Relationship Between Pharmacokinetic Parameters of Cyclosporin and the Incidence of Acute Rejection After Heart Transplantation

Aumente, M.D.; Arizón, J.M.; Segura, José; López, Antonio Luis Gámez; Albornoz, Remy Nelson; Cárdenas, M.; Segura, Carmen

doi:10.1016/j.transproceed.2005.09.149

Cited by 4 publications

(2 citation statements)

References 13 publications

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“…Despite marked effort and advances made during the past few years, with improved immunosuppression regimens and post-operative care, there are a number of problems that remain to be resolved, including poor long-term cardiac allograft outcomes, infections and malignancies (2)(3)(4). The introduction of cyclosporine (CsA) in immunosuppressive therapy has greatly improved the clinical outcome of cardiac transplantation (5,6). However, the side effects of CsA, including irreversible pulmonary hypertension, infection and cancer, are serious limitations due to the high dosage required (7,8).…”

Section: Introductionmentioning

confidence: 99%

Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis

Liu

Hong

Shao

et al. 2014

Molecular Medicine Reports

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Melatonin, a widespread physiological mediator, has been demonstrated to exhibit a dose‑dependent immunoregulatory effect in vitro and in vivo, including mediating physiological circadian rhythms, neutralizing free radicals and exerting antisenescence actions. In the present study, the efficacy and mechanism of melatonin alone or in combination with cyclosporine (CsA) in prolonging heart transplantation survival was examined. Daily treatment with melatonin (200 mg/kg/day) through a gavage, significantly prolonged the survival of cardiac grafts (mean survival time, 13.4±2.4 days; n=7; P<0.0001) compared with the untreated controls (5.8±1.2 days; n=7). When CsA (5 mg/kg/day) was co‑administered with melatonin (50 mg/kg/day), the survival rate improved (31.6±2.4 days; n=7; P<0.001), compared with that achieved by only 20 mg/kg/day CsA (22±2.8 days; n=7). As expected, melatonin significantly alleviated the inflammatory response and apoptosis as determined by TdT‑mediated dUTP‑biotin nick end labeling assay (P<0.05). Further analysis demonstrated that melatonin significantly reduced p65 activation and the release of inflammatory factors. Therefore, these findings indicate that melatonin in combination with CsA protected the cardiac allograft by inhibiting inflammation‑induced apoptosis. These results provide evidence for a novel therapeutic approach for future immunosuppressive agents in organ transplantation.

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Section: Introductionmentioning

confidence: 99%

Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis

Liu

Hong

Shao

et al. 2014

Molecular Medicine Reports

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“…The outcome of these procedures have improved using cyclosporine (CsA) as an immunosuppressive therapy (Aumente et al 2005), but this drug has several limitations due to its side effects (Baan et al 1994). Melatonin has been studied as an agent to protect against graft rejection.…”

Section: Cardiac Transplantationmentioning

confidence: 99%

Potential benefits of melatonin in organ transplantation: a review

Esteban‐Zubero

García-Gil

López-Pingarrón

et al. 2016

Journal of Endocrinology

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Organ transplantation is a useful therapeutic tool for patients with end-stage organ failure; however, graft rejection is a major obstacle in terms of a successful treatment. Rejection is usually a consequence of a complex immunological and nonimmunological antigen-independent cascade of events, including free radical-mediated ischemia-reperfusion injury (IRI). To reduce the frequency of this outcome, continuing improvements in the efficacy of antirejection drugs are a top priority to enhance the long-term survival of transplant recipients. Melatonin (N-acetyl-5-methoxytryptamine) is a powerful antioxidant and ant-inflammatory agent synthesized from the essential amino acidl-tryptophan; it is produced by the pineal gland as well as by many other organs including ovary, testes, bone marrow, gut, placenta, and liver. Melatonin has proven to be a potentially useful therapeutic tool in the reduction of graft rejection. Its benefits are based on its direct actions as a free radical scavenger as well as its indirect antioxidative actions in the stimulation of the cellular antioxidant defense system. Moreover, it has significant anti-inflammatory activity. Melatonin has been found to improve the beneficial effects of preservation fluids when they are enriched with the indoleamine. This article reviews the experimental evidence that melatonin is useful in reducing graft failure, especially in cardiac, bone, otolaryngology, ovarian, testicular, lung, pancreas, kidney, and liver transplantation.

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Pharmacokinetic Optimization of Immunosuppressive Therapy in Thoracic Transplantation: Part I

Monchaud

Marquet

2009

Clinical Pharmacokinetics

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Although immunosuppressive treatments and therapeutic drug monitoring (TDM) have significantly contributed to the increased success of thoracic transplantation, there is currently no consensus on the best immunosuppressive strategies. Maintenance therapy typically consists of a triple-drug regimen including corticosteroids, a calcineurin inhibitor (ciclosporin or tacrolimus) and either a purine synthesis antagonist (mycophenolate mofetil or azathioprine) or a mammalian target of rapamycin inhibitor (sirolimus or everolimus). The incidence of acute and chronic rejection and of mortality after thoracic transplantation is still high compared with other types of solid organ transplantation. The high allogenicity and immunogenicity of the lungs justify the use of higher doses of immunosuppressants, putting lung transplant recipients at a higher risk of drug-induced toxicities. All immunosuppressants are characterized by large intra- and interindividual variability of their pharmacokinetics and by a narrow therapeutic index. It is essential to know their pharmacokinetic properties and to use them for treatment individualization through TDM in order to improve the treatment outcome. Unlike the kidneys and the liver, the heart and the lungs are not directly involved in drug metabolism and elimination, which may be the cause of pharmacokinetic differences between patients from all of these transplant groups. TDM is mandatory for most immunosuppressants and has become an integral part of immunosuppressive drug therapy. It is usually based on trough concentration (C(0)) monitoring, but other TDM tools include the area under the concentration-time curve (AUC) over the (12-hour) dosage interval or the AUC over the first 4 hours post-dose, as well as other single concentration-time points such as the concentration at 2 hours. Given the peculiarities of thoracic transplantation, a review of the pharmacokinetics and TDM of the main immunosuppressants used in thoracic transplantation is presented in this article. Even more so than in other solid organ transplant populations, their pharmacokinetics are characterized by wide intra- and interindividual variability in thoracic transplant recipients. The pharmacokinetics of ciclosporin in heart and lung transplant recipients have been explored in a number of studies, but less is known about the pharmacokinetics of mycophenolate mofetil and tacrolimus in these populations, and there are hardly any studies on the pharmacokinetics of sirolimus and everolimus. Given the increased use of these molecules in thoracic transplant recipients, their pharmacokinetics deserve to be explored in depth. There are very few data, some of which are conflicting, on the practices and outcomes of TDM of immunosuppressants after thoracic transplantation. The development of sophisticated TDM tools dedicated to thoracic transplantation are awaited in order to accurately evaluate the patients' exposure to drugs in general and, in particular, to immunosuppressants. Finally, large cohort TDM studies need to be c...

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Relationship Between Pharmacokinetic Parameters of Cyclosporin and the Incidence of Acute Rejection After Heart Transplantation

Cited by 4 publications

References 13 publications

Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis

Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis

Potential benefits of melatonin in organ transplantation: a review

Pharmacokinetic Optimization of Immunosuppressive Therapy in Thoracic Transplantation: Part I

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