Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 8, Issue 3, 2010

Molecules able to modulate the levels of endogenous free radicals, such as reactive oxygen species (ROS) and nitric oxide (NO), are of pivotal interest for pharmacological and pharmaceutical sciences because of their potential therapeutic relevance. In fact, ROS and NO, which are normal products of cell metabolism, may play a dual beneficial/deleterious role, depending on local concentration and mode of generation. As such, they have been identified as key pathogenic factors for many inflammatory, vascular dysfunctional and degenerative disorders, including atherosclerosis, hypertension, cardiovascular and neurodegenerative diseases, cancer, diabetes mellitus, and ageing. Therefore, the identification and characterization of novel antioxidant/free radical scavenger molecules may expand the current therapeutic implements for the treatment and prevention of the above diseases. In this perspective, low molecular weight complexes of transition metals with organic scaffolds are viewed and investigated as promising pharmaceutical agents. These complexes take advantage of the known principles of inorganic chemistry, i.e. the ability of transition metals, FeII, CoII, MnII and RuII, to bind to and react with NO and/or ROS, to counterbalance excessive endogenous free radical generation in biological systems. Among NO scavengers, representative examples are iron complexes with dithiocarbamates or ruthenium compounds with polyamine-polycarboxylate scaffolds; on the other hand, manganesebased molecules appear effective as ROS scavengers. Of note, MnII-containing molecules, currently under study as ROS scavengers, have major functional similarities to Mn-superoxide dismutase (SOD), a Mn-containing enzyme acting as potent endogenous anti-oxidant. In this article, we briefly summarize the state-of-the-art concerning the chemical and biological properties of transition metal ion complexes with low molecular weight synthetic ligands as ROS/NO scavengers provided with therapeutic effectiveness in animal models of free radical-induced diseases. A proper design of the organic scaffolds may yield metal complexes which are stable in aqueous solution in a wide range of physical and chemical conditions, thus preventing release of the metal and the related toxicity. These metal-based compounds may be viewed as a novel class of drugs helpful to reduce vascular dysfunction and oxidative tissue injury due to derangements of the endogenous generation/catabolism of NO and ROS.

Estrogen receptors (ER) have been targets of pharmacological intervention for decades. The use of menopausal hormone therapy (MHT) for improving cardiovascular health is associated with serious adverse effects and therefore cannot be recommended as a first-line strategy. While recently menopausal women in good cardiovascular health may be more likely to benefit from MHT than older women with worse risk profiles, adverse MHT effects such as increased risk for stroke have been consistently shown. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene have been developed to avoid such negative aspects of MHT. Based on available evidence, however, SERMs are not endowed with greater cardiovascular efficacy and safety than conventional MHT. By contrast, the newly developed SERM lasofoxifene has been shown to reduce cardiovascular events in post-menopausal women, although it also increased venous thromboembolic events in line with other ER-targeting agents. Fundamental research has shown that endothelial progenitor cells are important targets of estrogen actions in the cardiovascular system. This indicates that preferential targeting of specific cells and tissues is likely to enhance safety over nonselective hormone agents. Similarly, increased ER-isoform selectivity along with deeper understanding of ER biology should assist in designing novel ER modulators that are more effective and safer than currently used agents. In this article, we summarize the potential connections between SERMs and EPC biology, uncovering novel possible routes to cardiovascular risk reduction.

Molecular inhibition of the epidermal growth factor receptor (EGFR) is a promising anticancer strategy and monoclonal antibodies (mAbs) to EGFR are undergoing extensive evaluation in preclinical and clinical trials. EGFR is frequently over expressed in many types of human malignancy and may be associated with prognosis, disease stage and survival. Therefore, EGFR represents an attractive target for cancer therapy. Two such agents that inhibit EGFR signaling by interfering with ligand-binding are cetuximab (Erbitux) and panitumumab (Vectibix). Common toxicities of agents targeting the EGFR differ from those associated with traditional chemotherapy. Although rare, cardiac toxicity is a significant complication associated with cetuximab and the clinical spectrum of these toxicities can range from subclinical abnormalities to being catastrophic, life-threatening and sometimes fatal events. This review aims to highlight an important albeit inadequately studied toxicity related to EGFR mAbs. We shall review preclinical and clinical literature to ascertain the etiology, incidence and management of cardiovascular complications of monoclonal antibodies to EGFR. As the potential clinical applications for these agents increase, clinicians using these agents need to remain vigilant regarding cardiovascular complications, especially in view of an aging cancer population.

Chronic kidney disease (CKD) is a widespread health problem in the world and anaemia of renal origin is a common problem. Anaemia associated with CKD covers significant risk for faster progression of chronic renal failure, decreased quality of life, and clinical manifestation of cardiovascular disease. The mainstay of anaemia treatment secondary to end-stage renal disease (ESRD) has become erythropoiesis stimulating agents (ESAs). More than 90 % of ESRD patients maintained on dialysis respond to traditional recombinant human erythropoietin (rHU EPO) or to EPO analogues, also called “biosimilars”. Iron deficiency often co-exists in dialysis patients and must be evaluated and treated to reduce ESA requirements. Partial, but not complete correction of renal anaemia is associated with improved outcomes in patients with CKD. The use of ESAs does carry risks such as hypertension, pure red cell aplasia, or cancer, and these agents need to be used judiciously.