Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 4, Issue 1, 2006

Cardiac side effects of the cytostatic agent 5-fluorouracil (5-FU) have an incidence of 1.2 - 7.6%. Potentially, arrhythmias, myocardial infarction and sudden cardiac death could occur. Life-threatening cardiotoxicity is rarely observed with a frequency <1%. Cardiotoxicity of 5-FU seems to differ from well known effects of other cytostatics, e.g., anthracyclines. Myocardial ischemia was suggested as potential mechanism due to occasionally observed ECG alterations during 5-FU administration. Experimental studies revealed potential mechanisms of cardiotoxicity ranging from direct toxic effects on vascular endothelium involving endothelial NO synthase leading to coronary spasms and endothelium independent vasoconstriction via protein kinase C. In addition, rheological side effects have to be considered. Coronary artery disease is judged to increase the risk of cardiac side effects. Despite lack of prospective trials, verapamil type calcium antagonists as well as nitrates seem to be useful for treatment of 5-FU induced coronary spasms. In addition, modification of the cytostatic regimen has to be considered in patients who had been symptomatic. It could be assumed that 5-FU toxicity is reversible in the majority of cases when acute complications, e.g., arrhythmias, are resolved.

Identifying the genetic predictors of the therapeutic response to drugs is the role of pharmacogenomics. Although polymorphisms in several genes have been associated with the blood pressure response to diuretics, β-blockers and ACE-inhibitors, the pharmacogenomics of essential hypertension is still attempting to find satisfactory scientific evidence to be translated into clinical practice. The main reasons for this apparent failure are: the small sample sizes of the cohorts of patients analyzed, the methodological variability, the complexity of the biological organization, the contextdependency and the genetic heterogeneity. This review will summarize the available data on antihypertensive drugs and the criteria used for study design and conduction, focusing on their strong points and limitations.

The initial realization that agents containing an imidazoline structure may interact with a distinct class of receptors, has led to a major class of cardiovascular agents, which now has the potential to enter a third generation. There is now general acceptance that there are three main imidazoline receptor classes, the I1 imidazoline receptor which mediates the sympatho-inhibitory actions to lower blood pressure, the I2 receptor which is an important allosteric binding site of monoamine oxidase and the I3 receptor which regulates insulin secretion from pancreatic β cells. Thus all three represent important targets for cardiovascular research. Interestingly, an I1- receptor candidate has been cloned (IRAS, imidazoline receptor antisera selected) which is a homologue of the mouse cell adhesion integrin binding protein Nischarin. There has been range of new agonists and antagonists with very high selectivity for I1, I2 and I3 receptors developed. Three different endogenous ligands have been characterized including agmatine (decarboxylated arginine), a range of β-carbolines including harman and harmane, and more recently imidazoleacetic acid-ribotide. The imidazoline field has recently seen an enormous diversification with discoveries that I1 and I2 receptors also play a role in cell proliferation, regulation of body fat, neuroprotection, inflammation and some psychiatric disorders such as depression. This diversification has continued with the addition of effective agents with imidazoline affinity in the fields of cancer, pain and opioid addiction, stress, cell adhesion, epilepsy and appetite. The imidazoline field has maturated considerably with a range of highly selective leader molecules, candidate receptors and endogenous ligands. We are therefore only at the threshold of an exciting new era as we begin to understand the diverse and complex nature of their function.

Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to direct cellular effects, antibodies can carry substances to the targeted cells, such as radioactive isotopes, toxins, and antineoplastic agents. At present monoclonal antibodies, directed against both lymphoid antigens (CD 20 and CD 52) and a myeloid antigen (CD33) are available for clinical use. In ALL, rituximab, a humanised anti CD20 antibody, has been combined to chemotherapy mainly in mature B-ALL and Burkitt's lymphoma and preliminary results are promising. Alemtuzumab is an anti-CD52 humanised antibody, which showed anti-tumour activity in CLL; clinical effects were observed in some patients with relapsed adult ALL. Monoclonal antibodies against myeloid antigens have been prevalently used in acute myeloid leukaemias (AML), where the most utilised immunological target is CD33. The CD33 molecule is expressed by approximately 90% of AMLs but not on CD34+ bone marrow-resident hematopoietic stem cells. The humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt AML, but it can eliminate minimal residual disease. Radioimmunotherapy with β-particle-emitting isotopes targeting CD33 shows a major efficacy. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin (GO) has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy. GO is composed of a humanised immunoglobulin G4 (IgG4) monoclonal antibody (mAb), targeting the CD33 antigen and linked to a calicheamicin derivative, a cytotoxic anthracycline antibiotic. GO has been approved by FDA as second-line therapy in older patients with AML. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumour lysis syndrome. Alemtuzumab causes immunosuppression, increasing the risk of infection. GO may cause hepatotoxicity.

