Uso de inhibidores de mTOR en el trasplante hepático pediátrico / No disponible

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Metabolite control of angiogenesis: angiogenic effect of citrate

Endothelial cells respond to hypoxic changes with resultant accumulation of several metabolites and switch over to angiogenic phenotype. Although certain intermediates of glycolytic and oxidative metabolic pathways have been known to affect angiogenesis, the effect of citrate, which accumulates in certain tumors, on angiogenesis is not known. Therefore, the effect of citrate on angiogenesis was studied using different model systems. Increased vascularization in chorioallantoic membrane assay, increased endothelial sprouting in rat aortic rings, and increased expression of CD31, E-selectin in endothelial cells suggested a possible proangiogenic effect of citrate. Upregulation of angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor suggested that the effect of citrate involves modulation of expression of angiogenic growth factors. LY 294002, an inhibitor of PI3K–Akt pathway, and wortmannin, an inhibitor of Akt pathway, reversed the effect of citrate in human umbilical vein endothelial cells. Citrate induced significant upregulation and activation of Akt in endothelial cells. Rapamycin, an inhibitor of mTOR, also reversed the effect of citrate in human umbilical vein endothelial cells and sprouting of aortic rings suggesting that the angiogenic effect of citrate involves activation of PI3K–Akt–mTOR pathway (AU)

[Drug interactions and immunosuppression in organ transplant recipients]. / Legemiddelinteraksjoner og immunsuppresjon hos organtransplanterte.

BACKGROUND: Immunosuppressive drugs are used to prevent rejection following organ transplantation. Most immunosuppressive drugs have narrow therapeutic concentration ranges. This increases the probability of clinically relevant drug interactions. In the following, we provide an overview of drug interactions that may be of importance to immunosuppressive treatment. MATERIAL AND METHODS: Data on the interaction of immunosuppressant drugs was obtained by means of a non-systematic literature search in PubMed. Articles were selected on the basis of their clinical relevance. RESULTS: The literature is primarily concerned with pharmacokinetic interactions. Calcineurin inhibitors (cyclosporine, tacrolimus) and mTOR inhibitors (sirolimus, everolimus) are particularly susceptible to the effects of substances that inhibit or induce cytochrome P450 (CYP) 3A4 and P-glycoprotein. These interactions may lead to the levels of the immunosuppressive drugs in blood altering by a factor of more than 10. Methylprednisolone and prednisolone may also be affected by substances that modulate CYP3A4 and P-glycoprotein. The level of mycophenolate is lowered by simultaneous use of some proton pump inhibitors, antibiotics and anion binders, and by valproic acid and rifampicin. Some immunosuppressive drugs also interact with one another: cyclosporine raises the level of mTOR inhibitors and lowers the level of mycophenolate. In general, the degree of pharmacological interaction will vary from one individual to the next. INTERPRETATION: In the event of an expected clinically relevant drug interaction, frequent measurements of the concentrations of the drug in question are a good means of achieving individual adjustment of the immunosuppressant treatment. Prior knowledge of drug interactions can thereby contribute to prevent undesirable changes in the immunosuppressant effect.

Evidencias clínicas sobre el uso de los fármacos anti-mTOR en el trasplante renal / Clinical evidence on the use of anti-mTOR drugs in renal transplantation

Los fármacos inhibidores de la calcineurina (ICN) constituyen los pilares de la moderna inmunosupresión en el trasplante renal. Sin embargo, contribuyen significativamente a la pérdida crónica de los injertos renales y a la elevada morbimortalidad en esta población por sus efectos deletéreos sobre el injerto renal, el perfil cardiovascular y la patología tumoral. Los fármacos anti-mTOR, sirolimus (SRL) y everolimus (EVE), son potentes inmunosupresores con capacidad antiproliferativa y antimigratoria, propiedades que les confieren un potencial papel protector en la disfunción del injerto, en la optimización de la función renal y en la aparición de tumores. En efecto, ensayos clínicos controlados y estudios observacionales de conversión han demostrado el efecto beneficioso de estos fármacos en términos de función renal, sin incremento significativo de las tasas de rechazo agudo. En esta revisión se analizan las evidencias del empleo de los fármacos anti-mTOR en los siguientes aspectos clínicos de los pacientes con trasplante renal: 1) prevención de la disfunción inmunológica precoz y preservación de la función renal en el uso de novo y conversión precoz o tardía; 2) disfunción crónica del injerto renal; 3)efectos cardiovasculares; 4) diabetes de novo postrasplante, y5) patología tumoral de novo (AU)

The calcineurin inhibitor drugs (CNI) are the mainstays of modern immunosuppression in renal transplantation, but they contribute significantly to the chronic graft loss and the high morbidity and mortality in this population for their deleterious effects on renal graft, cardiovascular profile and malignancies. The anti-mTOR drugs, sirolimus (SRL) and everolimus (EVE), are potent immunosuppressants with antiproliferative and anti-migration properties. This confers them a potential protective role in graft dysfunction, the optimization of renal function and the appearance of malignancies. Indeed, clinical trials and observational studies have demonstrated that conversion from CNI to anti-mTOR-based maintanace therapy has beneficial effects on transplant outcomes in terms of renal function, without significant increase in acute rejection rates. In this review, we analyze the evidence of the use of anti-mTOR in the following clinical situations following renal transplantation: 1) Prevention of immune dysfunction and renal function preservation in de novo kidney transplantation and after early or late CNI withdrawal; 2) Chronic, 3) Cardiovascular complications, 4) Diabetes de novo posttransplantation; and 5) De novo malignancies (AU)