Effects of AGI-1067 and Probucol After Percutaneous Coronary Interventions

Abstract

Background— AGI-1067, a metabolically stable modification of probucol, is an equipotent antioxidant to probucol but is pharmacologically distinct. In a multicenter trial, we studied whether AGI-1067 reduces restenosis assessed by intravascular ultrasound (IVUS) after percutaneous coronary intervention (PCI) compared with placebo and probucol used as a positive control. Methods and Results— Two weeks before PCI, 305 patients were randomly assigned to 1 of 5 treatment groups: placebo, probucol 500 mg BID, or AGI-1067 70, 140, or 280 mg once daily. Patients were treated for 2 weeks before and 4 weeks after PCI. Baseline and 6-month follow-up IVUS were interpreted by a blinded core laboratory. Stents were used in 85% of patients. Luminal area at the PCI site at follow-up was 2.66±1.58 mm 2 for placebo, 3.69±2.69 mm 2 for probucol, 2.75±1.76 mm 2 for AGI-1067 70 mg, 3.17±2.26 mm 2 for AGI-1067 140 mg, and 3.36±2.12 mm 2 for AGI-1067 280 mg ( P =0.02 for the dose-response relationship; P ≤0.05 for AGI-1067 280 mg and probucol versus placebo). There was a mean narrowing of 5.3 mm 3 of reference segment lumen in the placebo group and an enlargement in the AGI-1067 140- and 280-mg groups at follow-up ( P =0.05 for 140 mg). An increase in QTc interval >60 ms occurred in 4.8% of placebo patients, 17.4% of probucol patients, and 4.8%, 2.4%, and 2.5% of patients in the AGI-1067 groups ( P =0.02). Conclusions— AGI-1067 and probucol reduce restenosis after PCI. In contrast to probucol, AGI-1067 did not cause prolongation of the QTc interval and improved lumen dimensions of reference segments, suggestive of a direct effect on atherosclerosis.

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

“…Probucol is an anti-oxidant and lipid-reducing drug that has been in clinical use during the past few decades for the prevention and treatment of cardiovascular diseases. In experimental and clinical studies, probucol has been reported to reduce intimal proliferation following balloon injury in animals [12,13] and to inhibit restenosis after coronary angioplasty with [14] and without [15] stent in humans. Probucol also dramatically retards atherosclerosis in hyperlipidemic animals [16][17][18] .…”

Antioxidants: The good, the bad and the ugly

“…Patients were treated for two weeks before and four weeks after PCI in this phase 2 trial. The minimal lumen area at the site of PCI on follow-up intravascular ultrasound (IVUS) was on average 2.66 mm 2 in the placebo group, 3.69 mm 2 in the probucol group, 2.75 mm 2 in the AGI-1067 70 mg group, 3.17 mm 2 in the AGI-1067 140 mg group and 3.36 mm 2 in the AGI-1067 280 mg group (P<0.05 for AGI-1067 280 mg and probucol versus placebo) (39). There was also a significant dose-response relationship of AGI-1067 for the primary end point (P=0.02, Figure 1).…”

“…Volumetric (three-dimensional) changes of nonintervened coronary reference segments, away from the PCI site, were also evaluated with IVUS in a post hoc analysis in CART-1 (39). The mean change in lumen volume (follow-up minus baseline) in the reference segments was -5.3 mm 3 in the placebo group, -0.2 mm 3 in the probucol group and -2.4 mm 3 in the AGI-1067 70 mg group, but was +3.5 mm 3 in the AGI-1067 140 mg group and +1.8 mm 3 in the AGI-1067 280 mg group (P=0.05 for AGI-1067 140 mg versus placebo; P=0.077 for doseresponse relationship).…”

Prevention challenges: The era of atherosclerosis regression

“…The Aggressive Reduction of Inflammation Stops Events (ARISE) trial is testing a synthetic antioxidant that is structurally related to probucol (30) in more than 6000 patients with recent acute coronary syndromes. In addition, several other anti-inflammatory compounds are being tested, including those that target the leukotriene pathway and phospholipase A2 and serine protease inhibitors (31)(32)(33).…”