sirolimus and Aneurysm

Despite the use of newer immunosuppressors such as sirolimus (SRL) and tacrolimus (TRL) in heart transplantation, the rate of humoral rejection has remained unchanged. The aim of this study was to analyze the immunologic and histologic effects of cyclosporine (CsA), SRL, and TRL in a porcine model of arterial transplantation.. Each transplant recipient animal (n = 49) received an autograft and an allograft and was then allocated to one of four treatment groups and a 7- or 30-day follow-up period, as follows: a WOT group (without immunosuppressor treatment), 7 days (n = 6) and 30 days (n = 5); a CsA group, 7 days (n = 5) and 30 days (n = 6); an SRL group, 7 days (n = 7) and 30 days (n = 8); and a TRL group, 7 days (n = 6) and 30 days (n = 6). The presence of donor-specific antibodies (DSA) was tested at the end of the follow-up period. Morphometric parameters and inflammatory infiltration were analyzed in the explanted grafts.. At 30-day follow-up, SRL was the only treatment capable of suppressing DSA formation (0 of 7 vs 4 of 5 in the WOT group; p < 0.05). SRL completely prevented aneurismal dilation and reduced the number of macrophages in the allografts. TRL treatment achieved a greater reduction of T lymphocytes. CsA did not prevent the reduction in total vascular area at 7 days that was achieved with the SRL and TRL groups. Animals treated with CsA had the largest number of T lymphocytes and macrophages in both follow-up periods.. SRL prevented DSA formation and reduced the number of macrophages as compared with TRL and CsA.

Topics: Aneurysm; Angiography; Animals; Antibodies; Antibody Formation; Cell Count; Cyclosporine; Femoral Artery; Immunosuppressive Agents; Macrophages; Sirolimus; Swine; T-Lymphocytes; Tacrolimus; Time Factors; Tissue Donors; Transplantation, Autologous; Transplantation, Homologous; Vasodilation

Despite the lack of nephrotoxicity, adverse effects of the new antiproliferative immunosuppressant everolimus have been reported. By varying time point and dose of everolimus treatment as well as the degree of glomerular injury, the specific conditions and potential mechanisms leading to adverse actions in the anti-Thy1 model have been determined. Only the combination of early and high-dose everolimus treatment (1-3 mg/kg bw) with a severe glomerular lesion ('full-dose' anti-Thy1 model) caused adverse effects with a high mortality rate, progressive apoptosis, crescent formation and glomerulosclerosis. In contrast, either later start or low-dose (0.3 mg/kg bw) therapy or treatment of a less severe lesion ('reduced dose' anti-Thy1 model) appeared to be relatively safe for the glomerular architecture. The adverse effects of everolimus were linked to its marked inhibition of endothelial cell, but not necessarily mesangial cell proliferation. In addition, everolimus markedly inhibited the angiogenic cytokine vascular endothelial growth factor in nephritic glomeruli in vivo. These experimental results suggest special caution regarding the use of everolimus in all situations of severe glomerular cell injury requiring extensive capillary repair, where at least adaption to a low dose needs to be considered.

Topics: Aneurysm; Animals; Apoptosis; Capillaries; Cell Division; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Everolimus; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Immunosuppressive Agents; Isoantibodies; Kidney Glomerulus; Kidney Transplantation; Male; Mesangial Cells; Rats; Rats, Sprague-Dawley; Sirolimus; Vascular Endothelial Growth Factor A

Drug-eluting stents have reduced the frequency of in-stent restenosis. However, most of the results have been derived from simple lesions in noncomplex patients. In preclinical normal pig and rabbit studies, bare-metal stents show complete healing at 28 days, whereas drug-eluting stents show incomplete healing with persistence of fibrin and incomplete coverage of the stent struts by endothelial cells. In human beings similar delayed healing has been observed at 6 and 12 months in atherectomy specimens or at autopsy. The US Food and Drug Administration posted adverse event information for physicians regarding subacute thrombosis and hypersensitivity reaction following deployment of sirolimus-eluting stents in human beings. The authors have seen, at autopsy, late (18 months) stent thrombosis, aneurysm formation, and extensive inflammatory reaction limited to the arterial wall surrounding the stent that they interpret as a hypersensitivity reaction to the polymer. The authors advocate caution and aggressive use of nontoxic systemic drugs to prevent the complications of atherosclerosis along with better postmarket surveillance of patients and histologic examination of tissue from patients with drug-eluting stents.

Topics: Aneurysm; Angioplasty, Balloon, Coronary; Animals; Autopsy; Coronary Artery Disease; Coronary Restenosis; Disease Models, Animal; Drug Delivery Systems; Drug Hypersensitivity; Follow-Up Studies; Granuloma, Foreign-Body; Humans; Immunosuppressive Agents; Male; Middle Aged; Polymers; Rabbits; Randomized Controlled Trials as Topic; Safety; Sirolimus; Stents; Swine; Thrombosis; Time Factors