Current Pharmaceutical Design - Volume 15, Issue 8, 2009

The theory of metabolic modulation has recently assumed clinical relevance in the treatment of various cardiovascular disease. It is now clear that chronic ischemic heart disease, heart failure and diabetic cardiomyopathy have in common several alterations of cardiac metabolism shifted towards a greater utilization of free fatty acids and a reduced efficiency of the Krebs cycle. Over the past years, several drugs have been proposed to improve cardiac metabolism in patients with ischemic heart disease and more recently in those with heart failure. These drugs consist of long-chain 3-ketoacyl coenzyme A thiolase (LC3- KAT) inhibitors, such as trimetazidine and carnitine palmitoyl transferase (CPT)- I and/or -II inhibitors, such as etomoxir and perhexiline. Trimetazidine is the most investigated drug in this group. The last ESC guidelines on the management of patients with stable angina mention the efficacy of metabolic treatment in improving physical efficiency and decreasing the recurrence of pain. The available data suggest that combined therapy of trimetazidine and hemodynamic drugs is an effective antianginal treatment that reduces the risk of pain recurrence and improve the quality of life. The most recent studies also suggest that trimetazidine might be effective in patients with acute coronary syndromes, non-ischemic cardiomyopathy and heart failure. In this issue of Current Pharmaceutical Design, the rationale for metabolic therapy in ischemic and non-ischemic heart disease and chronic heart failure are carefully reviewed by international experts who have contributed in this area of research. Abozguia et al. [1] discuss the pathophysiological aspects of heart metabolism in ischemia and heart failure. Barsotti et al. [2] report the metabolic changes that occur in patients with diabetes mellitus and the metabolic therapeutic options available. Cesar et al. [3] discuss the effects of metabolic treatment on quality of life and effort angina in patients with chronic coronary artery disease. Tang [4] analyses the effects of metabolic treatment on left ventricle remodeling in patients with heart failure. Fragasso et al. [5] analyse the relevance of metabolic management in diabetic patient and highlight the need of optimization of cardiac metabolism. Thuillier R et al. [6] review the pathophysiological and clinical renal protective effects of metabolic therapy in patients with coronary artery disease and diabetes. Finally, Di Napoli et al. [7] analyze the possible prognostic relevance of the metabolic approach with trimetazidine in patients with chronic heart failure. I wish to thank all the authors for their essential contribution. I expect that this issue may represent a useful help in understanding the clinical relevance of the metabolic therapy in patients with ischemic heart disease and/or heart failure.

The morbidity and mortality of coronary heart disease and of heart failure remain unacceptably high despite major advances in their management. The main focus of treatment has been revascularisation for ischaemic heart disease and neuro-humoral modification for heart failure. There is an urgent need for new modalities of treatment to improve mortality and morbidity. Recently, there has been a great deal of interest in the role of disturbances in cardiac energetics and myocardial metabolism in the pathophysiology of both ischaemic heart disease and heart failure and of therapeutic potential of metabolic modulation. The myocardium is a metabolic omnivore, but mainly uses fatty acids and glucose for generation of Adenosine-5'-triphosphate (ATP). This review focuses on the key changes that occur to the metabolism of the heart in ischaemia and in heart failure and its effects on cardiac energetics.

Cardiovascular disease is a major health problem all over the world. The prevalence of type 2 diabetes mellitus has been rapidly increasing, together with the risk of cardiovascular events. Patients with diabetes, and/or with insulin resistance as well, have an impaired myocardial metabolism of glucose and free fatty acids (FFA) and accelerated and diffuse atherogenesis, with involvement of coronary artery tree. Significant metabolic alterations at heart level in diabetic patients are the decreased utilization of glucose and the increase in muscular and myocardial FFA uptake and oxidation, occurring as a consequence of the mismatch between blood supply and cardiac metabolic requirements. These metabolic changes are responsible both for the increased susceptibility of the diabetic heart to myocardial ischemia and for a greater decrease of myocardial performance for a given amount of ischemia, compared to non diabetic hearts. A therapeutic approach aimed at an improvement of cardiac metabolism, through manipulations of the utilization of metabolic substrates, may improve myocardial ischemia and left ventricular function. Modulation of myocardial FFA metabolism, in addition to optimal medical therapy, should be the key target for metabolic interventions in patients with coronary artery disease and diabetes. In diabetic patients with ischemic heart disease, the effects of modulation of FFA metabolism could even give greater benefit than in nondiabetic patients.

