Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 5, Issue 2, 2007

The chronic painful tendon (tendinopathy, tendinosis) is generally considered difficult to treat, not seldom causing long-term disability and sometimes ending the sports or work carreer. Most common sites for tendinopathy are the Achilles-, patellar-, extensor carpi radialis brevis (ERCB)-, and supraspinatus tendons. The origin of pain has for many years been unknown, but recently, by using ultrasound (US) + colour Doppler (CD), immunohistochemical analyses of tendon biopsies, and diagnostic injections of local anaestesia, we found a close relationship between areas with vasculoneural ingrowth and tendon pain. Sensory nerves (Substance-P-SP and Calcitonin Gene Related Peptide-CGRP) were found inside and outside the vascular wall. In following clinical studies we have demonstrated good short-and mid-term clinical results using treatment with US+CD-guided sclerosing polidocanol injections, targeting the area with neovessels outside the tendon. Two-year follow ups have showed remaining good clinical results, and sonographically signs of remodelling with a significantly thinner tendon with a more normal structure. Whether the effects of polidocanol are mediated through destruction of neovessels, activity on nerves or a combination, is under evaluation.

Relaxin is a hormone belonging to the so-called relaxin superfamily, which also includes insulin-like peptides. Relaxin is best known for its effects on the female reproductive system, which primarily include lengthening of the pubic symphysis and softening of the tissues of the birth canal, stimulating mammary and endometrial development, and maintenance of myometrial quiescence. In recent years, evidence has been accumulating that relaxin can have multiple and diverse effects on both reproductive and nonreproductive organs, tissues and cells, thus acting as a sort of ‘manager’ hormone to optimize the many physiological changes taking place during pregnancy. Among the specific relaxin targets, there are the blood vessels and the heart. In fact, relaxin is a potent vasodilatator of the systemic and coronary circulation, by a mechanism of action involving nitric oxide, and can influence cardiac beating rate. Identification of the numerous possible roles of relaxin in the pathophysiology of cardiovascular diseases, not to mention the possible therapeutical applications of relaxin, remains a difficult task. Based on the known biological effects of relaxin, it is becoming increasingly evident that the potential fields of clinical investigation of human relaxin as a cardiovascular drug could be in ischemic heart disease (acute and chronic myocardial infarction), in cardiac fibrosis, in cell transplantation for cardiac repair, and in obliterative peripheral arterial disease. Availability of the homologous human peptide, knowledge of its pharmacological, pharmacokinetic and pharmacodynamic profiles, and increasing interest of clinicians and pharmaceutical companies should synergistically act to transfer relaxin from the laboratory bench to the bedside.

Integrins are the principle mediators of molecular dialog between a cell and its extracellular matrix environment. The unique combinations of integrin subunits determine which extracellular matrix molecules are recognized by a cell. Recent studies have demonstrated that remodeling in heart and vasculature is linked to alterations in extracellular matrix and integrin expression. The roles of integrins in controlling cellular behavior have made these molecules highly attractive drug targets. New insights into mechanisms whereby the extracellular matrix takes part in the control of smooth muscle cell proliferation and cardiac growth suggest a number of putative targets for future therapies that can be applied to increase plaque stability, prevent the clinical consequences of atherosclerosis and improve outcomes after interventional procedures such as cardiac transplantation. Therapeutic candidates include antibodies, cyclic peptides, peptidomimetics and small molecules. The integrin inhibitors Integrilin and ReoPro have been approved as blood thinners in cardiovascular disease, and newer agents are undergoing testing. Although integrin function is important in the cardiovascular system, there are wide gaps in knowledge. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these molecules in the cardiovascular system.

