Current Pharmaceutical Design - Volume 11, Issue 4, 2005

Fondaparinux is the first drug from the pentassaccharide factor X inhibitor class of anticoagulants to be approved for clinical use. It has been shown to be effective in the prevention of deep vein thrombosis in patients undergoing major orthopaedic surgery of the lower limbs. The drug is also being evaluated for use in the acute coronary syndromes and established thromoboembolic events. The pharmacology of fondaparinux is discussed in this review, as well as the major clinical trials involving this drug. Arguments for (and against) the use of this drug are also summarised.

In-stent restenosis remains the limitation of coronary stent implantation despite numerous efforts of its prevention by catheter-based techniques or by drug therapy. Today, only intravascular irradiation has proven to effectively reduce neointima formation, restenosis rate and major adverse cardiovascular events by approximately 50%. Its efficiency is demonstrated for high-risk subsets like long lesions, lesions in saphenous venous bypass grafts or diabetic patients, indicating the extraordinary potential of vascular irradiation. Yet vascular irradiation has some limitations. Edge effect describes the phenomenon of excessive neointimal proliferation at the edges of an irradiated segment and is likely due to axial dose fall-off and / or barotrauma by the angioplasty procedure. Geographic miss, the combination of dose fall-off and vessel injury may be deleterious, especially if a new stent is implanted. The use of appropriate radiation source lengths to avoid geographic miss substantially reduces the incidence of edge effect. Late thrombosis, occurring even years after irradiation, had significantly diminished the benefit of vascular irradiation in initial clinical trials, but extension of ntiplatelet therapy up to 12 months after irradiation has reduced its rates to placebo levels. Vascular brachytherapy is of considerable clinical benefit in the prevention of restenosis and the only proven option for the treatment of in-stent restenotic lesions. This review will focus on the mechanisms of action of vascular irradiation, on the pathophysiological reasons for its complications and therapeutic options. Both angiographic and clinical results of randomised and observational studies will be updated in detail.

Levosimendan is a new calcium sensitizer developed for the treatment of congestive heart failure. Experimental studies indicate that levosimendan increases myocardial contractility and dilates both the peripheral and coronary vessels. Its positive inotropic effect is based on calcium-dependent binding of the drug to cardiac troponin C. It also acts as an opener of ATP-dependent potassium channels in vascular smooth muscle, thus inducing vasodilation. Although levosimendan acts preferentially as a calcium sensitizer it has also demonstrated selective phosphodiesterase III inhibitory effects in vitro. However, this selective inhibition does not seem to contribute to the positive action at pharmacologically relevant concentrations. Levosimendan has an active metabolite, OR-1896. Similarly to levosimendan, the metabolite exerts its positive inotropic and vasodilatory effects on myocardium and vasculature. The elimination half-life of levosimendan is about 1 hour. Thus, with intravenous administration, the parent drug rapidly disappears from the circulation after the infusion is stopped. The active metabolite, however, has a half-life of approximately 80 hours, and can be detected in circulation up to 2 weeks after stopping a 24-hour infusion of levosimendan. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure. Both patients with ischemic and non-ischemic etiology have participated in the studies. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance. With a loading dose, the effects on PCWP and cardiac ouput are seen within few minutes. There is no sign of development of tolerance even with a prolonged infusion up to 48 hours. Cardiac performance is improved with no significant increases in oxygen consumption or potentially malignant rhythm disorders. Due to the formation of an active metabolite, the hemodynamic effects are maintained up to several days after stopping levosimendan infusion. Compared to dobutamine, levosimendan produces similar increase in cardiac output but profoundly greater decrease in pulmonary capillary wedge pressure. On the contrary to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use. Levosimendan has been shown to have favourable effects on symptoms of heart failure superior to placebo and at least comparable to dobutamine. Mortality and morbidity in levosimendan treated patients has been shown to be significantly lower when compared to dobutamine or placebo treated patients. The most common adverse events associated with levosimendan treatment are headache and hypotension, as a likely consequence of the vasodilating properties of the compound. In conclusion, levosimendan offers a new effective option for the treatment of acutely decompensated heart failure. Unlike traditional inotropes, levosimendan seems also to be safe in terms of morbidity and mortality.

The clinical role of magnetic resonance in diseases of the heart and great vessels is rapidly evolving. Cardiovascular magnetic resonance (CMR) has become an established non-invasive imaging modality for the assessment of various cardiac disorders, such as congenital heart disease, cardiac masses, cardiomyopathies, aortic and pericardial diseases. Moreover, due to its accuracy and reproducibility, CMR is currently considered the gold standard for quantification of ventricular volumes, function, and mass. Thus, this technique is ideally suited to assess the efficacy of therapeutic interventions on ventricular hypertrophy and remodelling, which may allow a reduction in sample sise to show clinically relevant effects. Comprehensive functional assessment is possible by CMR due to its capability to measure flow velocity and flow volume, which is a basic requirement to quantify lesion severity in valvular heart disease. Within the past years, major technical advances have considerably improved acquisition speed and image quality making CMR a useful tool for the evaluation of patients with ischaemic heart disease. Although the clinical robustness of coronary magnetic resonance angiography still needs improvement, CMR currently provides valuable information to detect reversible ischemia, myocardial infarction, and residual viability. In this review we will present in detail the wellestablished indications of CMR accompanied by an outlook on new applications that are likely to enter the clinical arena in the near future.

The extracellular matrix (ECM) is a dynamic microenvironment and a major contributor to the adverse ventricular remodelling that follows myocardial infarction (MI), via activation of both direct pro-fibrotic pathways and matrix metalloproteinases (MMPs) that enhance collagenase activity. Reactive fibrosis, i.e. deposition of ECM materials remote from the region of the MI is clearly detrimental to ventricular function and contributory to adverse outcomes post- MI. Therefore, reversal of this process represents an important therapeutic target in post-MI management and treatment of established heart failure. A number of existing agents exert their beneficial effects in part via reductions in ECM deposition. Furthermore, specific anti-fibrotic drugs have been developed and are currently being explored for these and other cardiac conditions where pathological ECM deposition is felt to be contributory to disease progression.

