Search

The anticoagulant effect of apixaban is due to direct inhibition of FXa in the coagulation cascade. The main advantages apixaban has over the current anti-coagulant drugs is that it is active after oral administration, and its coagulation effect does not require monitoring. Apixaban has been compared to enoxaparin in the prevention of venous thromboembolism associated with knee and hip replacement, where it is as efficacious as enoxaparin, but causes less bleeding. However, apixaban is not the only FXa inhibitor that could replace enoxaparin for this indication, as the FXa inhibitor rivaroxaban is as efficacious and safe as enoxaparin in preventing thromboembolism associated with these surgical procedures. Until the results of the AMPLIFY Phase III trial are known, it is too early to consider apixaban as an alternative to enoxaparin in symptomatic thromboembolism. Apixaban should not be used to prevent thromboembolism in medical immobilised subjects or acute coronary syndromes, as it causes excess bleeding in these conditions without benefit.

Although the LDL cholesterol-lowering statins have reduced the mortality and morbidity associated with coronary artery disease (CAD), considerable mortality and morbidity remains. Increasing HDL cholesterol levels is associated with reduced CAD mortality and morbidity. In healthy subjects with mild dyslipidemia, treatment with JTT-705 decreased cholesteryl ester transfer protein (CETP) activity, increased HDL cholesterol and decreased LDL cholesterol. Similarly, another CETP inhibitor, torcetrapib, has recently been shown to increase HDL cholesterol by 46%, decrease LDL cholesterol by 8% and have no effect on triglycerides in subjects with HDL cholesterol levels below 1.0 mmol/l. Increasing HDL cholesterol with inhibitors of CETP represents a new approach to dyslipidemia that requires further investigation, especially in patients with CAD.

Cytochrome P-450 enzymes (CYPs) are present in the heart and coronary circulation. The activation of CYP2J2/3 to increase the production of epoxyeicosatrienoic acids (EETs) may be cardioprotective in cardiac ischemia and reperfusion. On the other hand, inhibition of CYP2C9 with cimetidine, or more selectively with sulfaphenazole, is cardioprotective in the perfused rat heart. In a dog model of cardiac ischemia and reperfusion, inhibitors of CYP co-hydroxylases (e.g., CYP4A, CYP4F) reduce infarct size. Inhibition of selected CYPs as an approach to the treatment of myocardial infarction should therefore be further developed. The function of CYPs in the coronary artery and other blood vessels is varied and complex, and only just beginning to be elucidated. In the coronary artery, when nitric oxide (NO) bioavailability is inhibited, the activity of CYPs may be increased, with the production of vasodilatory EETs. Conversely, when CYP2C9 is inactivated in humans with coronary artery disease (CAD), acetylcholine-induced NO-mediated vasodilatation is enhanced. In the presence of CAD/oxidized LDL, the EET vasodilator/system may be inhibited. Drugs that target CYPs and/or EETs are thus expected to be useful in the elucidation of the role of this system, and may also have therapeutic utility. Copyright

Selective superoxide dismutase (SOD) mimetics are potentially useful in pathological conditions in which there is an overproduction of the superoxide anion O-2.(-). These pathological conditions include inflammation, ischemia/reperfusion, shock, various cardiovascular disorders, amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. A major step forward in this field was the development of small-molecule selective SOD mimetics that penetrate cell membranes, These selective SOD mimetics catalytically remove O-2.(-) without interfering with nitric oxide (NO), peroxynitrite (ONOO-) or other radicals such as hydroxyl radical or hydrogen peroxide (H2O2). These selective SOD mimetics (SC-52608, SC-55858, M-40403 and M-40401) have been shown to have benefits in animal models of inflammation, ischemia/reperfusion, shock, thrombosis and diabetes. The next challenge with selective SOD mimetics is to develop therapeutic potential into therapeutic agents.

