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1.
Randomized, open-label, comparative phase IV study on the bioavailability of Ciclosporin Pro (Teva) versus Sandimmun® Optoral (Novartis) under fasting versus fed conditions in patients with stable renal transplants.
Gäckler, A, Dolff, S, Rohn, H, Korth, J, Wilde, B, Eisenberger, U, Mitchell, A, Kribben, A, Witzke, O
BMC nephrology. 2019;(1):167
Abstract
BACKGROUND The influence of pre- or postprandial administration on pharmacokinetics of cyclosporine is supposed to be less in gel-based formulations than in microemulsions. This study was designed to investigate the influence of a high-fat meal on the pharmacokinetic profile of the two cyclosporine containing formulations Ciclosporin Pro (gel-based emulsion) and Sandimmun®Optoral (microemulsion) in renal transplant recipients. METHODS A randomized, open-label, repeated-measurement, comparative phase IV trial was conducted with two sequence groups for nutrition condition (fasting→fed, fed→fasting) and two treatment phases (Sandimmun® Optoral → Ciclosporin Pro), each covering both nutrition conditions. Primary pharmacokinetic variable of interest was the reduction of bioavailability due to high-fat food compared to fasting conditions measured by the difference D of ln-transformed bioavailability variables (AUCSS, τ, Css, max, und Css, min). RESULTS A nutrition effect was found for both study medications with respect to the parameters AUCSS, τ and CSS, max, but not to CSS, min. The reduction of bioavailability caused by high-fat food was not significantly different for Sandimmun®Optoral and Ciclosporin Pro. CONCLUSIONS An effect of high-fat breakfast prior to the morning dose on AUCSS, τ and CSS, max was found for Sandimmun® Optoral and for Ciclosporin Pro. Trough level monitoring did not capture ingestion-related variability. Conversion to Ciclosporin Pro seems to be safe with regard to intra-individual pharmacokinetic variability. TRIAL REGISTRATION EudraCT No. 2009-011354-18 (29th April 2019).
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2.
Efficacy and safety of tacrolimus compared with ciclosporin-A in renal transplantation: 7-year observational results.
Krämer, BK, Montagnino, G, Krüger, B, Margreiter, R, Olbricht, CJ, Marcen, R, Sester, U, Kunzendorf, U, Dietl, KH, Rigotti, P, et al
Transplant international : official journal of the European Society for Organ Transplantation. 2016;(3):307-14
Abstract
The European Tacrolimus versus Ciclosporin-A Microemulsion (CsA-ME) Renal Transplantation Study demonstrated that tacrolimus decreased acute rejection rates at 6 months. Primary endpoints of this investigator-initiated, observational 7-year follow-up study were acute rejection rates, patient and graft survival rates, and a composite endpoint (BPAR, graft loss, and patient death). We analyzed data from the original intent-to-treat population (n = 557; 286 tacrolimus, 271 CsA-ME). A total of 237 tacrolimus and 208 CsA-ME patients provided data. At 7 years, Kaplan-Meier estimated rates of patients free from BPAR were 77.1% in the tacrolimus arm and 59.9% in the CsA-ME arm, graft survival rates amounted to 82.6% and 80.6%, and patient survival rates to 89.9% and 88.1%. Estimated combined endpoint-free survival rates were 60.2% in the tacrolimus arm and 47.0% in the CsA-ME arm (P = <0.0001). A higher number of patients from the CsA-ME arm crossed over to tacrolimus during 7 year follow-up: 19.7% vs. 7.9% (P = <0.002). More patients in the tacrolimus group stopped steroids and received immunosuppressive monotherapy. Significantly, more CsA-ME patients received lipid-lowering medication and experienced cosmetic and cardiovascular adverse events. Tacrolimus-treated renal transplant recipients had significantly higher combined endpoint-free survival rates mainly driven by lower acute rejection rates despite less immunosuppressive medication at 7 years.
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3.
Side effects of the calcineurin inhibitor, such as new-onset diabetes after kidney transplantation.
Borda, B, Lengyel, C, Várkonyi, T, Kemény, E, Ottlakán, A, Kubik, A, Keresztes, C, Lázár, G
Acta physiologica Hungarica. 2014;(3):388-94
Abstract
New-onset diabetes after transplantation (NODAT) is one of the frequent complications following kidney transplantation. Patients were randomized to receive cyclosporine A- or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following three groups based on the results: normal, impaired fasting glucose/impaired glucose tolerance (IFG/IGT), or NODAT. NODAT developed in 14% of patients receiving cyclosporine A-based immunosuppression and in 26% of patients taking tacrolimus (p = 0.0002). Albumin levels were similar, but uric acid level (p = 0.002) and the age of the recipient (p = 0.003) were significantly different comparing the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection (ACR) and interstitial fibrosis/tubular atrophy (IF/TA) were significantly different in the NODAT group. The pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.