The effectiveness of drug therapy in controlling angina and the resulting improvement in exercise capacity were reviewed. We performed a Medline search of published reports on ranolazine, trimetazidine, and other medicines that act metabolically. Quality of life with regards to work capacity alone was analyzed. Most reports were about trimetazidine, with strong evidence of its efficacy and tolerability. Its effect on episodes of angina, total exercise time, and time to the onset of ischemia on ECG is impressive with no negative effects found on double product (workload) and improvement in quality of life. The second most evaluated drug was ranolazine, particularly regarding quality of life. Results are similar to those with trimetazidine but are not as significant for quality of life issues. For the other drugs, L-carnitine, ribose, and dichloroacetate, accumulated experimental data provide a physiological background in which clinical trials have been started, but as yet very few patients have been enrolled. Also, studies that intended to evaluate, by echocardiography, ischemic dysfunction induced by dobutamine-atropine stress were examined; these also showed a reduction in ischemia and fewer anginal episodes, but only with trimetazidine in this regard. Taken together, these drug effects are important to ameliorate quality of life. The issue of quality of life was evaluated in specific reports, and the results of the application of validated questionnaires (SF36, 5-dimensional EuroQol Instrument, and Seattle Angina Questionnaire) attest to the positive drug effects on patients’ perception of wellness, particularly with the use of trimetazidine, and less with ranolazine.

Metabolic modulation has been an attractive therapeutic approach to heart failure as scientific evidence for an altered metabolic state in the failing heart has been demonstrated for decades. However, the ability to safely alter the substrate metabolism in the myocardium without adverse effects while at the same time be able to provide long-term benefits have not been widely investigated. Meanwhile, the ability to alter long-term molecular, cellular, and hormonal changes as a result of progressive cardiac dysfunction has been directly associated with improvement in clinical outcomes. Among the drugs that have been studied, glucagon-like peptide-1 (GLP-1) analogs and trimetazidine have demonstrated promise in this area. Data on GLP-1, although promising, remain to show short-term improvements. In contrast, trimetazidine has extensive long-term experience with favorable effects on reverse remodeling. However, the appropriate candidate to receive such therapies and the appropriate targets of therapy remain unclear, which may warrant further investigations.

The pivotal therapeutic role of myocardial metabolic modulation in ischemic heart disease (IHD) is increasingly recognized. Among the others, inhibitors of free fatty acids (FFA) oxidation have been consistently shown to play an important role in the therapeutic strategy of IHD patients. Additionally, abnormalities of glucose homeostasis are consistently present in patients with IHD, definitely contributing to the progression of the primary disease. If not adequately treated, in most patients glucose metabolism abnormalities will heavily contribute to the occurrence of complications, of whom severe left ventricular dysfunction is at present one of the most frequent and insidious. Apart from a meticulous metabolic control of frank diabetes, special attention should be also paid to insulin resistance, a condition that is generally underdiagnosed as a distinct clinical entity. An important metabolic alteration in diabetic patients is the increase in free fatty acid concentrations and the increased muscular and myocardial free fatty acid uptake and oxidation. The increased uptake and utilization of free fatty acid and the reduced utilization of glucose as source of energy during stress and ischemia are responsible for the increased susceptibility of the diabetic heart to myocardial ischemia and to a greater decrease of myocardial performance for a given amount of ischemia compared to non diabetic hearts. In order to shift cardiac metabolism from FFA to preferential glucose utilization, the use of FFA inhibitors has been advocated. Among FFA inhibitors etomoxir, perhexiline, oxfenicine and trimetazidine have been evaluated. Among them, trimetazidine, specifically a 3- ketoacyl coenzyme A thiolase inhibitor, has been shown to improve overall glucose metabolism in IHD patients with diabetes and left ventricular dysfunction. The observed combined beneficial effects of FFA inhibitors on myocardial ischemia, left ventricular function and glucose metabolism, represent an additional advantage of these drugs, especially when myocardial and glucose metabolism abnormalities coexist. In this paper, the recent literature on the beneficial therapeutic effects of FFA oxidation inhibitors on myocardial ischemia, left ventricular dysfunction and glucose metabolism in patients with ischemic heart disease and abnormalities of carbohydrate metabolism is reviewed and discussed.

