XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)
New approaches to the treatment of dyslipidemias and atherosclerosis are currently under investigation, ranging from the use of small peptides or recombinant proteins to inhibitors of cholesterol absorption and of lipoprotein secretion.

Stockholm, Sweden -- In addition to discussions on old and new statins, their pleiotropic effects, and the possibility of employing these drugs for the treatment of different diseases such as osteoporosis, a workshop of the XII^th International Symposium on Atherosclerosis was focused on new approaches to the treatment of dyslipidemia and atherosclerosis.

HDL Modifying Agents
HDL-cholesterol is increasingly emerging as an important target for old and new drugs. Dr R.S. Newton (Esperion Therapeutics, Ann Arbor, MI, USA) presented a number of data clearly showing the ability of small peptides or recombinant proteins to increase HDL levels and inhibit progression or induce regression of atherosclerosis in different animal models. A small peptide of 22 amino acids (Esp 24218), mimicking the apoA-I a-helix, can promote cholesterol efflux and activate LCAT as apoA-I in vitro; moreover, when injected into rabbits at the dose of 10 mg/kg, it significantly increases HDL levels. The most promising product presently under development at Esperion is a recombinant form of the A-I_Milano, a natural variant of apoA-I. This protein, infused in phospholipid vesicles as "synthetic HDL particles" in a variety of animal models of restenosis and atherosclerosis, have confirmed the beneficial effects of this therapy for mobilizing cholesterol from arteries and/or reducing complications of vascular disease. Dr. Newton concluded that Esperion plans to move to humans this year. Dr C.R. Sirtori (Institute of Pharmacological Sciences, University of Milano, Italy) focused his presentation on new data obtained with the recombinant A-I_Milano. In a rabbit model of soft carotid plaque, the 1-2-hour infusion of a single dose of 1,000 mg of protein reassembled with phospholipid promoted a 30% reduction in the plaque area, as analyzed by intravascular ultrasonography.

Cholesterol Absorption Inhibitors
Ezetimibe (SCH58235) is a potent inhibitor of cholesterol absorption in the intestine. Pre-clinical data were reported by Dr H.H. Davis (Shering-Plough Research Institute, Kenilworth, NJ, USA). In hamster, ezetimibe decreased dose-dependently plasma and liver cholesterol, with a ED₅₀ of 40 mg/kg. In normocholesterolemic cynomologous monkeys treated with a single dose of 10 mg/kg, unesterified cholesterol and cholesteryl esters were reduced with no changes in triglycerides. In a crossover experiment treating hypercholesterolemic monkeys with 100 µg/kg/day, ezetimibe reduced plasma cholesterol levels by 57% within 3 days. Davis reported that in a pivotal phase II study in hypercholesterolemic patients, ezetimibe at doses 0.25 - 10 mg/day reduced LDL cholesterol by 10-19% and gave better results when administered in combination with a statin.

Lipoprotein Secretion Inhibitors
Pre-clinical data on implitapide (BAY 13-9952), an inhibitor of MTP, were discussed by Dr R. Gruetzmann (Cardiovascular Research, Bayer AG, Wuppertal, Germany). In HepG2 cells the molecule, an a-carboline derivative, inhibited the secretion of VLDL with an IC50 value of 1.1 nM. Data in animal models show that the molecule is able to inhibit liver VLDL secretion in rats, with a ED⁵⁰ of 1 mg/kg and to reduce plasma triglycerides by 40-50% in hamster. Moreover, in cholesterol-fed rabbits and in apoE kockout mice implitapide reduced plaque area by 66-93%. Targeting this mechanism may offer a new approach in treating and preventing coronary artery disease.

Metoprolol and Atherosclerosis
The effect of metoprolol CR/XL treatment on subclinical atherosclerosis, measured by B-mode ultrasound in the carotid artery, in subjects with hypercholesterolemia was discussed by Dr G. Bondjers (Astra Zeneca, Gothenburg, Sweden). One hundred and three hypercholesterolemic patients treated with lipid lowering drugs were enrolled in a 3-year prospective, randomized, double-blind, placebo controlled study. Intima media tickness of the common carotid artery in the metoprolol CR/XL (100 mg) group decreased significantly, after the first year of follow-up, suggesting the beneficial effect of metoprolol CR/XL on the development of atherosclerosis.