sirolimus and Granuloma

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.

Topics: Aging; Animals; Cell Transformation, Neoplastic; Drug Evaluation, Preclinical; Granuloma; Immunoglobulins; Leukocyte Count; Liver; Liver Cirrhosis; Longevity; Male; Maze Learning; Mice; Mice, Inbred C57BL; Muscle Strength; Oxygen Consumption; Phenotype; Platelet Count; Psychomotor Performance; Sirolimus; Survival Analysis; T-Lymphocytes; Thyroid Gland; TOR Serine-Threonine Kinases

The time-dependent changes in endothelial and healing properties of coronary arteries implanted with a biodegradable polymer-based biolimus A9-eluting stent (BioPol-BES) have not been investigated. We evaluated the short-term and the long-term in vivo response of BioPol-BES, as compared to a permanent polymer-based sirolimus-eluting stent (PermPol-SES), and a bare metal stent (BMS).. Overlapping stents were placed in 33 swine (n=11 for BES, SES, and BMS, respectively) for two and four weeks and single stents in 30 miniature pigs (n=18 for BES, n=9 for SES, n=3 for BMS) for three, nine and 15-month evaluations. The vessel patency, arterial healing and endothelialisation were assessed by angiography, histopathology and scanning electron microscopy. At four weeks, the endothelialisation at overlapping stent regions was greater with BioPol-BES (87.8±3.7%) and BMSs (98.0±0.4%) than with PermPol-SES (66.4±3.2%). The inflammation score in vessels implanted with single BioPol-BES increased slightly from three to 15 months (0.00±0.00 to 0.28±0.14), while this increase was more pronounced with PermPol-SES (0.11±0.07 to 1.56±0.68). Compared to BMS moderate lymphocyte infiltration was seen with BioPol-BES, and marked granulomatous formation with PermPol-SES.. The level of endothelial coverage in BioPol-BES was comparable to BMS at four weeks, with no significant increase of inflammatory reaction up to 15 months.

Topics: Angioplasty, Balloon; Animals; Cardiovascular Agents; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Endothelial Cells; Granuloma; Inflammation; Lactic Acid; Lymphocytes; Metals; Microscopy, Electron, Scanning; Models, Animal; Polyesters; Polymers; Prosthesis Design; Sirolimus; Swine; Swine, Miniature; Time Factors; Ultrasonography; Vascular Patency; Wound Healing

Drug-eluting stents effectively reduce restenosis but may increase late thrombosis and delayed restenosis. Persistent polymer, the drug, or a combination of both could be responsible. Local delivery of Biolimus A9, a rapamycin derivative, from a polymer-free BioFreedom stent (Biosensors International) may prevent these complications.. We compared high-dose (HD) (225 microg/14 mm Biolimus A9) and low-dose (LD) (112 microg/14 mm Biolimus A9) BioFreedom stents with a polymer-coated sirolimus-eluting Cypher stent (SES) and a bare-metal stent (BMS) at 28 days and 180 days in an overstretch coronary mini-swine model with histomorphometric and histological analysis. At 28 days, there was a reduction in neointimal proliferation by HD, LD, and SES compared with BMS (neointimal thickness: HD, 0.080+/-0.032; LD, 0.085+/-0.038; SES, 0.064+/-0.037; BMS, 0.19+/-0.111 mm; P<0.001; BMS > HD/LD/SES). At 180 days, both BioFreedom stents were associated with reduced neointimal proliferation, whereas SES exhibited increased neointima (neointimal thickness: HD, 0.12+/-0.034; LD, 0.10+/-0.040; SES, 0.20+/-0.111; BMS, 0.17+/-0.099 mm; P<0.001; SES > HD/LD; BMS > LD). At 180 days, BioFreedom stents showed decreased fibrin and inflammation, including granuloma and giant cells, compared with SES.. The polymer-free Biolimus A9-coated stent demonstrates equivalent early and superior late reduction of intimal proliferation compared with SES in a porcine model. After implantation of BioFreedom stent, delayed arterial healing was minimal, and there was no increased inflammation at 180 days compared with SES implantation. The use of polymer-free stents may have a potential long-term benefit over traditional polymeric-coated drug-eluting stents.

Topics: Animals; Cell Proliferation; Coronary Restenosis; Drug-Eluting Stents; Fibrin; Giant Cells; Granuloma; Inflammation; Sirolimus; Swine; Swine, Miniature; Tunica Intima; Wound Healing