Coronary artery disease (CAD) is due to subintimal deposition of atheromatous plaques in large and mediumsized coronary arteries. Different risk factors have been identified such as hypertension, hypercholesterolemia, diabetes and smoking. Both hypertension and diabetes mellitus affect the same major target organs. The common hypertensive/ diabetic target is the vascular tree, hence renal function is particularly exposed in these patients and often reduced by vascular injury. Consequently, renal protection is a major concern for patients with CAD and/or diabetes who are facing vascular or abdominal surgery, potential nephrotoxic treatment or contrast agents-induced nephropathy. Ischemia reperfusion injury (IRI) is also a common and important clinical cause of renal disease such as renal transplantation and following shock from any cause. Acute renal failure and chronic renal insufficiency are significant complications associated with prolonged warm ischemia (WI). The WI duration remains the most important factor governing the return of postoperative renal function in surgical procedure in which renal blood flow is interrupted. Beside traditional therapy, metabolic therapy is another approach for the treatment of myocardial ischemia at the cellular level itself, with agents that have the capacity to exert their action on the cell without affecting the hemodynamic condition. Such therapies could also be of major interest in the prevention of renal damage and limitation of long term effect of renal IRI, particularly for patients with reduced functional nephron mass. The absence of hemodynamic effect is useful in situations such as shock.

Progressions in acute cardiac care have improved survival after acute myocardial infarction, but in contraposition with this, there has been an increase in mortality because of heart failure. For this reason congestive heart failure is an increasingly widespread, costly and deadly disease, frequently named as epidemic of the XXI century. Despite advancement in modern treatment, mortality rate in heart failure patients remains high. In these patients more importance was attributed in the management of the left ventricle dysfunction. In fact, the heart failure patients have still a poor prognosis due to the ineluctable progression of contractile dysfunction and ventricular remodeling. The classical management of left ventricle dysfunction includes the pharmacological treatment with β-blockers, ACE-inhibitors and aldosterone antagonists, and various surgical or electrophysiological interventions. Emerging evidence suggests that myocardium dysfunction is also due to substrate metabolism alterations. In particular, there is evidence that, in the failing heart, shifting metabolism away from a preference for fatty acids towards more carbohydrate oxidation could recover contractile function. Trimetazidine has been shown to improve symptoms and ventricular function and to have a beneficial effect on the inflammatory profile and endothelial function in these patients. Recently, it has been suggested that trimetazidine could also reduce ventricular remodeling, slowing down the progression of pump failure, and improve prognosis. These results suggest that trimetazidine is a useful adjunct to our current armamentarium for the treatment of heart failure patients.

An urgent need of more effective and personalized treatments for cancer and other genetic diseases is becoming a generalized claim. This is pushing forward experimental alternative approaches based on targeted nanoconjugates, which are designed to be specifically directed against target cells. These constructs, although suitable to carry conventional chemical drugs, are specifically appropriate to deliver expressible or antisense DNA molecules, silencing RNAs or functional proteins as novel biopharmaceuticals. In this new scenario, the specificity and adequateness of director moieties to target cells is fundamental to achieve successful therapies. In this regard, natural or modified proteins or short peptides offer appropriate tools to functionalize vehicles for targeted drug delivery. Besides, conventional protein engineering allows combining, by recombinant DNA technologies, different active peptides in single-chain polypeptides with modular architecture. This offers intriguing possibilities for the development of multifunctional and smart drug vehicles at the nanoscale. In this review we first discuss the pharmacological applications of recombinant proteins, the procedures to identify, obtain and engineer functional and multifunctional polypeptides for target drug delivery and the potential applications of such constructs in emerging cancer therapies. For that, we discuss in detail the molecular traits in the biology of cancer that are critical for the identification and selection of suitable targets for protein-based drug delivery.

Blood Brain Barrier (BBB) represents a major hurdle for the delivery of bioactives in the brain. It serves as a major constraint for the entry of hydrophilic drugs and the efflux pumps present on its surface restrain the intracellular accumulation of pharmacological moieties in the brain. Nanoparticles (NPs) in this regard can serve as a potential module for ferrying large doses of drugs across the BBB. These can be coated at surfaces or fabricated with a targeting moiety, so as to gain access in the brain thus, minimizing the toxicity of therapy. Therefore, the NPs can serve as an exclusive dais for spatial and temporal distribution of pharmacological agents across the brain, escalating the probability of disease free survival. The current review explores the various possible mechanisms so that the NPs can gain access in the brain viz a viz adsorption, receptor mediated endocytosis, transcytosis, inhibiting p-glycoprotein efflux pump, membrane permeabilization effect and disrupting the BBB. The article also accounts the prospects of NPs to enhance the transport of therapeutic agents across the brain, providing refined drug delivery.