New drugs for the treatment of hypercholesterolaemia

Abstract

Endogenous and exogenous pathways determine plasma levels of cholesterol and lipoproteins. Plasma cholesterol levels and coronary heart disease risk can be reduced pharmacologically by decreasing cholesterol synthesis, increasing its elimination and/or reducing its absorption from the intestine. The more profound knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin and pitavastatin), are being studied for their ability to improve lipid profiles. Rosuvastatin is a potent, hepato-selective and relatively hydrophilic statin with a low propensity for muscle toxicity and drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome p450-mediated drug interactions. Rosuvastatin seems to be more potent than other available statins while pitavastatin presents with a similar potency to that of atorvastatin. Another promising approach for lowering total and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity for inhibiting the intestinal cholesterol absorption is currently being investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both in monotherapy and in combination with other lipid-lowering drugs. Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal side effects, improving tolerability and patient compliance. Other lipid-lowering drugs with the ability to act at the enterocyte level, such as avasimibe and implitapide, are currently being investigated in humans.

Effects of Pitavastatin in Japanese Patients With Chronic Heart Failure

“…Pitavastatin also has high bioavailability and is minimally metabolized by the cytochrome P450 system. 15, 16 The Pitavastatin Heart Failure (PEARL) study was designed to evaluate the beneficial effects of pitavastatin on the incidence of cardiac death and hospitalization for worsening HF in Japanese patients with CHF. 17 …”

Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor

“…Similar serum triglyceride (TG) levels could be achieved by doses of pitavastatin (2 mg/d) lower than those of atorvastatin or rosuvastatin (10 mg/d). Lowering potentiality of pitavastatin on serum LDL-cholesterol is greater than that of pravastatin and is similar to atorvastatin (23,24). As pitavastatin is hardly metabolized by cytochrome P450 compared with other statins, pitavastatin has advantage of not having unexpected interactions with other drugs.…”

Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

“…5. Included in the advantages of the new ''superstatins'' is resistance to metabolic enzymes, reduced probability for drug-drug interactions, and increased potency [56].…”