tranilast and Coronary-Artery-Disease

Despite significant advances in technology and technique, coronary restenosis remains the primary limitation of percutaneous transluminal coronary angioplasty (PTCA). Among patients undergoing PTCA, between 20% and 50% of patients who do not receive a stent and 10%-30% of those who do receive a stent develop restenosis within 6 months of the procedure. Drug-eluting stents, which release high local concentrations of antiproliferative or immunosuppressive agents directly into the vessel wall at the site of the lesion, have dramatically reduced the incidence of restenosis in patients undergoing PTCA. However, even with drug-eluting stents, a significant percentage of higher-risk patients develop in-stent restenosis. These data suggest that a role remains for effective, well-tolerated systemic pharmacologic therapies to further reduce the rate of restenosis. To date, the majority of systemic agents tested for restenosis prevention have failed to show significant benefit. Only 2 agents, probucol and cilostazol, have consistently demonstrated efficacy in preventing restenosis. In addition, the investigational agent AGI-1067 has demonstrated promising efficacy in early clinical trials. Together with drug-eluting stents, these therapies may for the first time reduce the rate of restenosis to near zero, even in high-risk patients, such as individuals with diabetes mellitus.

Topics: Angioplasty, Balloon, Coronary; Cilostazol; Coated Materials, Biocompatible; Coronary Artery Disease; Coronary Restenosis; Drug Therapy, Combination; Humans; ortho-Aminobenzoates; Pioglitazone; Platelet Aggregation Inhibitors; Probucol; Risk Factors; Stents; Tetrazoles; Thiazolidinediones; Trapidil; Treatment Outcome

In this article, the authors intend to provide an update on clinical trials of pharmacologic prevention of restenosis after percutaneous coronary interventions, placed in the perspective of the use of orally administered therapy for the prevention of atherosclerosis progression and clinical events.. AGI-1067, the mono-succinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed v-protectants. It has strong antioxidant properties equipotent to those of probucol and antiinflammatory properties. It inhibits gene expression of VCAM-1 and MCP-1 and has been effective at preventing atherosclerosis in all tested animal models including the non-human primate. In the Canadian Antioxidant Restenosis Trial (CART) 1, AGI-1067 and probucol improved lumen dimensions at the site of percutaneous coronary intervention. AGI-1067 also improved luminal dimensions of non-intervened coronary reference segments in the Canadian Antioxidant Restenosis Trial, which suggests a direct antiatherosclerosis effect. Probucol reduced post-percutaneous coronary intervention restenosis and progression of carotid atherosclerosis in other clinical trials. Although statins reduce atherosclerotic events, they do not appear to have a significant effect on restenosis. The failure of folate therapy to protect against restenosis in the Folate After Coronary Intervention Trial (FACIT) occurred despite significant reductions in homocysteine levels.. Prevention of both post-percutaneous coronary intervention restenosis and atherosclerosis progression with a pharmacologic agent such as AGI-1067 may be an attractive treatment paradigm. Two important trials that test the antioxidant/antiinflammatory hypothesis are ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial 2, which assesses its value for the reduction of both atherosclerosis progression and post-percutaneous coronary interventions restenosis, and the Aggressive Reduction of Inflammation Stops Events (ARISE) trial which is evaluating its effects on cardiovascular events.

Topics: Anti-Inflammatory Agents; Anticholesteremic Agents; Antioxidants; Clinical Trials as Topic; Coronary Artery Disease; Coronary Restenosis; Folic Acid; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; ortho-Aminobenzoates; Oxidative Stress; Probucol; Sirolimus; Vitamins

The aim of this research was to determine the influence of bifurcation lesions on the outcome of patients undergoing percutaneous coronary intervention (PCI) in the recent era.. The treatment of bifurcation lesions by PCI has been associated with an increased complication rate. Whether recent improvements of interventional practice have translated into improved outcomes in this patient subgroup is unknown.. The 11,482 patients enrolled in the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) were stratified according to the presence (n = 1,412) or absence (n = 10,068) of at least one bifurcation lesion treated by PCI. Baseline characteristics and outcome of patients undergoing PCI for bifurcation lesions were compared to those of patients treated for nonbifurcation lesions.. Patients treated for bifurcation lesions were less likely to have prior myocardial infarction (MI), prior coronary artery bypass graft surgery, and had a higher proportion of current stable angina (p < 0.01 for all comparisons). Bifurcation lesions involved more frequently the left anterior descending coronary artery and were more complex (angulated, eccentric, ostial, and tortuous) than nonbifurcation lesions. Percutaneous coronary intervention of bifurcation lesions was characterized by less frequent stent implantation (71% vs. 80%); PCI of bifurcation lesions was associated with an increased rate of combined end point death/MI/target vessel revascularization (TVR) at nine months (18% vs. 15%, p = 0.002) because of increased rates of TVR (17% vs. 14%, p < 0.001), whereas death (1%) and MI (1%) were not different between groups.. Percutaneous coronary intervention of bifurcation lesions is associated with higher TVR at follow-up. However, the risk of death, MI, death/MI was similar in patients treated for bifurcation or nonbifurcation lesions.

