Notes: The synthetic compound DX-9065a represents a low molecular weight, direct, competitive inhibitor of factor Xa (FXa) with a high affinity and selectivity for the enzyme. Under experimental conditions DX-9065a exerts strong anticoagulant actions in vitro and in vivo and is antithrombotically effective in various thrombosis models. It inhibits proliferation of vascular smooth muscle cells in cell culture systems as well as in in vivo models. As a small molecule inhibitor, DX-9065a inactivates both free and fibrin-bound FXa. By this mechanism it effectively affects the clot-associated procoagulant activity which might be responsible for the propagation of intravascular thrombi as well as for recurrent thrombosis and thrombotic reocclusion after lysis. Although DX-9065a is effective after oral administration, its oral bioavailability is relatively low and seems not to be sufficient for a long-term therapeutic use of the drug. However, first clinical trials in healthy volunteers and in patients with cardiovascular diseases demonstrated a predictable pharmacokinetic and pharmacodynamic behavior of DX-9065a after either intravenous bolus injection or constant infusion, as well as its high safety, especially a lower bleeding risk compared with other commonly used drugs. Further experimental studies and ongoing clinical trials will evaluate the inhibitory profile of the drug, its effectiveness and its possible superiority over other drug regimens in various cardiovascular indications.

Notes: Endothelins are powerful vasoconstrictor agents produced by endothelial cells and identified by Yanagisawa et al. in 1988. Two types of receptors for endothelins have been identified: ETA receptors are located on smooth muscle cells of the vascular wall and are responsible for endothelin-induced vasoconstriction while ET B receptors are located on endothelial cells and induce these cells to release NO and prostacyclin. Moreover, these peptides not only cause a potent and prolonged vasoconstriction but are also known to enhance cell proliferation and to stimulate extracellular matrix accumulation. High levels of plasma or tissue endothelins have been found in patients with heart failure, diabetes, stroke, primary pulmonary hypertension, liver cirrhosis and other diseases. Given these effects of endothelins, blocking their receptors might be a new way to reduce blood pressure and to treat other illnesses. Accordingly, many endothelin antagonists have been developed and evaluated in animals and humans. Enrasentan is a mixed ETA and ETB receptor antagonist with a higher affinity for ETA receptors, although it cannot be considered a selective antagonist. In an animal model of hypertension and cardiac hypertrophy the drug has reduced blood pressure, prevented cardiac hypertrophy and preserved myocardial function. In rats with hyperinsulinemia and hypertension enrasentan normalized blood pressure and prevented cardiac and renal damage. In rats with stroke the drug reduced the ischemic area in the brain. Enrasentan has been added to conventional treatment in patients with heart failure (NYHA Class 2-3) and no addictive effect of the drug has been observed. This is in contrast with results obtained in animal models and still has not been explained. In conclusion, many possible clinical applications can be suggested for this drug, but further studies are necessary to better evaluate its therapeutic efficacy.

Notes: Significant numbers of patients at risk for coronary heart disease (CHD) fail to reach National Cholesterol Education Program (NCEP)-designated low density lipoprotein cholesterol (LDL-C) goals in spite of the wide range of currently available treatments, including combination therapies. Ezetimibe, the first in a class of novel cholesterol absorption inhibitors, demonstrated lipid-lowering and antiatherosclerotic activity in experimental and clinical hypercholesterolemia. Studies in hypercholesterolemic dogs showed that ezetimibe coadministered with statins caused greater lipid-lowering effects compared to either drug alone. These effects were confirmed in clinical studies of patients with primary hypercholesterolemia where initiation of treatment with ezetimibe plus a statin, or addition of ezetimibe to ongoing statin therapy, produced significant incremental reductions in LDL-C, as well as incremental increases in high-density lipoprotein cholesterol (HDL-C) and reductions in triglyceride levels. Combination therapy also significantly increased the number of patients attaining LDL-C goal at the end of treatment, compared to statin monotherapy. In studies using simvastatin, atorvastatin, pravastatin, and lovastatin, addition of ezetimibe to low dose statin was as effective as a 2- to 3-fold upward titration of the corresponding statin dose. Ezetimibe-statin combination therapy provided similar improvements in patients with primary hypercholesterolemia, as well as with heterozygous and homozygous familial hypercholesterolemia. Ezetimibe monotherapy effectively reduced plasma campesterol and sitosterol in patients with homozygous sitosterolemia. Clinical studies showed that ezetimibe was well tolerated, with a safety profile comparable to placebo when administered as monotherapy and comparable to statin alone when coadministered with a statin. These data provide strong evidence that, through their complementary lipid-lowering mechanisms, ezetimibe coadministered with a statin offers an effective combination treatment option for patients with hypercholesterolemia, including those with genetically inherited disease.

