Immunosuppression in liver transplantation: Beyond calcineurin inhibitors

Fung, John J.; Kelly, D. L.; Kadry, Zakiyah; Patel-Tom, Kusum; Eghtesad, Bijan

doi:10.1002/lt.20373

Cited by 79 publications

(57 citation statements)

References 92 publications

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“…Even in a transplantation setting, CsA is being supplanted by newer less toxic immunosuppressants. 39 In this regard, NIM811, a nonimmunosuppressive derivative of CsA that inhibits MPT pore opening, 24 may be a more useful cytoprotective agent than CsA. In addition to protecting against storage/reperfusion injury (Figs.…”

Section: Discussionmentioning

confidence: 99%

Minocycline and N -methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition

et al. 2008

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Graft failure after liver transplantation may involve mitochondrial dysfunction. We examined whether prevention of mitochondrial injury would improve graft function. Orthotopic rat liver transplantation was performed after 18 hours' cold storage in University of Wisconsin solution and treatment with vehicle, minocycline, tetracycline, or N-methyl-4-isoleucine cyclosporin (NIM811) of explants and recipients. Serum alanine aminotransferase (ALT), necrosis, and apoptosis were assessed 6 hours after implantation. Mitochondrial polarization and cell viability were assessed by intravital microscopy. Respiration and the mitochondrial permeability transition (MPT) were assessed in isolated rat liver mitochondria. After transplantation with vehicle or tetracycline, ALT increased to 5242 U/L and 4373 U/L, respectively. Minocycline and NIM811 treatment decreased ALT to 2374 U/L and 2159 U/L, respectively (P < 0.01). Necrosis and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) also decreased from 21.4% and 21 cells/field, respectively, after vehicle to 10.1% and 6 cells/field after minocycline and to 8.7% and 5.2 cells/field after NIM811 (P < 0.05). Additionally, minocycline decreased caspase-3 activity in graft homogenates (P < 0.05). Long-term graft survival was 27% and 33%, respectively, after vehicle and tetracycline treatment, which increased to 60% and 70% after minocycline and NIM811 (P < 0.05). In isolated mitochondria, minocycline and NIM811 but not tetracycline blocked the MPT. Minocycline blocked the MPT by decreasing mitochondrial Ca 2؉ uptake, whereas NIM811 blocks by interaction with cyclophilin D. Intravital microscopy showed that minocycline and NIM811 preserved mitochondrial polarization and cell viability after transplantation (P < 0.05). Conclusion: Minocycline and NIM811 attenuated graft injury after rat liver transplantation and improved graft survival. Minocycline and/or NIM811 might be useful clinically in hepatic surgery and transplantation. (HEPATOLOGY 2008;47:236-246.)

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Section: Discussionmentioning

confidence: 99%

Minocycline and N -methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition

et al. 2008

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“…Die Neuro-und Ne phro to xi zi tät von Ta cro li mus und Cy clos po rin kann zur Um stel lung der im mun sup pres si ven The ra pie zwingen [8]. Bei My co phe no lat und Ra pa mycin kann u. a. eine Hä ma to to xi zi tät auf treten.…”

Section: To XI Zi Tätunclassified

Folgeerkrankungen nach gastrointestinalen Operationen

2006

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Gastrointestinal surgery may not only lead to early postoperative complications but also chronic consequences. These have therapeutic implications for affected patients. The kind and extent of surgical intervention determines the spectrum of postsurgical phenomena which may occur. These chronic consequences are due to changes in gastrointestinal anatomy, the synchronization of digestive processes, or the ability to digest and absorb food. In case of transplantation surgery, adverse effects of immunosuppression have to be considered. Sometimes, chronic consequences of surgical procedures are difficult to recognize. The knowledge of typical problems associated with gastrointestinal surgery is necessary to enable early and timely diagnosis and treatment. Some negative effects can be avoided by early therapeutic interventions. This article summarizes typical chronic consequences of gastrointestinal surgery.

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“…In addition, sirolimus is under investigation for use as prophylaxis following liver, heart and bone marrow transplantation, and graft-vs-host disease. At present, there is not yet an established protocol of immunosuppressive therapy including sirolimus for liver transplantation (Fung et al, 2005;Trotter, 2003;Zaghla et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Liquid chromatographic method for the determination of sirolimus in blood using electrochemical detection

Mochizuki

Suka

Matsumoto

et al. 2008

Biomedical Chromatography

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Therapeutic drug monitoring of sirolimus (rapamycin) is important for immunosuppressive therapy in solid organ transplantation. We have developed a simple and reliable method for determining blood concentrations of sirolimus using reversed-phase HPLC with electrochemical detection (ECD). The E(2) potential was set at +900 mV. The potential of guard cell was set at +950 mV and that of the E(1) cell at +400 mV. The method was linear for a concentration range of 1-50 ng/mL when 0.5 mL blood was used. The correlation coefficients of all standard curves were greater than or equal to 0.999. The limit of detection was 0.5 ng/mL. The inter-assay precision ranged from 3.22 to 7.48%, and the coefficient of variation (CV) for a quality control sample at 10 ng/mL was 7.48% with a bias of 8.4% from the target value. The intra-assay precision ranged from 0.72 to 3.71%, and the CV for a quality control sample at 10 ng/mL was 0.72% with a bias of 6.8% from the target value. In a solid organ transplant recipient, trough concentrations of sirolimus were well within the analytic range of the HPLC/ECD procedure. The method described here is suitable for management of sirolimus therapy in solid organ transplantation.

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Immunosuppression in liver transplantation: Beyond calcineurin inhibitors

Cited by 79 publications

References 92 publications

Minocycline and N -methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition

Minocycline and N -methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition

Folgeerkrankungen nach gastrointestinalen Operationen

Liquid chromatographic method for the determination of sirolimus in blood using electrochemical detection

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