Current Medicinal Chemistry - Cardiovascular & Hematological Agents - Volume 2, Issue 4, 2004

Enzyme replacement therapy has recently been introduced to treat Fabry disease, a rare X-linked lysosomal storage disorder. The disease occurs due to deficient activity of α-galactosidase A, leading to progressive accumulation of globotriaosylceramide in multiple organs and tissues. Renal, cardiac and cerebrovascular manifestations of the disease result in premature death in both hemizygous males and heterozygous females. This paper outlines the clinical signs, symptoms and diagnosis of Fabry disease, and the development of the two available enzyme replacement therapies - agalsidase alfa and agalsidase beta. Agalsidase alfa and agalsidase beta are produced in a human cell line and in Chinese hamster ovary cells, respectively, resulting in products with the same amino acid sequence as the native human enzyme, but with different patterns of glycosylation. Correct post-translational glycosylation is important in terms of the pharmacokinetics, biodistribution, clinical efficacy and tolerability of genetically engineered protein therapeutics. Differences in glycosylation, which may affect immunogenicity and mannose-6-phosphate receptor-mediated cellular internalisation of administered enzyme, possibly account for the differences in dosing, clinical effects and safety profiles reported for agalsidase alfa and agalsidase beta.

Aldosterone production in the heart as well as aldosterone plasma levels are increased after myocardial infarction and in congestive heart failure, correlating with the severity of disease. Aldosterone promotes sodium and water retention, sympathoadrenergic activation, endothelial dysfunction, and cardiovascular fibrosis and hypertrophy. Even maximally recommended doses of ACE inhibitors do not completely prevent formation of aldosterone. The Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS) demonstrated that aldosterone receptor blockade markedly reduces mortality among patients with heart failure. This review summarizes recent clinical and experimental data on the effect of aldosterone antagonists on left ventricular remodeling and function in ischemic heart failure with special emphasis on potential underlying mechanisms. While reduction of excessive extracellular matrix turnover leading to decreased fibrosis appears to be the most important effect of mineralocorticoid receptor antagonism in heart failure, other mechanisms such as regression of hypertrophy, improvement of endothelial function, reduction of superoxide formation, and enhanced renal sodium excretion may contribute. Recent data showed that in rats with left ventricular dysfunction after extensive myocardial infarction, eplerenone on top of ACE inhibition more effectively improved cardiac remodeling and molecular alterations than ACE inhibition alone.

Modification of polymer surfaces to achieve a surface with enhanced compatibility is an important means of obtaining improved biomaterials. The molecular design of the novel technologies is carried out with attention to create a biomembrane-mimicking surface on medical devices. This review focusses on the comparison of the chemical composition of recent novel surface modifying additives and coating technologies, their biomaterial evaluation and clinical efficacy under the scope of our previous studies and current literature.

α2-Antiplasmin (α2AP) is the primary inhibitor of plasmin, a proteinase that digests fibrin, the main component of blood clots. Two forms of α2AP circulate in human plasma: a 464-residue protein with methionine as the aminoterminus (Met-α2AP) and an N-terminally-shortened 452-residue form with asparagine as the amino-terminus (Asn-α2AP). Huma n pla sma α2AP concentration is 1 mM and c onsists of ∼30% Met-α2AP a nd ∼70% Asn-α2AP. The major form (Asn- α2AP) is rapidly crosslinked to fibrin during blood clotting by activated coagulation factor XIII and as a consequence, fibrin becomes more resistant to fibrinolysis. It is apparent that α2AP is important in modulating the effectiveness and persistence of fibrin with respect to its susceptibility to digestion and removal by plasmin. Hence, the physiologic role of α2AP suggests that it may be a useful target for developing more effective treatment of thrombotic diseases. Research on α2AP appears to be moving in two main directions: (1) efforts to use variant forms of α2AP to reduce bleeding secondary to thrombolytic therapy while not slowing thrombolysis; and (2) efforts to use variant forms to diminish the activity of α2AP as a plasmin inhibitor so that fibrinolysis becomes enhanced. Methods to accomplish these two goals mostly involve manipulation of defined functional domains within the molecular structure of α2AP, or inhibition of a newly described novel plasma proteinase, termed antiplasmin-cleaving enzyme, that generates the more favorable form of α2AP, Asn- α2AP, for crosslinking to fibrin. The antiplasmin-cleaving enzyme has similarity in primary structure and catalytic properties to fibroblast activation protein / seprase. This review summarizes recent studies that may hold promise for modulating α2AP activity and its interactions with certain proteins as new therapeutic strategies for preventing and treating thrombotic disorders.

The optimal drugs employed in the antithrombotic treatment and prophylaxis have ideally been suggested to have high efficacy and safety and to be easy to use as regards the administration route and the fashion of monitoring the anticoagulant effect. A number of agents are under development in order to improve such requirements. Among them, the present review is focussed on a selective factor Xa inhibitor (pentasaccharide fondaparinux) and the direct thrombin inhibitors now available on a clinical ground. Fondaparinux is the first of a new class of selective antithrombin-dependent factor Xa inhibitors; it does not interact with plasma proteins other than antithrombin, leading to a predictable pharmacokinetics, which renders monitoring and dose adjustment unnecessary. The efficacy and safety of fondaparinux has been assessed in a number of clinical trials. In patients undergoing major orthopaedic surgery, a 2.5 mg s.c administration once daily induced a 50% average relative risk reduction for overall venous thromboembolism in comparison with enoxaparin but also an increased rate of major bleeding. Parenteral direct thrombin inhibitors include hirudin, bivalirudin and argatroban. these inhibitors have been studied in patients with coronary heart disease. In particular, in patients undergoing percutaneous coronary interventions, bivalirudin showed equivalent or higher efficacy but lower bleeding in comparison with unfractionated heparin. Another series of molecules capable of inhibiting thrombin is derived from the site of fibrinogen to which thrombin binds. Inogatran and melagatran have a low bioavailability when given orally, whereas the chemically modified prodrug ximelagatran has a higher bioavailability. Ximelagatran is safe and effective at least as low molecular weight heparin in patients undergoing major orthopaedic surgery and is safe and effective also in prevention of recurrence in patients with venous thromboembolism or myocardial infarction; ximelagatran is more effective than oral anticoagulants in prevention of arterial embolism due to atrial fibrillation, with comparable safety.

