| Effects of apolipoprotein and low density lipoprotein receptor gene polymorphisms on lipid metabolism, and the lipid risk factors of coronary artery disease | ||
|---|---|---|
| Prev | Chapter 2. Review of the literature | Next |
The increased risk of CAD associated with an elevated serum cholesterol level (Multiple Risk Factor Intervention Trial Research Group 1986, Martin et al. 1986) can be reduced by lowering the blood cholesterol concentration (Lipid Research Clinics Program 1984b, Frick et al. 1987, Brown et al. 1990). In diet-resistant hypercholesterolemia, pharmacological treatment should be started at an early age in order to prevent premature coronary artery disease. However, the treatment of hypercholesterolemia is occasionally difficult, as moderate hypercholesterolemia gives no symptoms, and the patients often experience side-effects of cholesterol-lowering drugs (Illingworth 1988, Blane 1989, Simons 1993). The ideal drug would be efficacious in lowering plasma lipid levels with no subjective side-effects, would have a documented effect on the clinical endpoint, and would be safe on a long-term basis (Olsson & Mölgaard 1988).
Enprostil is a synthetic prostaglandin E2 analogue developed for the treatment of peptic ulcer (Schwartz & Saito 1989). Analyses of data from studies on patients receiving enprostil have demonstrated a significant lowering of serum cholesterol, LDL cholesterol and apo B, while the ratio of HDL cholesterol to total cholesterol has increased or remained unchanged (Schwartz et al. 1988). Additional studies have demonstrated a suppression of alimentary lipemia by enprostil in diabetics (Reaven et al. 1988) and healthy volunteers (Schwartz & Saito 1989).
RS-86505-007 is an optic isomer of enprostil. In vitro animal studies suggest that RS-86505-007 may interfere with the active and passive transport of compounds in the small intestine mediated by specific receptor interaction (Grass et al. 1990), suggesting that the site of lipid-lowering action by the drug might be the gastrointestinal tract.
Colestipol prevents the passive and active reabsorption of bile acids, leading to hepatic depletion of bile acids. As a consequence, the hydroxymethylglutaryl (HMG) coenzyme A (CoA) reductase is activated and the LDL receptors are up-regulated, resulting in enhanced catabolism of LDL precursors and a lowering of the LDL cholesterol level. Triglyceride production is increased due to the release of feedback inhibition by bile acids on phosphatidic acid phosphatase (Gaw et al. 1996).
Statins inhibit the HMG CoA reductase, thus reducing the intrahepatic pool of free cholesterol and reciprocally up-regulating the LDL receptors (Dujovne 1997). They have also been reported to reduce the VLDL apo B production (Watts et al. 1995) and the esterification rate of cholesterol (Homma et al. 1995), and to enhance the catabolism of VLDL prior to its conversion to LDL (Sehayek et al. 1994). Outcome studies with statins (Scandinavian Simvastatin Survival Group 1994, Shepherd et al. 1995, Sacks et al. 1996) have shown reductions in cardiovascular morbidity and all-cause mortality in hypercholesterolemic people.