusion of CsA across the sclera from the episcleral space was not a feasible method of drug delivery to the equine eye. However, placing a deep scleral lamellar CsA implant adjacent to the suprachoroidal space was effective in achieving therapeutic ocular drug concentrations and controlling uveitis in horses with ERU.

Cyclosporine-Associated Leukoencephalopathy in Organ Transplant Recipients: Experience of Three Clinical Cases

Leukoencephalopathy is a structural alteration of cerebral white matter mainly involving damage to myelin. Several reports have linked cyclosporine (CsA) with this alteration. The clinical features vary from qualitative alterations of consciousness to neurological deficits. Magnetic resonance imaging (MRI) of the brain demonstrates the damage to the white matter, which is essential for the differential diagnosis. We describe three clinical cases of leukoencephalopathy. The first case is a 43-year-old man received a cadaveric kidney transplant using immunosuppression with of mycophenolate mofetil, prednisone, and CsA. Four months later he developed meningism and bilateral sixth nerve palsy. The second case is a 50-year-old man with a cadaveric kidney transplant received immunosuppressive treatment with azathioprine and prednisone. As a result of gouty arthritis of the ankle, azathioprine was replaced with CsA to allow addition of allopurinol. Two weeks later he developed confusion and personality changes. The third case is a 16-year-old man received a orthotopic liver transplant. Postoperatively he suffered generalized tonic-clonic seizures. In all patients the CsA levels were toxic and signs of neurological alterations were present on MRI. All patients recovered rapidly after CsA withdrawal.

Cyclosporine reduction causes decreasing of angiotensin II and transforming growth factor-beta expression in chronic allograft nephropathy

Summary Background High cyclosporine (CsA) levels might lead to nephrotoxicity due to increasing angiotensin II (AII) and transforming growth factor-beta (TGF-β) production. We hypothesized that a chronic reduction in CsA levels would decrease local renal AII and TGF-β expression and result in improvement of renal function and renal pathological changes in renal transplant recipients. Methods We determined the AII and TGF-β expression by immunohistochemical staining (IHCS) in sequential human renal biopsy specimens in patients with chronic allograft nephropathies (time between biopsies: 15.9 ± 0.8 months) after they had their CsA levels reduced by 50%. Pathological evaluation included percentage expression (%) of interstitial fibrosis and tubular atrophy (FIB), vascular sclerosis (VS), transplant glomerulopathy (TG), and vascular hyalinosis (VH). Serum creatinine (CR, mg/dl) and BUN (mg/dl) levels were also investigated. Results Renal pathological score significantly improved with chronic reduction in CsA blood levels (FIB: from 52 to 26%, p p p p p p Conclusion These data indicate that chronic reduction in CsA diminishes production of renal tissue AII and AT1 receptor expression, and results in decreased fibrosis and improvement of renal function in patients with chronic allograft nephropathy.

Pleocytosis after hemopoietic stem cell transplantation

Frequency and clinical significance of cerebrospinal fluid (CSF) pleocytosis in hemopoietic stem cell (HSC) transplantation were surveyed. Cyclosporine (CSA)- or tacrolimus (FK506)-based regimens were used as graft-vs-host disease (GVHD) prophylaxis in allogeneic HSC transplantation. CSF pleocytosis with or without neurologic symptoms was detected in 12 of 25 patients receiving allogeneic HSC transplants but in none of 11 patients receiving autologous HSC transplants. Of the 12 patients with CSF pleocytosis, only one patient developed leukoencephalopathy later. There was a correlation between CSF cell numbers and trough levels of CSA but not with those of FK506. In patients receiving allogeneic HSC transplants, CSF pleocytosis may be relatively common and may reflect neurologic damage associated with calcineurin inhibitors.

Daily Monitoring of Cyclosporine (Csa) Allows Better Control of Graft vs. Leukaemia Effect (GvL): Single Centre Experience.