The heart is a pump, but also a furnace able to produce at each moment a large amount of energy and to adapt fast enough to face the changes in both fuel supply and energy demand. The pharmacological treatment of angina has been largely focused on the “pump” through hemodynamic agents aimed at decreasing cardiac effort to decrease energy demand. A new concept arose focusing the “furnace” through metabolic agents aimed at decreasing the oxygen cost of ATP production. This goal can be achieved by shifting energy production from fatty acid β-oxidation to glucose oxidation. CPT1 inhibitors were developed to prevent the fatty acid entry into mitochondria but induced cardiac hypertrophy. Regulation of carnitine biology either by carnitine supply or by γ-butyrobetaine hydroxylase inhibitors have led to controversial data both in pharmacological and clinical concerns. Trimetazidine and ranolazine increase the glucose / fatty acid oxidation balance and exhibit benefical effects in animal studies as well as in clinical trials, both in monotherapy and in association with a traditional hemodynamic drug. The association of metabolic and hemodynamic agents brings additive benefits in angina, whereas associations of hemodynamics do not. The mecanism of these drugs has not been fully understood in terms of specific target. In animal studies, dietary docosahexaenoic acid allowed similar protection, through a mechanism related to membrane conformation without specific enzymic target. From the mechanistic research published in this field, enough has now been understood to foresee some future possible targets, mainly related to the cardiomyocyte fatty acid metabolism.

The discovery of B-type natriuretic peptide (BNP) and n-terminal pro BNP (nt-proBNP) as markers for the diagnosis, severity and prognosis of patients with congestive heart failure has been called a true breakthrough for patients and physicians faced with this disorder. Moreover, the literature on their prognostic value in other clinical conditions like acute coronary syndromes, right-sided heart failure and even in the general population is rapidly growing. This review aims to sort out the current evidence on the clinical utility of the natriuretic peptides with a focus on their diagnostic and prognostic values. With respect to their diagnostic properties, the test is best used to rule out heart failure in patients with acute dyspnoe, because low levels of these neurohormones in this clinical context make the presence of heart failure very unlikely. In patients with elevated values of BNP or nt-proBNP, further cardiological assessment is necessary, as their plasma levels are affected not only by left ventricular function.]

Ximelagatran is an oral direct thrombin inhibitor (DTI), the active form of which is melagatran. Approximately 20% of an oral ximelagatran dose becomes bioavailable as melagatran, which binds noncovalently and reversibly to both fibrin-bound and freely circulating thrombin. Oral ximelagatran dosing not only inhibits thrombin activity rapidly, competitively, and potently, but also delays and suppresses thrombin generation. In humans, oral ximelagatran exhibits anticoagulant, antiplatelet, and profibrinolytic effects, with only minor prolongation of the capillary bleeding time. Oral ximelagatran exhibits a stable and predictable pharmacokinetic profile during repeated dosing, with low intra- and inter-individual variation, and a low potential for interaction with other medications. It is excreted primarily as melagatran via the kidney, without unexpected bioaccumulation. Dosing requirements do not vary with age, gender, ethnicity, obesity, or food or alcohol intake. Clinical trials (total n > 30,000) have evaluated oral ximelagatran in four indications: the prevention of venous thromboembolism (VTE, comprising deep venous thrombosis with or without and pulmonary embolism) after elective hip- or knee-replacement surgery (with approval granted by France, as the Reference Member State for the European Union); treatment and long-term secondary prevention of VTE; the prevention of stroke and other systemic embolic events associated with nonvalvular atrial fibrillation; and the prevention of cardiovascular events after an acute myocardial infarction. The results of these trials suggest that the benefit-risk profile of oral ximelagatran therapy, administered at a fixed-dose without coagulation monitoring, compares favorably with that of currently approved standard therapy.

The pivotal role of leptin in regulating body weight and energy homeostasis is very well established. More recently, leptin also emerged as an important regulator of T-cell-dependent immunity. Reduced leptin levels, as observed during periods of starvation, correlate with an impaired cellular immune response, whereby especially the TH1 proinflammatory immune response appears to be affected. Physiologically, this could reflect the high energy demand of such processes, which are suppressed in animals or people with nutrient shortage. Several autoimmune diseases are TH1 T-cell dependent. In line with a pro-inflammatory role for leptin, animal models of leptin deficiency are markedly resistant to a variety of T-cell dependent autoimmune diseases. Here, we review the role of leptin in immune responses, with emphasis on autoimmune diseases. The design and potential use of leptin antagonists is also discussed.

The identification of protein kinase C isozymes in distinct localities within the cell has led to the suggestion that each isozyme mediates a unique function. This has necessitated the development of methodologies that are capable of assigning specific function to an isozyme. For many years the location of individual isozymes in a particulate fraction was used to correlate specific isozymes with cellular function. More recently over-expression of selective isozymes and genetic knockouts have provided tissue-specific and developmentally regulated information on function. It is now known that specific proteins act as isozyme selective receptors for activated C kinase (RACKs) which determine subcellular localization of specific isozymes. As a result, peptides have been designed from the interaction site between the isozyme and its RACK that prevent the binding of isozymes to their respective RACKs. This has allowed the modulation of function of individual isozymes. This review will examine the development of the peptides as isozyme selective inhibitors or activators of PKC and its impact on understanding the role of isozymes in cellular function in the healthy and diseased heart. The possible development of isozyme-specific drugs for therapeutic use will be discussed.