Current Pharmaceutical Design - Volume 19, Issue 21, 2013

Successful treatment of hypertension often requires the association of drugs from different classes. Combination therapy takes advantage of complementary mechanisms of action, in order to reach target blood pressure (BP) earlier and to minimize the side effects of medications. In the last decade, several randomized trials have demonstrated the efficacy of combining a renin-angiotensin-aldosterone system (RAAS) inhibitor with a calcium channel blocker (CCB) or with a diuretic in different populations. The ACCOMPLISH trial was the only large clinical trial that directly compared the two combination strategies. In hypertensive individuals at high cardiovascular risk, benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing the primary composite endpoint of cardiovascular events plus death from cardiovascular causes. Small randomized trials have evaluated the two combination therapies in surrogate endpoints, such as microalbuminuria, with contrasting result. Current European and American guidelines recommend combination therapy as first-line when BP is at least 20/10 mmHg above treatment goals. However, the choice of the best combination therapy is still debated: the National Institute for Health and Clinical Excellence guidelines recommend a RAAS inhibitor plus a CCB, while the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines underline the pivotal role of thiazide diuretics. The combination of a RAAS inhibitor with a CCB demonstrated the best efficacy in reducing cardiovascular endpoint. However, the combination of a RAAS inhibitor with a diuretic has shown beneficial results in particular subgroup of patients, such as patients with heart failure or with African American origin. This review will focus on the rationale and current evidences about combination therapy in the management of arterial hypertension.

Even though patients who develop ischemic stroke despite taking antiplatelet drugs represent a considerable proportion of stroke hospital admissions, there is a paucity of data from investigational studies regarding the most suitable therapeutic intervention. There have been no clinical trials to test whether increasing the dose or switching antiplatelet agents reduces the risk for subsequent events. Certain issues have to be considered in patients managed for a first or recurrent stroke while receiving antiplatelet agents. Therapeutic failure may be due to either poor adherence to treatment, associated co-morbid conditions and diminished antiplatelet effects (resistance to treatment). A diagnostic work up is warranted to identify the etiology and underlying mechanism of stroke, thereby guiding further management. Risk factors (including hypertension, dyslipidemia and diabetes) should be treated according to current guidelines. Aspirin or aspirin plus clopidogrel may be used in the acute and early phase of ischemic stroke, whereas in the long-term, antiplatelet treatment should be continued with aspirin, aspirin/extended release dipyridamole or clopidogrel monotherapy taking into account tolerance, safety, adherence and cost issues. Secondary measures to educate patients about stroke, the importance of adherence to medication, behavioral modification relating to tobacco use, physical activity, alcohol consumption and diet to control excess weight should also be implemented.

Dual antiplatelet therapy of clopidogrel added aspirin is an established treatment strategy to prevent recurrent ischemic event occurrence in coronary artery disease patients. Generally, a one size fits all nonselective strategy is used without an assessment of pharmacodynamic efficacy of clopidogrel therapy. However, pharmacodynamic studies revealed various limitations of clopidogrel metabolism and numerous factors such as genetic and, drug-drug interactions influence the antiplatelet response to clopidogrel therapy. Translational platelet function investigations performed in the percutaneous coronary intervention (PCI)-treated population receiving clopidogrel have identified high platelet reactivity (HPR) to adenosine diphosphate as a major risk factor for both acute as well as long-term ischemic event occurrence, including stent thrombosis. Recent studies have highlighted the relation of single nucleotide polymorphisms of genes involved in clopidogrel absorption and metabolism to reduced pharmacokinetic and pharmacodynamic responses to clopidogrel. Cytochrome (CYP) 2C19 loss-of-function (LoF) allele carriage has been associated with increased thrombotic risk in the PCI population. However, clopidogrel is pharmacodynamically effective in about two thirds of patients undergoing PCI; these patients do not have HPR. Therefore, selectively treating two thirds of patients with generic clopidogrel may provide significant cost savings. Unselected therapy with the new P2Y12 receptor blockers is associated with increased bleeding. The introduction of generic clopidogrel holds the strong possibility of inducing a change in practice whereby genetic and platelet function testing are performed more frequently in patients receiving a stent.

Patients with nonvalvular atrial fibrillation (AF) and risk factors for stroke need anticoagulation to avoid thromboembolic complications. Vitamin K antagonists (VKAs) are an established pharmacological group the use of which is recommended by guidelines. However, VKAs (like warfarin) have major disadvantages, such as a variable dose-effect relationship, drug and food interactions, the need for regular blood testing and dose titration, and, finally, a substantial risk of bleeding. New oral anticoagulants are intended to replace warfarin, being at least as safe and effective, and lacking some of the disadvantages of VKAs. Clinical data for dabigatran, rivaroxaban, apixaban and edoxaban, and other new drugs, are discussed in this article with special focus on their use in nonvalvular AF.

Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. However, it appears that currently available risk assessment tools often underestimate risk, especially for patients in the intermediate-risk category. Considering the socioeconomic cost, it is imperative to correctly identify patients in the intermediate-risk category who would benefit from more aggressive treatment. A plethora of experimental and observational studies provide support that lipoprotein associated phospholipase A2(Lp-PLA2) and secretory phospholipases A2(sPLA2) as well as high sensitivity C-reactive protein (hsCRP) are useful biomarkers of cardiovascular risk. Particularly, Lp-PLA2 has also been addressed as pharmacological target and we are eagerly awaiting the results of ongoing phase III clinical trials. In this review we discuss the current literature regarding the pros and cons of these biomarkers.

Low density lipoproteins (LDL) and high density lipoproteins (HDL) are independent risk factors for coronary heart disease (CHD); decreasing LDL-cholesterol (LDL-C) levels with statin therapy represents the primary goal in the management of cardiovascular disease. However, despite the efficacy of statins in reducing cardiovascular morbidity and mortality, a significant residual risk has been observed even after reaching the LDL-C target, suggesting that other risk factors beyond LDL-C should be addressed, including low levels of HDL-cholesterol (HDL-C). Several clinical trials have shown an inverse relationship between HDL-C levels and cardiovascular risk, and 1 mg/dl increment in HDL-C is associated in epidemiological studies with a 2-3% decrease in cardiovascular risk, suggesting that raising HDL-C levels might have beneficial effects to reduce cardiovascular disease. However, several lines of evidence indicate that the functional properties of HDL may be relevant as well. In patient with CAD and normal HDL-C levels, HDL exhibit significantly reduced protective functions, and rather appear to be pro-atherogenic; on the other hand some genetic mutations causing low levels of HDL-C are not associated with increased atherosclerosis. Furthermore, although niacin significantly increased HDL-C levels, no further clinical benefit was observed from the addition of niacin to statin therapy, suggesting that increasing HDL-C levels is not sufficient and perhaps functional properties of HDL must be considered when choosing a therapeutic strategy to reduce the residual cardiovascular risk.

As the population becomes more obese and the prevalence of diabetes and the metabolic syndrome increases, low-density lipoprotein-cholesterol (LDL-C) may lose its value as a sole predictor for cardiovascular risk among lipids. Combined dyslipidemia is typically characterized by elevations in LDL-C and triglyceride levels, often accompanied by decreased high-density lipoproteincholesterol (HDL-C) concentrations and increased levels of small, dense LDL. This common disorder results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins. In the last few years most of the international scientific guidelines as well as several expert panels have confirmed that LDL-C represents the primary or even the only target of treatment. Yet, increasing evidence suggests moving away from a LDL-C target-based approach to a more tailored treatment approach. For example, non- HDL-C has been introduced in the last few years as a target of treatment.

Plasma low-density lipoprotein cholesterol (LDL-C) is one of the biomarkers of cardiovascular disease (CVD) risk. LDL is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway. Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the LDLR. PCSK9 inhibition is attractive as a new strategy for lowering LDL-C levels, especially in combination with lipid lowering drugs such as statins. We review data from the available studies which focus on PCSK9 as a potential target in the treatment of hyperlipidemia. Further studies are still necessary to investigate the potential underlying mechanisms involved.

Mycobacterial enoyl acyl carrier protein (ACP) reductase is an attractive target for focused design of novel antitubercular agents. Structural information available on enoyl-ACP reductase in complex with different ligands was used to generate receptor-based pharmacophore model in Discovery Studio (DS). In parallel, pharmacophore models were also generated using ligand-based approach (HypoGen module in DS). Statistically significant models were generated (r2= 0.85) which were found to be predictive as indicated from internal and external cross-validations. The model was used as a query tool to search Zinc and Maybridge databases to identify lead compounds and predict their activity in silico. Database searching retrieved many potential lead compounds having better estimated IC50 values than the training set compounds. These compounds were then evaluated for their drug-likeliness and pharmacokinetic properties using DS. Few selected compounds were then docked into the crystal structure of enoyl-ACP reductase using Dock 6.5. Most compounds were found to have high score values, which was found to be consistent with the results from pharmacophore mapping. Additionally, molecular docking provided useful insights into the nature of binding of the identified hit molecules. In summary, we show a useful strategy employing ligand- and structure-based approaches (pharmacophore modeling coupled with molecular docking) to identify new enoyl- ACP reductase inhibitors for antimycobacterial chemotherapy.

Coumarin compounds represent an important type of naturally occurring and synthetic oxygen-containing heterocycles with typical benzopyrone framework. This type of special benzopyrone structure enables its derivatives readily interact with a diversity of enzymes and receptors in organisms through weak bond interactions, thereby exhibit wide potentiality as medicinal drugs. So far, some coumarin-based drugs such as anticoagulant and antineurodegenerative agents have been extensively used in clinic. Coumarin-containing supramolecular medicinal agents as a new increasing expansion of supramolecular chemistry in pharmaceutical science have also been actively investigated in recent years. Coumarin-derived artificial ion receptors, fluorescent probes and biological stains are growing quickly and have a variety of potential applications in monitoring timely enzyme activity, complex biological events as well as accurate pharmacological and pharmacokinetic properties. This review provides a systematic summary and insight of the whole range of medicinal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of coumarinbased medicinal chemistry are also presented.