Atherosclerosis is well recognized as an inflammatory disease and circulating markers of inflammation such as C-reactive protein and soluble adhesion molecules are strong predictors of atherosclerotic lesion development and future cardiovascular events. Several cells (endothelial, smooth muscle and macrophages) and proteins (inflammatory cytokines and adhesion molecules) contribute to this inflammatory process and lesion development. Although lipid management with statins does reduce levels of circulating inflammatory markers, this appears to be unrelated LDL-lowering. Thus, the recent focus has been shifted to develop molecules that directly affect the atherosclerotic process without effects on plasma lipids. Much of this research was initially focused on cytokine antagonists and adhesion molecule expression inhibitors, which are now at different stages pre-clinical and clinical development. Additional targets have begun gaining prominence in the past few years - modulation of proteins involved in reverse cholesterol transport and lipid metabolism in the vessel wall such as ApoA1 / apoE / ABCA1, ACAT, and LpPLA2 and regulation of molecules involved in matrix remodeling and cell proliferation such as matrix metalloproteinases and heparan sulfate proteoglycans. The current approaches for the treatment of atherosclerosis are 1) reduction of risk factors for the disease - e.g., lipids, hypertension and diabetes and 2) direct disease modifiers. The purpose of this review is to examine key scientific advances and the prospect of these approaches in the prevention of cardiovascular disease.

The urocortins, together with corticotropin releasing hormone (CRH), have a long evolutionary pedigree. In the brain, CRH largely mediates anxiogenic effects associated with the stress response, while the urocortins are concerned with adaptive and coping behaviour. The urocortins, in particular, are also expressed in peripheral sites, including the heart. Here, they may play an autocrine / paracrine role, since CRH-R2 receptor subtypes, which preferentially bind the urocortins, are also expressed in the heart. Endogenous cardiac urocortin expression is enhanced by ischaemia / reperfusion injury in vitro, and addition of exogenous urocortins reduces cell death caused by ischaemia / reperfusion in vitro, ex vivo and in vivo. In the isolated perfused heart, urocortin improves haemodynamic recovery, and partially prevents the reduction in high energy phosphates following ischaemia / reperfusion. Urocortin-mediated cardioprotection involves several mechanisms, including increased expression of Kir6.1 KATP channels and HSP90, although other as yet poorly understood mechanisms have also been implicated. Moreover, there is early data suggesting that urocortin has beneficial haemodynamic effects in an ovine model of heart failure, and further studies of the value of both endogenous and exogenous urocortins in the compromised heart are clearly needed. In man, there is suggestive, though indirect, data, that urocortin may also provide an endogenous myocyte salvage mechanism against iatrogenic ischaemia / reperfusion injury associated with bypass surgery. These experimental studies suggest that assessment of the clinical use of urocortins as direct and / or cardioplegic therapies in ischaemia / reperfusion, and maybe heart failure, should be actively pursued.

The soluble guanylate cyclase (sGC) / cyclic guanosine monophosphate (cGMP) second messenger system provides a complex and highly regulated mechanism for signal transduction events and ensuing functional responses through a cascade of serine / threonine protein kinase-dependent pathways. Nitric oxide (NO) and carbon monoxide (CO), two unique diatomic gases endogenously produced by the respective enzymes nitric oxide synthase (NOS) and heme oxygenase (HO), stimulate cellular sGC and synthesize cGMP within the vasculature. Emerging evidence suggests that the independent NOS and HO systems provide reciprocal and complimentary approaches that act to regulate cardiovascular and hematological homeostasis as well as provide protection to the vasculature in response to inimical stimuli or following the onset of vasoproliferative disease. Recent results from our laboratory and others suggest that the newly identified, chemically synthesized benzyl indazole derivative YC-1 is capable of exerting multifunctional and broad-ranging effects in the cardiovascular and hematological systems. YC-1 has been demonstrated to possess redundant biochemical mechanisms that confer significant stimulation upon NO- and CO-regulated, cyclase-dependent events. Ultimately, these acute molecular processes eventuate in YC-1-dependent modulation of platelet and vascular smooth muscle cell (SMC) and endothelial cell (EC) function under both eutrophic and deleterious conditions. Based on accumulating evidence, YC-1 has been suggested to serve as a potential therapeutic adjuvant to be used in interventional medicine, and these results may indicate the existence of an endogenous “YC-1-like” compound that would be the focus of much anticipated investigation. The purpose of this review, therefore, is to provide update information on the mechanisms and physiologic and pathophysiologic roles of the pivotal new multifunctional agent YC-1 in the cardiovascular and hematological systems, and to provide evidence for its potential use as a clinically relevant salutary agent.