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4.
Everolimus-treated renal transplant recipients have a more robust CMV-specific CD8+ T-cell response compared with cyclosporine- or mycophenolate-treated patients.
Havenith, SH, Yong, SL, van Donselaar-van der Pant, KA, van Lier, RA, ten Berge, IJ, Bemelman, FJ
Transplantation. 2013;(1):184-91
Abstract
BACKGROUND In renal transplant recipients, mammalian target of rapamycin (mTOR) inhibitors have been reported to protect against cytomegalovirus (CMV) disease. Here, we questioned whether mTOR inhibitors specifically influence human CMV-induced T-cell responses. METHODS We studied renal transplant recipients treated with prednisolone, cyclosporine A (CsA), and mycophenolate sodium (MPS) for the first 6 months after transplantation followed by double therapy consisting of prednisolone/everolimus, which is an mTOR inhibitor (P/EVL; n=10), prednisolone/CsA (P/CsA; n=7), or prednisolone/MPS (P/MPS; n=9). All patients were CMV-IgG positive before transplantation. CMV reactivation was detectable in the first 6 months after transplantation and not thereafter. None of the patients included in this study suffered from CMV disease. Both CD27CD8 and CD27CD28CD4 effector-type T-cell counts, known to be associated with CMV infection, were measured before transplantation and at 6 and 24 months after transplantation. Additionally, we determined both number and function of CMV-specific CD8 T cells at these time points. RESULTS The number of total CD8 T cells, CD27CD8 T cells, and CD28CD4 T cells increased significantly after switch to therapy with P/EVL but not after switch to P/CsA or P/MPS. Specifically, CMV-specific CD8 T-cell counts significantly increased after switch to therapy with P/EVL. Furthermore, the mTOR inhibitor sirolimus strongly inhibited alloresponses in vitro, whereas it did not affect CMV-specific responses. CONCLUSION We observed a significant increase in (CMV-specific) effector-type CD8 and CD4 T-cell counts in everolimus-treated patients. These findings may at least in part explain the reported low incidence of CMV-related pathology in everolimus-treated patients.
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5.
Topical ciclosporin in the treatment of vernal keratoconjunctivitis in Rwanda, Central Africa: a prospective, randomised, double-masked, controlled clinical trial.
De Smedt, S, Nkurikiye, J, Fonteyne, Y, Tuft, S, De Bacquer, D, Gilbert, C, Kestelyn, P
The British journal of ophthalmology. 2012;(3):323-8
Abstract
AIM: To compare the short-term efficiency and safety of topical ciclosporin A (CsA) 2% with dexamethasone 0.1% in the treatment of predominantly limbal vernal keratoconjunctivitis (VKC) in Rwanda, Central Africa. METHODS Consecutive patients with VKC were randomised in a prospective, double-masked, clinical trial to receive either topical CsA 2% dissolved in olive oil vehicle or dexamethasone 0.1% drops for 4 weeks. Both groups then received sodium chromoglycate 2% drops for maintenance therapy for a further 4 weeks. The primary outcome was the reduction in composite score for VKC-related symptoms and signs at 4 weeks. Secondary outcomes included side effects, best-corrected visual acuity, comfort rating of the trial drops during 4 weeks' test medication and relapse rate thereafter. RESULTS The 366 participants recruited had the limbal (91.5%) or mixed form of VKC. At the end of the 4-week treatment period, the composite score had decreased significantly (p<0.001) from baseline without any significant difference between CsA and dexamethasone (p=0.20). There were no severe adverse reactions, but CsA drops caused more stinging than the oil placebo and dexamethasone (p<0.001). In both treatment groups, the visual acuity had improved at 4 weeks compared with baseline (p<0.001) with no significant difference between the treatment arms. The relapse rate following cessation of the trial treatments was similar (p=0.84) in both groups. CONCLUSION There is no significant difference between the efficiency of topical CsA 2% and dexamethasone 0.1% for the management of acute VKC in Central Africa, but tolerance needs to be improved.
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6.
Acute effects of calcineurin inhibitors on kidney allograft microperfusion visualized by contrast-enhanced sonography.
