Current Pharmaceutical Design - Volume 12, Issue 13, 2006

This issue of Current Pharmaceutical Design, for which I have the honour to be Executive Guest Editor, addresses topical issues relating to the clinical management and treatment of hypertension, its pathophysiology and the clinical use of antihypertensive drugs. MacFadyen et al. [1] discusses the perception of symptoms in hypertensive patients and the relevance to the application of anti- hypertensive drug therapy. Lim et al. [2] then addresses the role of hyperglycaemia and the hypercoagulable state in the pathogenesis of cardiovascular events in diabetes mellitus, with iimplications for hypertension management. Specifically, the implications for current and new drugs for hypertension are succinctly reviewed. Nadar et al. [3] then addresses the important issue of target organ damage in hypertension, with a succinct review of the pathophysiology and implications for drug therapy. Varughese et al. [4] then address novel concepts of statin therapy for cardiovascular risk reduction in hypertension. As we are increasingly addressing cardiovascular risk reduction in hypertensives, these drugs are increasingly part of routine management of our hypertensive patients. This is followed by an article by Jaumdally et al. [5] which traditional risk factors for coronary atherosclerosis in Indo Asians - including hypertension and metabolic syndrome (of which hypertension is a key component) - and the need for a reappraisal to put these data in context of current management strategies. Finally, we end on a pathophysiological flavour, when Boos et al. [6] provide a comprehensive review of hypertension as an inflammatory Process, which includes a discussion of the implications for current pharmaceutical design. Given the excellence of reviews contained in this issue, I hope that the readers of Current Pharmaceutical Design will find this issue useful for updating their knowledge of the many developments of the exciting field of antihypertensive drugs. References [1] MacFadyen RJ, et al. Perception of symptoms in hypertensive patients and the relevance to the application of anti- hypertensive drug therapy. Curr Pharm Design 2006; 12(13): 1557-1565. [2] Lim HS, et al. The role of hyperglycaemia and the hypercoagulable state in the pathogenesis of cardiovascular events in diabetes mellitus: implications for hypertension management. Curr Pharm Design 2006; 12(13): 1567-1579. [3] Nadar S, et al. Target organ damage in hypertension: pathophysiology and implications for drug therapy. Curr Pharm Design 2006; 12(13): 1581-1592. [4] Varughese G, et al. Novel concepts of statin therapy for cardiovascular risk reduction in hypertension. Curr Pharm Design 2006; 12(13): 1593-1609. [5] Jaumdally R, et al. Traditional Risk Factors For Coronary Atherosclerosis In Indo Asians: The Need For A Reappraisal. Curr Pharm Design 2006; 12(13): 1611-1621. [6] Boos CJ, Lip GYH. Is Hypertension an inflammatory Process? Implications for current pharmaceutical design. Curr Pharm Design 2006; 12(13): 1623-1635.

While symptoms are common during the detection and treatment of hypertensive patients it is rarely the case that either uncomplicated essential hypertension (of whatever severity) or treatment presents insurmountable problems. Unfortunately they frequently result in changes in effective therapy or encourage clinicians and prescribers to settle with altered and inadequate treatment goals. This review considers the association of patients' symptoms in the management of hypertension. It considers the relationship of symptoms at the time of diagnosis and the impact of symptoms voiced during active drug treatment. The data relating antihypertensive therapy to adverse symptoms during chronic therapy and the consequences of this on treatment goals are summarised.

Population studies have identified diabetes mellitus as a risk factor for cardiac and vascular events, with a common association with hypertension. Observational studies have consistently demonstrated blood glucose as a continuous cardiovascular risk factor. Experimental studies suggest that elevated blood glucose, through a range of biochemical pathways can promote atherogenesis and increase the tendency for thrombosis. The resultant state promotes occlusion of arterial flow and increase cardiovascular event rates. However, an unconvincing temporal relationship (raised blood glucose preceding cardiovascular events) and the limited impact of glucose reduction in patients with diabetes on cardiovascular events do not support blood glucose as a major cause of cardiovascular disease. In this review, we discuss the relationship between hyperglycaemia and a hypercoagulable state in diabetes and the implications of this relationship for the treatment of patients with diabetes, who also commonly have hypertension.

Hypertension is a well known risk factor for cardiovascular and cerebrovascular events such as heart attacks and strokes. In addition, it is associated with earlier changes in organ systems in the body, such as left ventricular hypertrophy (LVH), proteinuria and renal failure, retinopathy and vascular dementia which are grouped under the term "target organ damage"(TOD). There are many processes involved in the pathogenesis of TOD and these include endothelial activation, platelet activation, increased thrombogenesis, changes in the renin aldosterone angiotensin system (RAAS), and collagen turnover. All these changes work hand in hand and lead to the production of hypertensive TOD. In this review, we aim to provide an overview of the recent advances in pathophysiology of hypertensive TOD, and examine how these changes lead to the production of TOD. A better understanding of these pathogenic processes would help us better devise treatment strategies in preventing the dreaded complications associated with hypertension.