In pulmonary hypertension (PH), thrombosis and thromboembolism may occur as primary events associated with inherited or acquired thrombophilia. Alternatively, in situ thrombosis may develop as a complication of pre-existing vasculopathy as in the case of idiopathic PH and related disorders (so called pulmonary arterial hypertension). In these disorders, a number of abnormalities has been described involving endothelial cells, platelets and other circulating cellular and soluble elements. These abnormalities are suggestive of a shift of pulmonary vascular microenvironment toward a procoagulant, prothrombotic and antifibrinolytic pattern. The abnormalities described so far include circulating antiphospholipid antibodies, increased plasma levels of platelet aggregating agents (serotonin, thromboxane), adhesion molecules (P-selectin, von Willebrand factor), antifibrinolytic enzymes (plasminogen activator inhibitor 1) and cytokines. Also, decreased endothelial production of natural anticoagulants (thrombomodulin) and platelet antiaggregating substances (nitric oxide, prostacyclin) have been demonstrated. The present review is focused on the procoagulant, prothrombotic and antifibrinolytic mechanisms so far identified in PH, in both clinical setting and animal models. Understanding of these mechanisms is crucial for a proper selection of anticoagulant and antithrombotic therapies and provides the rationale for development of novel therapeutic options.

Endogenous Ouabain (EO) and Adducin enhance the Na-K pump function and play an important role in sodium homeostasis and blood pressure (BP) regulation. In the general population, plasma EO modulates BP either by inhibiting the prohypertensive effect of an excessive salt intake or counteracting the depressor action of normal-moderate salt intake. Almost 50% of hypertensive patients have increased circulating plasma levels of EO. EO has been associated both to left ventricular dysfunction and hypertrophy. A new antihypertensive agent, PST2238, (17β-(3-furyl)-5β- androstan-3β, 14β, 17α-triol a digitoxigenin derivative) able to selectively antagonize both the EO and adducin prohypertensive and molecular effects, has been developed. In hypertensive rats (MHS strain) carrying both adducin mutations and increased plasma EO and in ouabain-infused rats (OS), PST2238 lowers BP by normalizing the renal Na-K pump function. In OS rats, PST antagonized the cardiac and renal pro-hypertrophic ouabain effect associated to the activation of the Src-EGFr-ERK1/2 signaling cascade. Phase 1 clinical studies demonstrated a high tolerability of PST2238. In a preliminary phase 2 study on 42 mild never-treated hypertensive patients, PST2238 given for 3 months at 0.5 mg/day, significantly reduced BP in subjects with moderate salt intake, implying that it may be selectively effective in conditions where EO plays a prohypertensive role. In conclusion, PST2238, because of its peculiar action mechanism, represents a new tool to disentangle the complex relationship between salt intake, genetic control of renal sodium handling and EO effect.

Angiotensin receptor blockers are the newest class of antihypertensive agents marketed for the treatment of hypertension. There is now an important amount of evidence indicating that this class of drugs exerts beneficial effects in patients with a variety of cardiovascular disorders. Evidence-based medicine includes well controlled studies with mortality and morbidity endpoints in patients with left ventricular dysfunction after a myocardial infarction, congestive heart failure, cerebrovascular disease, type-2 diabetic subjects with renal dysfunction and high-risk hypertensive patients. In addition to these hard endpoints, treatment with angiotensin receptor blockers prevents the development of type-2 diabetes, promotes a more pronounced regression of left ventricular hypertrophy, decreases microalbuminuria and proteinuria in renal patients, ameliorates coronary and peripheral vascular endothelial dysfunction and decreases plasma levels of several markers of vascular inflammation. In summary, angiotensin receptor blockers are antihypertensive drugs with a very good profile in terms of efficacy, tolerability and cardiovascular protection. They represent an important step in the search for the ideal antihypertensive agent.

Over the last decade a wealth of studies have shed new light on the role of aldosterone in the pathogenesis of cardiovascular diseases. It is now evident that in addition to its classical role in increasing sodium reabsorbtion in the kidney , aldosterone also exhibits several nonepithelial effects such as the induction of inflammation, fibrosis and necrosis in various organs. Herein we review the experimental evidences for the protective effects of mineralocorticoid receptor blockade in the prevention and treatment of target organ damage, both in animals and in humans. We also discuss the pharmacological and clinical differences between the two available mineralocorticoid receptor blockers, spironolactone and eplerenone.