Kihm, LP, Blume, C, Seckinger, J, Hankel, V, Stoffler, D, Morath, C, Zeier, M, Schwenger, V
Transplantation. 2012;(11):1125-9
Abstract
BACKGROUND Calcineurin inhibitors induce detrimental vascular remodeling, which may be one cause of chronic allograft failure. Real-time contrast-enhanced sonography (CES) is a relatively new technique in providing quantitative information on microvascular tissue perfusion in kidney allografts in more detail. The purpose of the study was to explore whether acute changes of kidney allograft microperfusion due to the administration of cyclosporine A (CsA) and tacrolimus (Tac) can be evidenced using real-time CES. METHODS In an explorative single-center clinical trial, renal parenchymal tissue perfusion of 32 stable kidney allograft recipients was evaluated with CES before and 2 hr after the intake of CsA or Tac. In addition to laboratory and clinical parameters, Doppler indices and estimated glomerular filtration rate were measured. RESULTS Although systolic and diastolic blood pressure and color Doppler indices did not significantly differ, there was a significant decrease of renal blood flow 2 hr after the intake of CsA compared with baseline (4.78±2.31 dB/s, 49%, respectively). In contrast, kidney allograft microperfusion was neither significantly reduced in patients receiving CsA paralleled by calcium channel blockers nor significantly reduced in patients receiving Tac. Furthermore, there was a significant correlation between renal blood flow obtained before drug administration and kidney function. CONCLUSIONS CES revealed a 49% reduction of kidney allograft microperfusion 2 hr after the intake of CsA, which might be abrogated by calcium channel blockers. In comparison to CsA, Tac did not result in a significant decrease of kidney blood flow.
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7.
Changes in oxidative stress in renal graft patients receiving calcineurin inhibitors: cyclosporine versus tacrolimus.
Akbasli, AC, Keven, K, Erbay, B, Nebioglu, S
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2012;(5):439-45
Abstract
OBJECTIVES The effects of calcineurin inhibitors on oxidative stress after renal transplant are obscure. This study sought to investigate the changes in plasma oxidative stress and lipid levels in patients receiving cyclosporine or tacrolimus before and after renal transplant for 6 months. MATERIALS AND METHODS Twenty-one patients and 15 healthy controls were involved in our study. Twelve of the patients were treated with cyclosporine and 9 were treated with tacrolimus. Plasma malondialdehyde, nitrite/nitrate, vitamin C, vitamin E, and plasma glutathione levels, as well as total cholesterol and triglyceride levels, were evaluated before and after transplant for 6 months. RESULTS Before the transplant, patients had higher malondialdehyde and plasma glutathione levels than did healthy controls (3.76 ± 0.79 nmol/mL vs 3.21 ± 0.57 nmol/mL; P < .05, and 66.6 ± 23.2 μmol/L vs 43.3 ± 26.9 μmol/L; P < .05). In the overall group of patients, a significant increase in malondialdehyde levels was detected 3 and 6 months after transplant (3.76 ± 0.79 nmol/mL vs 4.38 ± 0.87 nmol/mL in the third month; P = .02; and 3.76 ± 0.79 nmol/mL vs 4.28 ± 0.69 nmol/mL in the sixth month; P = .04). A significant reduction in plasma glutathione levels 1 month after transplant and nitrite/nitrate levels 6 months after transplant was found. No changes in vitamin C and vitamin E levels were detected before and after transplant. After 3 and 6 months of transplant, cyclosporine-treated patients had higher levels of total cholesterol and triglycerides when compared with tacrolimus-treated patients. CONCLUSIONS An enhancement in plasma malondialdehyde levels was found after transplant at 6-month follow-up. However, no significant change in vitamin C, vitamin E, nitrite/nitrate levels between patients and controls was recorded. Although both calcineurin inhibitors showed similar effects on oxidative stress, cyclosporine-treated patients had higher levels of total cholesterol and triglycerides.
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8.
Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial.
Haeck, IM, Knol, MJ, Ten Berge, O, van Velsen, SG, de Bruin-Weller, MS, Bruijnzeel-Koomen, CA
Journal of the American Academy of Dermatology. 2011;(6):1074-84
Abstract
BACKGROUND Cyclosporin A (CsA) is frequently used in the treatment of severe atopic dermatitis (AD). Enteric-coated mycophenolate sodium (EC-MPS) may be an alternative with equal efficacy and fewer side effects. OBJECTIVE The aim of this observer-blinded randomized controlled trial was to compare EC-MPS with CsA as long-term treatment in adult patients with severe AD. METHODS Fifty five patients with AD were treated with CsA (5 mg/kg) in a 6-week run-in period. Thereafter, patients either received CsA (3 mg/kg; n = 26) or EC-MPS (1440 mg; n = 24) during a maintenance phase of 30 weeks and there was a 12-week follow-up period. Disease activity was measured using the objective SCORAD and serum thymus and activation-regulated chemokine (TARC) levels and side effects were registered. RESULTS During the first 10 weeks the objective SCORAD and serum TARC levels in the EC-MPS study arm were higher in comparison with the CsA study arm. In addition, 7 of the 24 patients treated with EC-MPS required short oral corticosteroid courses. During maintenance phase disease activity was comparable in both study arms. Side effects in both study arms were mild and transient. After study medication withdrawal, disease activity of the patients in the CsA study arm significantly increased compared with the EC-MPS study arm. LIMITATION The nonblinding of patients and prescriber of rescue medication are limitations. CONCLUSIONS This study shows that EC-MPS is as effective as CsA as maintenance therapy in patients with AD. However, clinical improvement with EC-MPS is delayed in comparison with CsA. Clinical remission after stopping EC-MPS lasts longer compared with CsA.