Hypertension is associated with an increase in cardiovascular events. Pathophysiological mechanisms of this include endothelial damage / dysfunction, inflammatory activation, insulin resistance, platelet activation and alterations in the coagulation cascade leading to a prothrombotic state. Dyslipidaemia acts synergistically with hypertension in increasing cardiovascular risk. HMG CoA reductase inhibitors (statins) are lipid-lowering drugs and more recently have been shown to have a significant pleiotropic effect on endothelial function, inflammation, platelet activation and coagulation. Statins affect the whole pathophysiology of atherogenesis from deposition to plaque rupture and thrombogenesis because of its pleiotropic effects. Therefore it is intuitive that statins may be of benefit in hypertensive patients with conventionally normal lipid levels by preventing the pathological effects of hypertension. There is an increasing clinical evidence base for statins use in patients with hypertension. In this article, the novel pleiotropic and conventional mechanisms of statins, and clinical data of statin therapy in patients with hypertension are reviewed.

Our ability to assess individual patient cardiovascular risk is based on "traditional" risk factors including patient's characteristics (age, sex and body mass index), hypertension, diabetes, smoking, lipid profile and family history of premature coronary disease. These factors are important for the clinician in order to calculate risk and initiate treatment in both primary and secondary settings. As the morbidity and mortality from vascular disease in United Kingdom migrant populations of Indo Asian origin is significantly higher (∼50%) than the Western Europeans, an accurate assessment of risk and preventative therapies can reduce cardiovascular risk and improve clinical outcome. Indeed, scoring systems like the Framingham consistently underestimate risk in Indo Asians. This review assesses differences between traditional risk factors in Indo Asians and summarizes the relevance of more novel factors in a more comprehensive evaluation of cardiovascular risk in the Indo Asian population. Greater appreciation of these traditional risk factors for coronary atherosclerosis in Indo Asians - including hypertension and metabolic syndrome (of which hypertension is a key component) - suggests the need for a reappraisal to put these data in context of current management strategies.

The risk factors for hypertension are only partly known, and accounts for the some of the deficiencies in current primary prevention strategies and in the design of new drugs for the management of this common condition. Recently, chronic low grade low-grade inflammation has been identified as an integral part in the pathogenesis of vascular disease. Of note, inflammation may also be implicated in the development of hypertension, either as a primary or secondary event. Indeed, several clinical studies have demonstrated increased numbers of well recognised pro-inflammatory markers, such as high sensitive C-reactive protein (hsCRP), in patients with hypertension, even after adjustment for potential confounding factors. Furthermore, elevated hsCRP levels have also been shown to be predictive for the development of hypertension in prehypertensive and normotensive patients. Pathophysiologically, inflammation has been implicated in both endothelial (dys)function and arterial stiffness in hypertension, with reduced availability of nitric oxide (NO) being integral to this process. Oxidative stress also appears to be a key feature in the reduced availability of NO and is aggravated by increased circulating angiotensin II (Ang II). Importantly, there is some evidence that drugs commonly used in the management of hypertension, such as statins, angiotensin converting enzyme inhibitors and Ang II receptor blockers have anti-inflammatory properties that can positively influence outcomes in patients with hypertension. The inflammatory state in hypertension may pose a new therapeutic target for future drug design.

Whey is a natural by-product of cheese making process. Bovine milk has about 3.5 % protein, 80 % of which are caseins and the remaining 20 % are whey proteins. Whey proteins contain all the essential amino acids and have the highest protein quality rating among other proteins. Advances in processing technologies have led to the industrial production of different products with varying protein contents from liquid whey. These products have different biological activities and functional properties. Also recent advances in processing technologies have expanded the commercial use of whey proteins and their products. As a result, whey proteins are used as common ingredients in various products including infant formulas, specialized enteral and clinical protein supplements, sports nutrition products, products specific to weight management and mood control. This brief review intends to focus on scientific evidence and recent findings related to the therapeutic potential of whey proteins and peptides.

Traumatic brain injury (TBI) is a devastating disease, predominantely affecting young people. Although the prognosis for TBI victims has improved in recent years, many survivors of TBI suffer from emotional, cognitive and motor disturbances and a decreased quality of life. In recent years, there has been a rapid increase in the number of pharmacological targets evaluated in clinically-relevant experimental TBI models, showing improved cognitive and motor outcome and decreased loss of brain tissue. Despite the completion of several recent clinical trials using compounds showing neuroprotection in preclinical studies, pharmaceutical treatment strategies with proven clinical benefit are still lacking. This paper reviews the preclinical pharmacological treatment studies evaluated to date in experimental models of TBI. Although human TBI is a complex and multifaceted disease, these studies provide encouraging translational data suggesting that pharmacological compounds, delivered in a clinically-relevant time window, may improve the outcome of TBI patients.