Around 50% of men 51-60 years of age have pathological benign prostatic hyperplasia (BPH). Pharmacotherapy for BPH includes the 5alpha-reductase inhibitor finasteride, and alpha(1)-adrenoceptor antagonists. Finasteride reduces prostate volume and symptom scores, while increasing peak urinary flow rates. The main problem with finasteride treatment is that it increases the incidence of ejaculation disorders. All of the alpha(1)-adrenoceptor antagonists have been shown to reduce symptom scores and increase peak urinary flow rates in BPH. The nonselective alpha(1)-adrenoceptor antagonists (prazosin, terazosin and doxazosin) were developed as antihypertensives, and hypotensive-related side effects are the main problem with these agents in BPH. These side effects can be diminished by reducing peak concentrations of the drugs, as with once-daily alfuzosin, or by using the uroselective antagonist tamsulosin. Phytopharmaceuticals are commonly used in the treatment of BPH, such as saw palmetto berry which has been shown to improve the symptoms and peak urinary flow rate. Androgen receptor antagonists are not used in BPH because of their adverse effects. Newer drugs under development for the treatment of BPH include alpha(1)-adrenoceptor antagonists that show more selectivity for alpha(1A)-adrenoceptors than tamsulosin, combined 5alpha-reductase/alpha(1)-adrenoceptor inhibitors and combined type 1/type 2 5alpha-reductase inhibitors. New targets for the drug treatment of BPH include indothelin, growth factors, estrogens and the phosphodiesterase isoenzymes.

Efforts to discover new treatments for osteoporosis led to the identification of the potent and selective, small-molecule calcium receptor antagonist NPS-2143. NPS-2143 is the prototype calcilytic drug, designed to act on calcium receptors on the surface of parathyroid glands, stimulating the release of the body's own stores of native parathyroid hormone (PTH). In osteopenic ovariectomized rats, daily oral administration of NPS-2143 resulted in moderate but sustained increases in plasma PTH levels and marked increases in bone formation and resorption, with no net bone gain or loss. The combination of NPS-2143 and estrogen increases bone formation and density to a greater extent than either agent alone. These results suggest that NPS-2143 may be useful in the treatment of established osteoporosis.

Humans have used animals for centuries to understand their own biology. From September 2-4, 2001, scientists from around the world converged on Brisbane, in Australia, to discuss the use of animal models in cardiovascular research at a satellite meeting to the 34th International Congress of Physiological Sciences (August 26-September 1, 2001, Christchurch, New Zealand). The appropriateness of each model to the human disease was a major consideration. Other themes were the use of models to understand pathological processes, and to determine potential new targets for pharmacological intervention.

One of the satellite meetings to the International Congress of Physiological Sciences concerned smooth muscle function in health and disease. In this report I have highlighted one of the areas of disease that were discussed: namely, bladder disease. In the treatment of unstable bladder, antimuscarinic agents are effective but cause unacceptable side effects. Thus, in order to prevent the side effects, new antimuscarinic agents are being prepared that show selectivity for the bladder and new methods for local delivery of antimuscarinics to the bladder are being developed. Potential new targets for the unstable bladder include P2X receptors and the nerve growth factor pathway. In detrusor-external sphincter dyssynergia, there is evidence to support a clinical trial of nitric oxide donors. The unpleasant and painful condition of interstitial cystitis has, to date, proven difficult to treat. Preliminary clinical data suggests that the leukotriene D(4) receptor antagonist montelukast may be useful in the treatment of IC. (c) 2001 Prous Science. All rights reserved.

Brain natriuretic peptide (BNP) is predominantly a cardiac ventricular hormone that promotes natriuresis and diuresis, inhibits the renin-angiotensin-aldosterone axis, and is a vasodilator. Plasma BNP levels are raised in essential hypertension, and more so in left ventricular (LV) hypertrophy and heart failure. Plasma BNP levels are also elevated in ischemic heart disease. Attempts have been made to use plasma BNP levels as a marker of LV dysfunction, but these have shown that plasma BNP levels are probably not sensitive enough to replace echocardiography in the diagnosis of LV dysfunction. Pericardial BNP or N-BNP may be more suitable markers of LV dysfunction. Plasma BNP levels are also elevated in right ventricular dysfunction, pregnancy-induced hypertension, aortic stenosis, age, subarachnoid hemorrhage, cardiac allograft rejection and cavopulmonary connection, and BNP may have an important pathophysiological role in some or all of these conditions. Clinical trials have demonstrated the natriuretic, diuretic and vasodilator effects, as well as inhibitory effects on renin and aldosterone of infused synthetic human BNP (nesiritide) in healthy humans. BNP infusion improves LV function in patients with congestive heart failure via a vasodilating and a prominent natriuretic effect. BNP infusion is useful for the treatment of decompensated congestive heart failure requiring hospitalization. The clinical potential of BNP is limited as it is a peptide and requires infusion. Drugs that modify the effects of BNP are furthering our understanding of the pathophysiological role and clinical potential of BNP. Increasing the effects of BNP may be a useful therapeutic approach in heart failure involving LV dysfunction. The levels of plasma BNP are increased by beta-blockers, cardiac glycosides and vasopeptidase inhibitors, and this may contribute to the usefulness of these agents in heart failure. (c) 2001 Prous Science. All rights reserved.