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9.
Tubular toxicity in sirolimus- and cyclosporine-based transplant immunosuppression strategies: an ancillary study from a randomized controlled trial.
Franz, S, Regeniter, A, Hopfer, H, Mihatsch, M, Dickenmann, M
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2010;(2):335-43
Abstract
BACKGROUND Sirolimus has been promoted as an agent to provide immunosuppression for kidney transplant recipients that, in contrast to calcineurin inhibitors, would not be nephrotoxic. However, several reports have observed proteinuria in patients treated with sirolimus, ranging from low grade to nephrotic range. Accordingly, we compared markers of tubular and glomerular damage in an ancillary study of a randomized trial comparing sirolimus and cyclosporine. STUDY DESIGN Single-center, open-label, randomized, prospective trial. SETTING & PARTICIPANTS Patients undergoing cadaveric or living donor kidney transplant at the University Hospital in Basel, Switzerland, between January 2001 and July 2004. INTERVENTION Immunosuppression regimen consisting of cyclosporine, mycophenolate mofetil, and prednisone versus sirolimus, mycophenolate mofetil, and prednisone. OUTCOMES The primary outcome was kidney function, assessed using serum creatinine level. Secondary outcomes included patient and graft survival, number of rejections, and evidence of kidney damage, assessed using glomerular and tubular urine biomarker levels. MEASUREMENTS Urine and serum were collected at 0, 7, 30, and 90 days. Kidney function was estimated using serum creatinine level. Urinary markers included alpha(1)-microglobulin and retinol-binding protein (tubular), transferrin and albumin (glomerular), and semiquantitative assessment of glucosuria. Protocol kidney biopsies were performed at days 90 and 180. RESULTS There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, whereas levels of markers associated with glomerular damage (albumin, 19.5 vs 8.96 mg/mmol creatinine; P < 0.001; transferrin, 13.1 vs 5.7 mg/mmol creatinine; P < 0.001) and those associated with tubular damage (alpha(1)-microglobulin, 11 vs 7.6 mg/mmol creatinine; P = 0.004; retinol-binding protein, 19.6 vs 9.6 mg/mmol creatinine; P = 0.002) were higher beginning at day 7 in patients randomly assigned to sirolimus therapy, with similar findings through day 90. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy beginning by day 30 (65% vs 30% on day 30; P = 0.002; 51% vs 22% on day 90; P < 0.001). On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy. LIMITATIONS Small sample size, short-term follow-up likely insufficient to appreciate calcineurin-associated nephropathy. CONCLUSION Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy.
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10.
Comparison of immunosuppressive therapeutic regimens in patients with nephrotic syndrome due to idiopathic membranous nephropathy.
Kosmadakis, G, Filiopoulos, V, Smirloglou, D, Skarlas, P, Georgoulias, C, Michail, S
Renal failure. 2010;(5):566-71
Abstract
In this prospective randomized trial, we compared the effects of cyclosporine- and cyclophosphamide-based treatment regimens in patients with idiopathic membranous nephropathy. Twenty-eight patients were randomized to receive treatment with one of the three therapeutic regimens: cyclosporine with methylprednisolone, cyclophosphamide with methylprednisolone or lisinopril (control). Renal function and nephrotic syndrome parameters were determined at baseline and during a 9-month treatment period. At the end of the study period, renal function improved significantly in the cyclophosphamide and deteriorated significantly in the cyclosporine group. Serum albumin levels increased significantly in the cyclosporine and cyclophosphamide group. Total cholesterol levels and proteinuria were significantly reduced in all groups. In the comparison between the groups, serum albumin levels were significantly lower in the control group and there were no differences in the rest of the studied parameters at the end of the study. Six patients from the cyclosporine group (1/10 complete and 5/10 partial), all cyclophosphamide-treated (4/8 complete and 4/8 partial) and all 10 lisinopril-treated patients (10/10 partial) were on remission at the end of the study. In conclusion, cyclosporine-based regimens are not inferior to cyclophosphamide-based regimens. Cyclophosphamide is associated with more complete remissions after 9 months of treatment. Lisinopril is associated with a significant proteinuria reduction and without inducing any complete remissions.