The most important consideration in modern SCT practices is the fine balance that is required to achieve adequate immunosuppression and stable engraftment thus allowing the platform to mount an effective GVL response. Though CsA facilitates this objective, it is associated with several adverse clinical manifestations due to its narrow therapeutic index (TI) and wide variability in the absorption kinetics. Weekly monitoring of trough CsA levels are used to adjust the dose. The aim of this study is to determine whether daily monitoring of CsA levels enables better achievement of these goals and yet reduce the serious toxicities.Patients & methods: Twenty three patients (M=15, F=8, median age 46yrs range 19–63) received an allogeneic transplant (sibling-15, MUD-7 mismatched unrelated-1) since March 2004 when we started to monitor daily CsA levels (Biostat TDX analyser using fluorescent immunoassay) from the day of first administration until the time of discharge. The transplants included full intensity (FI=11), reduced intensity (RI=11) or customised (1) for various haematolymphoid malignancies. Patients received uniform GVHD prophylaxis with IV CsA (RI+FI) and methotrexate (FI) as per standard loading doses. The CsA target level was adjusted to 200–220 ng/ml from Day-1 onwards and was later modified according to the treatment strategy. Oral CsA administration was started when patients were able to switch over. Results Nine of 23 (40%) patients developed acute GVH (n=7 grade1–2, n=2 grade 3–4) at a median of 23.5 days (10–28). Two of 9 patients required addition of steroids by Day+30. The median CsA level at the first occurrence of GVH was 247ng/ml (113–333) and the median CsA level during hospitalisation was 207 ng/ml (136–291). Only one patient who received T cell addback required increased dose of IV CsA to manage Grade 4 GVH. Twenty two/22 patients engrafted with a median day to neutrophil recovery being 13 days (8–35). One patient lost his graft due to a low initial cell dose and the inability of the MUD donor to donate any further cells. There was no significant difference in the baseline and Day30 creatinine levels (median highest creatinine 108μmol/l range 58–267) or bilirubin levels (median highest bilirubin 27μmol/l, range15–251). Five/22 patients developed CMV reactivation/infection and 1 developed RSV infection. No patients developed seizures and in one patient pre-existent neuropathy was exacerbated which was directly attributable to CsA. Twenty one/22 patients (95.5%) switched to oral CsA by Day+25. In 8/22 (36.36%) patients, the target CsA levels was around 100–150 ng/ml at the time of discharge. The median duration of hospital stay was 35days (24–130).Conclusions: These observations suggests that daily monitoring of CsA is safe and successful. This allowed successful engraftment and a more liberal management of Grade 1–2 GVH thus allowing us to maximise the GVL effect. Despite concomitant use of other toxic drugs, side effects were minimal and reversible. Close observation of early clinical manifestations enabled us to modify the immunosuppressive strategy at later time periods. This approach also allowed us to better manage patients suffering from CMV and EBV/PTLD (patient number 10 on day+88) by reducing the dose during active infections.

Comparison of Cyclosporine Concentrations 2 Hours Post-Dose Determined Using 3 Different Methods and Trough Level in Pediatric Renal Transplantation

Immunosuppression has been one of the great challenges in pediatric recipients of kidney allografts. Cyclosporine (CsA) has evolved during the past 25 years of transplantation. It requires frequent blood level monitoring because of its narrow therapeutic window and interpatient and intrapatient variability. Neoral (Novartis) is no exception. Ideally, monitoring of blood levels should also include determination of the area under the time-concentration curve (AUC) to better target the therapeutic window, thus avoiding underdosing or overdosing, especially in pediatric patients. A single blood concentration measurement 2 hours after Neoral administration (C2) has been shown to be a more for accurate predictor of drug exposure than trough levels (C0). Therefore, its use may lead to reduction in the incidence and severity of cellular rejection and of CsA toxicity. Some studies have shown that the metabolites/CsA ratio is substantially lower using C2 than C0, however, the between-assay differences for C2 monitoring have not been considered. The purpose of this study was to evaluate CsA C0 and C2 levels, determined using monoclonal fluorescence polarization immunoassay (FPIA)/TDx and enzyme multiplied immunoassay (EMIT). CsA levels were determined using a radioimmunoassay (RIA) in 30 pediatric transplant recipients with stable renal function within 42.7 mean months follow-up. Mean age was 13.4 years; 15 children were girls; 23 patients were recipients of cadaveric kidneys. The mean CsA microemulsion dose was 5.7 mg/kg/d. The 3 methods showed a high correlation between C0 and C2 ( r ≥ 0.97). A linear regression slope was significantly higher for C0 than C2 ( P < .001). The CsA concentrations both at C0 and C2 were significantly higher with FPIA than with RIA ( P < .009) but no differences were found for EMITT ( P = .2). The mean C0 level for FPIA was 22% and 26% higher than RIA and EMIT, respectively. The mean C2, for FPIA was 7% and 12% higher than RIA and EMIT, respectively. In conclusion, CsA levels determined using RIA or EMIT are better than using FPIA/Tx; also, C2 CsA levels are more accurate than C0 in pediatric transplantation patients.