Topics: Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Stenosis; Female; Humans; Male; Middle Aged; ortho-Aminobenzoates; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

A 54-year-old woman treated with cobalt-chromium everolimus eluting stents (CoCr-EES) for her left distal circumflex and diagonal branch lesions suffered from repeated in-stent restenosis in both lesions. Neointimal proliferation occurred rapidly and almost simultaneously in the two lesions. The cause was established to be metal allergy, as determined by patch tests which were strongly positive for bare metal stents and weakly positive for CoCr-EES. Following the third successive angioplasty, we initiated treatment with prednisolone (30 mg daily) and the anti-allergic and anti-proliferative drug tranilast (300 mg daily). An elective angiogram performed 3 months later showed no evidence of in-stent restenosis in any of the stented lesions. Furthermore, the patient has remained angina-free for 15 months. The unique features of this case include: (1) near-simultaneous repeated multivessel in-stent restenosis in a patient with skin test-documented metal allergy to cobalt-chromium stents; (2) adjunctive systemic medical therapy with prednisolone and tranilast appeared to terminate the malignant restenotic cycle.

Topics: Anti-Allergic Agents; Cardiovascular Agents; Chromium Alloys; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Drug Therapy, Combination; Drug-Eluting Stents; Everolimus; Female; Glucocorticoids; Humans; Hypersensitivity; Middle Aged; Neointima; ortho-Aminobenzoates; Patch Tests; Percutaneous Coronary Intervention; Predictive Value of Tests; Prednisolone; Prosthesis Design; Recurrence; Risk Factors; Tomography, Optical Coherence; Treatment Outcome

Cardiac allograft vasculopathy is a major complication after cardiac transplantation, often limiting long-term recipient survival. N-(3,4-Dimethoxycinnamoyl)anthranilic acid (tranilast) inhibits cyclin-dependent kinase activity through p21(Waf1/Cip1) induction and arrests vascular smooth muscle cell proliferation in vitro. We tested a hypothesis that tranilast inhibits the vasculopathy characterized by diffuse intimal thickening in a murine heart transplantation model. Hearts from DBA/2 mice were heterotopically transplanted into B10.D2 mice as allografts. Oral administration of tranilast started 3 days before transplantation at doses of 550 or 1040 mg/kg per day until the animals were killed. Cardiac allograft vasculopathy was defined as luminal stenosis caused by neointimal formation. The percentage of luminal stenosis and cardiac rejection were analyzed 14 and 28 days after transplantation. Tranilast administration was associated with a marked reduction in luminal occlusion but with no significant effect on cardiac rejection. Immunohistochemical study of the tranilast-treated graft coronary arteries revealed enhancement of p21(Waf1/Cip1) and decreased expression of proliferating cell nuclear antigen in the neointima. The significant reduction in allograft vasculopathy concomitant with the enhancement of p21(Waf1/Cip1) indicates that tranilast has an antiproliferative effect that could be applicable to clinical treatment of cardiac allograft vasculopathy.

Topics: Animals; Apoptosis; Body Weight; Coronary Artery Disease; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Graft Survival; Heart Transplantation; Immunohistochemistry; Kinetics; Male; Mice; Mice, Inbred DBA; ortho-Aminobenzoates; Proliferating Cell Nuclear Antigen; Transplantation, Homologous; Tumor Suppressor Protein p53

Accelerated coronary arteriosclerosis remains a major problem for the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood and there is no effective therapy. Tranilast is a promising drug that may prevent post-angioplasty restenosis. Here, we investigated whether orally administered tranilast inhibits the development of intima hyperplasia in a mouse model of cardiac transplantation. Cardiac allografts from BALB/c mice were transplanted heterotopically into C3H/He mice. Mice were administered either vehicle or tranilast everyday by gavage. Morphometrical analysis of the cardiac allografts harvested at 2 months revealed that the administration of tranilast significantly reduced the development of coronary atherosclerosis. In the mice treated with tranilast, up-regulation of the cyclin-dependent kinase inhibitor p21 was observed in the allografts, accompanied by a reduced number of proliferating cells. Tranilast also suppressed transforming growth factor-beta (TGF-beta) expression. Tranilast may be effective in preventing transplant-associated arteriosclerosis through its anti-inflammatory and anti-proliferative effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Division; Coronary Artery Disease; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Heart Transplantation; Hyperplasia; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Muscle, Smooth, Vascular; ortho-Aminobenzoates; Transforming Growth Factor beta