Advances in molecular biology and functional genomics have demonstrated that the “one gene-one phenotypeone drug” paradigm, that has dominated pharmaceutical industry and clinical pharmacology thinking, is too simplistic for management of complex polygenic traits. The traditional highly specific drugs with unique target have proven their clinical usefulness. However, they do not always display the required efficacy versus side-effect profile, in major part because polygenic traits are determined by redundant mechanisms. Simultaneously modulating multiple targets may enhance therapeutic efficacy in the treatment of a range of disorders. Multi-targeting can be achieved by the combination of different drugs having specific single target activity. This approach introduces potential problems with pharmacokinetic interactions, toxicity and patient compliance. High efficacy can be achieved, alternatively, by administering selectively nonselective drugs with complex pharmacological profiles directed towards various molecular targets and affording pleiotropic actions. Dual- or multiple-ligands can be discovered accidentally, but can also be rationally designed according to validated medicinal chemical approaches. The merits of multiple-target versus single-target approaches for cardiovascular disease traits are assessed in the present review. The main aim is to make evident the molecular biological basis of the possibility for targeting multiple sites and the subsequently emerging strategies for interventions with superior clinical value by harnessing receptor tyrosine kinases (RTKs) such as VEGFR, PDGFR, bFGFR, as well as G protein-coupled receptors (GPCRs). The premises for lead discovery in this new area and the challenges of medicinal chemistry behind the rational design of multitasked ligands are also discussed.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. The more severe form of the disease, known as neovascular AMD, is characterized by aberrant growth of blood vessels from the choroid into the subretinal space. This pathologic choroidal neovascularization can have drastic consequences, often seriously impairing vision in affected individuals. Current treatment approaches focus on combination therapies that include photodynamic therapy in conjunction with numerous forms of antiangiogenic or anti-inflammatory drug intervention. To date, however, no adequate treatment is available for the majority of affected individuals. The threat of a rapidly aging population provides the impetus for aggressive efforts to control the prevalence and progression of this disease. This review will outline the currently available pharmacotherapies, discussing the justification for their use as well as their shortcomings. Furthermore, drugs that are currently under investigation as monotherapies and adjuncts will be highlighted. The potential for alternate targets will also be examined, with a focus on the most promising candidates.

The conditionally essential amino acid L-arginine is the substrate for nitric oxide (NO) synthesis, a key second messenger involved in physiological functions including endothelium-dependent vascular relaxation and inhibition of platelet adhesion and aggregation. Extracellular L-arginine transport seems to be essential for the production of NO by the action of NO synthases (NOS), even when the intracellular levels of L-arginine are available in excess (L-arginine paradox). Chronic renal failure (CRF) is a complex clinical condition associated with accelerated atherosclerosis and thrombosis leading to cardiovascular events. Various studies document that markers of malnutrition and inflammation, such as low body mass index (BMI), C-reactive protein (CRP) and interleukin-6 (IL-6), are strong independent predictors of cardiovascular mortality in patients with end-stage renal disease (ESRD). There is considerable literature demonstrating that a disturbance in the nitric oxide control mechanism plays a role in mediating the haemodynamic and haemostatic disorders present in CRF. Endogenous analogues of L-arginine, ADMA and L-NMMA, which can inhibit NO synthesis and Larginine transport, are increased whilst L-arginine is reduced in plasma from all stages of CRF patients. In this context, the uptake of L-arginine in blood cells is increased in undialysed CRF patients and in patients treated by CAPD and haemodialysis. In platelets obtained from haemodialysis patients, the activation of L-arginine transport and NO production was limited to well-nourished patients.Impairment in nitric oxide bioactivity, coupled with malnutrition and inflammation, may contribute to increased incidence of atherothrombotic events in CRF. This article summarizes the current knowledge of L-arginine-nitric oxide pathway and malnutrition in CRF and briefly describes possible therapeutic interventions.

Fibrinogen is a complex glycoprotein involved in the final step of the coagulation cascade as the precursor of fibrin monomers that participate in the formation of the haemostatic plug. Three genes (FGA, FGB, and FGG) clustered on chromosome 4q31.3-4q32.1 encode the three polypeptide chains (Aα, Bβ, and γ), which in a pairwise fashion form the hexameric circulating molecule. Among congenital fibrinogen deficiencies, quantitative defects (also called type I deficiencies; i.e. congenital afibrino-genemia [CAF] and hypofibrinogenemia) are characterized by the concomitant absence or reduction of coagulant activity and immunoreactive protein, while qualitative defects (type II deficiencies; i.e. dysfibrinogenemia and hypodysfibrino-genemia) show low clotting protein in contrast with normal or moderately reduced antigen. Patients affected by CAF (Mendelian Inheritance in Man, [MIM] #202400) or severe hypofibrinogenemia (MIM+134820, *134830, and *134850) may experience bleeding manifestations varying from mild to catastrophic. Although many cases of fibrinogen deficiencies have been described from a clinical point of view, only in a minority of cases the causal mutation was identified. The genetic defects so far described, most unique for any analyzed family, are invariantly located in the fibrinogen cluster; for only few of them the pathogenic role either at the protein or at the mRNA level has been investigated. This review, besides providing a concise description of the main structural and functional properties of fibrinogen and giving an overview of the clinical manifestations, the laboratory diagnosis and therapeutic approches, will be focused on the present knowledge on the genetic basis of quantitative fibrinogen deficiencies. Our systematic analysis of the available clinical and genetic data on these disorders evidences their high allelic heterogeneity, the existence of different pathogenic mechanisms, and the absence of strong genotype/phenotype correlations.