Cyclosporine microemulsion C2 monitoring in Chinese adult liver transplant recipients: a preliminary randomized control trial

To evaluate the safety and reliability of cyclosporine microemulsion (CsA-ME) C(2) monitoring and to determine the target level of C(2) in Chinese adult liver transplant recipients. 53 Chinese adult liver transplant recipients were randomly divided into three groups (group C(0), n = 17; group high level C(2), n = 18; group low level C(2), n = 18). Blood chemistry reflecting heart, liver and renal function and CsA level were examined at certain interval during follow-up. The change of immune status and episodes of rejection were also observed closely. The group low level C(2) had the lowest CsA oral dose (2.51 +/- 0.37 mg/kg/d), and had significant difference compared with the other groups (P < 0.01). The best liver, heart and renal function was observed in group low level C(2). The CD(4)(+)/CD(8)(+) ratio of group low level C(2) was 1.04 +/- 0.68, which had no significant difference with C(0) group. The rejection incidence of the three groups had no significant difference. group low level C(2) had highest clinical benefit ratio (72.22%), while the clinical benefit of group high level C(2) is the lowest (11.11%). With rational target level, C(2) monitoring can show us the proper oral dose of CsA which can decrease the side effects remarkably without rejection episodes increasing. The target level of C(2) in Chinese adult liver transplant recipients might be: 600-800 ng/ml 1 to 6 months posttransplant, 400-600 ng/ml 7-12 months posttransplant.

Randomized Trial of Alemtuzumab for Prevention of Graft Rejection and Preservation of Renal Function after Kidney Transplantation1

A randomized, multicenter, controlled trial was undertaken to evaluate the safety and efficacy of Alemtuzumab, a powerful lytic agent for both T and B lymphocytes, in the prophylaxis of rejection in renal transplantation (RTx). Thirty patients were randomized to receive Alemtuzumab together with low-dose cyclosporine (CsA) monotherapy (CAMPATH, n = 20) or to full doses of CsA with azathioprine and corticosteroids (Standard, n = 10). CsA was administered at doses to achieve whole-blood trough CsA levels of 90 to 110 ng/mL and 180 to 225 ng/mL in CAMPATH and Standard groups, respectively. Per protocol, CsA trough levels were lower in patients assigned to CAMPATH post-RTx (median trough level of 119 vs. 166 ng/mL at 6 months, CAMPATH vs. Standard; 95% confidence interval, -92 to -34). At 6 months post-RTx, serum creatinine, graft and patient survivals, incidence of biopsy proven acute rejection (25% vs. 20%, CAMPATH vs. Standard), overall treatment failure, and severe and moderate infections were comparable. Whereas all patients receiving Standard therapy required maintenance corticosteroids at 6 months, of the 17 of 20 patients with functioning grafts in CAMPATH, 15 (88%, 95% confidence interval, 53%-97%) were steroid free. These results suggest that Alemtuzumab is an effective induction agent that permits low-dose steroid-free immunosuppression in RTx.

Intraocular implantation of cyclosporine A drug delivery system in the treatment of experimental uveitis

To investigate the effects and safety of cyclosporine A drug delivery system (CsA DDS) implanted into vitreous cavity on the treatment of experimental rabbit uveitis. A model of uveitis was established in 30 New Zealand white rabbits (30 eyes). The rabbits were randomized into control group (group A, 6 eyes), intravitreal non-medicated DDS group (group B, 6 eyes), oral CsA group (group C, 6 eyes) and intravitreal CsA DDS group (group D, 12 eyes). The inflammatory parameters such as floating cells, flaring and exudation in anterior chamber were graded. The cells infiltration and degree of opacity in vitreous were scored as well. The electroretinography and histopathological examination in eye, liver and kidney were recorded. In addition, CsA level in vitreous cavity was measured by HPLC in another 13 New Zealand white rabbits that received intravitreal implantation of CsA DDS. Uveitis was successfully induced in the 30 eyes. The inflammation in groups A, B and C was more severe than group D. There was no significant difference between groups D and A or B (P < 0.05). The electroretinography showed more significant b-wave depression in groups A and B than group D (P < 0.05). A large amount of inflammatory cells infiltration and marked tissue disorganization were found at ciliary body and retina in groups A and B. The mean drug level in vitreous cavity ws (491.0 +/- 481.6) ng/ml at 4 weeks, (575.2 +/-0373.2) ng/ml at 8 weeks and (301.5 +/- 128.5) ng/ml at 12 weeks. No toxicity could be detected in histological examination by light microscopy. Sustained therapeutic drug level could be achieved by implanting CsA DDS into vitreous cavity. It may effectively reduce the ocular inflammation in the rabbit model of uveitis.