Notes: FM-VP4 is a novel inhibitor of cholesterol absorption that has lipid lowering and body weight reducing properties. In vitro and in vivo studies were performed to investigate the lipid-lowering effects, mechanism of action, pharmacokinetics, and toxicity of FM-VP4. FM-VP4 decreased cholesterol accumulation in Caco-2 cells by approximately 50%; its activity appeared to be independent of pancreatic lipase, p-glycoprotein, or cholesterol incorporation in micelles. In animal studies, FM-VP4 was added to the diet or drinking water and the following results were obtained. In gerbils 2% FM-VP4 produced mean 56 and 53% reduction in total cholesterol (TC) after 4 and 8 weeks, respectively. This reduction was entirely due to the loss of the low-density lipoprotein (LDL) pool, which was reduced to undetectable levels at either time point. At 8 weeks, high-density lipoprotein (HDL) concentration had risen by a mean of 34% whereas total triglyceride (TG) concentrations had decreased by a mean of 60%. FM-VP4 also had a profound effect on body weight in these animals. At 8 weeks, the mean body weight was in the 4% FM-VP4 treatment group 25% lower than in the control group. No hepatic or renal toxicity was associated with these changes. In Apo E-deficient mice, after 4- and 8-week treatments FM-VP4 caused a significant decrease in both TC and TG concentrations compared to controls. After 12 weeks, the areas of atherosclerotic lesion involvement in the aortic roots were decreased by a mean of 80% in the 0.5, 1, and 2% FM-VP4 treatment groups compared to controls. Taken together, these results suggest that FM-VP4 is a potential new drug with lipid-lowering and weight loss potential, without apparent toxicity.

Notes: The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to reduce major cardiovascular events in both primary and secondary prevention, and statins became one of the most widely prescribed classes of drugs throughout the world. Previously, statins have been well tolerated and have shown favorable safety profiles. However, the voluntary withdrawal of cerivastatin from the market because of a disproportionate number of reports of rhabdomyolysis-associated deaths drew attention to the pharmacokinetic profile of statins, which may possibly have been related to serious drug-drug interactions.Pitavastatin (NK-104, previously called itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) is a novel, fully synthetic statin, which has a potent cholesterol-lowering action. The short-term and long-term lipid-modifying effects of pitavastatin have already been investigated in subjects with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, hypertriglyceridemia, and type-2 diabetes mellitus accompanied by hyperlipidemia. Within the range of daily doses from 1 to 4 mg, the efficacy of pitavastatin as a lipid-lowering drug seems to be similar, or potentially superior, to that of atorvastatin.According to the results of pharmacokinetic studies, pitavastatin showed favorable and promising safety profile; it was only slightly metabolized by the cytochrome P450 (CYP) system, its lactone form had no inhibitory effects on the CYP3A4-mediated metabolism of concomitantly administered drugs; P-glycoprotein-mediated transport did not play a major role in its disposition, and pitavastatin did not inhibit P-glycoprotein activity.It could be concluded that pitavastatin could provide a new and potentially better thera-peutic choice for lipid-modifying therapy than do the currently available statins. The ef-ficacy and safety of higher dose treatment, as well as its long-term effects in the pre-vention of coronary artery disease, should be further investigated.

Notes: Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoproteins such as very low-density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and a decrease in plasma high-density lipoprotein cholesterol (HDL-C). The increase in plasma TG and decrease in plasma HDL-C are risk factors for cardiovascular disease. Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction of plasma TG and an increase in plasma HDL-C, resulting in protection against the development of atherosclerosis. To test this hypothesis, Otsuka Pharmaceutical Factory, Inc. synthesized the LPL activator NO-1886.NO-1886 increased LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 also decreased plasma TG concentration and caused a concomitant rise in plasma HDL-C. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortas. Multiple regression analysis suggested that the increase in plasma HDL-C and the decrease in plasma TG protect from atherosclerosis. The atherogenic lipid profile is changed to an antiatherogenic profile by increasing LPL activity, resulting in protection from atherosclerosis. Therefore, the LPL activator NO-1886 or other possible LPL activating agents are potentially beneficial for the treatment of hyper-triglyceridemia, hypo-HDL cholesterolemia, and protection from atherosclerosis.

Notes: Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7α-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50–500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.

Notes: The Angiotensin I converting enzyme (ACE, EC 3.4.14.1, kininase II) and neutral endopeptidases (NEP, NEP 24.11) are mechanistically related metallopeptidases. They play a key role in the regulation of blood pressure, body fluid homeostasis and cell growth. Therefore, they are implicated in the pathogenesis of arterial hypertension, congestive heart failure, left ventricular remodeling after myocardial infarction and other cardiovascular diseases. Furthermore, since these two metallopeptidases possess some subsite and substrate similarities, as indicated by their interaction with certain mercaptoalkanoyl inhibitors, they are regarded as an important common target for pharmacological inhibition with a single drug. MDL 100,240 is a pro-drug that, upon conversion to MDL 100,173, acts as a potent dual inhibitor of ACE and NEP with a balanced activity on both enzymes. Only very limited pharmacokinetic studies with MDL 100,240 have been published. These studies used a high pressure liquid chromatography method with UV absorbance detection to quantify the drug. According to the studies in dogs the terminal t1/2 of MDL 100,173 was 35.7 h. The area under the curve for total MDL 100,173 was nearly 10-fold greater than the sum of the areas under the curve for MDL 100,240 and for unconjugated MDL 100,173. These results support the hypothesis that MDL 100,240 is hydrolyzed in plasma to the active thiol, MDL 100,173, which is rapidly conjugated with endogenous plasma thiols thus providing a pathway for elimination. Studies in vivo in experimental models of hypertension and congestive heart failure confirmed the vasodilatory and natriuretic effects of MDL, which appear to be independent of the degree of activation of the renin-angiotensin-aldosterone system. In addition, MDL 100,240 showed an impressive effectiveness both in preventing and in regressing hypertension-induced vascular remodeling and cardiac hypertrophy. Accordingly, MDL 100,240 is being developed for the treatment of cardiovascular diseases, including hypertension and congestive heart failure. If the promises of this novel therapeutic strategy are fulfilled, clinical trials are expected to demonstrate advantages of MDL 100,240 over pure ACE inhibitors.