Current Pharmaceutical Design - Volume 10, Issue 29, 2004

This issue of Current Pharmaceutical Design, for which I have the honour to be Executive Guest Editor, addresses topical issues relating to the treatment of hypertension, its pathophysiology and the clinical use of antihypertensive drugs. Davis et al. [1] discusses antihypertensive drug development and the importance of ethnicity. They apply valuable lessons learnt from heart failure management and discuss the implications for hypertension treatment. Grassi [2] then addresses sympathetic and baroreflex function in hypertension. The implications for current and new drugs for hypertension are succinctly reviewed. Nadar et al. [3,4] then addresses the commonly seen problem of endothelial dysfunction in hypertension. In their first article [3], methods of assessment of the endothelium and application to hypertension are reviewed in detail, which would be of use in designing studies to determine the effects of antihypertensive agents on the endothelium. In the second article [4], the effects of current antihypertensive therapy on endothelial function are comprehensively reviewed. Increasing evidence points towards the importance of hypertension in peripheral artery disease, and Clement et al. [5] elegantly review this area with respect to hypertension. Finally, Wofford and Hall [6] provide a comprehensive review of obesity hypertension, which is a topic increasingly relevant to pharmaceutical design, with antiobesity drugs and the epidemic of obesity contributing to cardiovascular disease. 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.

Heart failure is a common condition, associated with both poor prognosis and poor quality of life. In contrast to all other cardiovascular diseases, the prevalence of heart failure is increasing in the western world, and is likely to continue to do so as the population ages. In the UK, a significant proportion of patients with heart failure come from South Asian and African Caribbean ethnic groups. A large body of evidence exists that there may be epidemiological and pathophysiological differences between patients with heart failure from different ethnic groups. Treatments such as ACE inhibitors, which are now part of standard heart failure therapy, have an evidence base consisting of trials in patients of almost exclusively white ethnicity. Such treatments may not be equally effective in patients from other ethnic groups. This review will discuss the current evidence for heart failure management with respect to ethnicity, and consider the implications for future drug development and implications for antihypertensive therapy.

The sympathetic nervous system has moved towards center stage in cardiovascular medicine. The importance of the sympathetic activation in heart failure and in renal insufficiency progression and mortality is indeed now well established. In essential hypertension evidence has been provided that this may be the case, because sympathetic overactivity is a key factor in the pathophysiology of the disease, thereby promoting not only the blood pressure increase but also the development and progression of the hypertension-related cardiovascular and metabolic complications, such as left ventricular hypertrophy, vascular hypertrophy, endothelial dysfunction, cardiac rhythm disturbances and insulin resistance. In this review article the main pathophysiologic and mechanistic features of the sympathetic overactivity characterizing the essential hypertensive state will be examined. This will be followed by an analysis of the effects of 1) the hyperadrenergic state on the cardiovascular risk profile as well as on the end organ damage and 2) the different antihypertensive compounds on sympathetic and baroreflex function. The rationale for obtaining during antihypertensive drug treatment an effective sympathoinhibition will be finally highlighted.

Interest in the endothelium has been growing in recent decades and the traditional belief that it provides an inert interface between blood and the vessel wall is no longer the case. It is now clear that the endothelium produces a large number of substances that influence blood flow, and it is in turn affected by changes in the blood and the pressure of blood flow. Nitric oxide and endothelins are the major regulators of the vascular tone, and thereby the blood pressure. Historically speaking, concepts such as endothelial cell damage and injury were described in the 1960s and 1970s. More recently, terms such as endothelial cell activation and dysfunction have also been introduced. Although similar in some respects or part of a continuum, these terms differ in the actual effects on the endothelium, and hence differentiation is important. In hypertension, the delicate balance between the vasodilators and the vasoconstrictors is upset, with disturbance in the nitric oxide pathways that lead to a predominance of the vasoconstrictors. This in turn leads to many other changes that take place in the endothelium, setting up a vicious cycle that maintains the high blood pressure. Therefore, accurate assessment of vascular function is important in linking pathophysiology with clinical disease, such as hypertension. Indeed, there are several methods currently employed experimentally to assess endothelial dysfunction. However, the most widely studied and accepted tests are the estimation of plasma markers such as von Willebrand factor, E-selectin and thrombomodulin, and studies of forearm circulation in response to hypoxia induced stress (‘flow mediated dilatation’, FMD) or intra arterially administered drugs such as acetyl choline. The present document examines these topics. Whilst acknowledging the debt owed to animal models in the study of hypertension, we shall focus on work where primary study is in homo sapiens. A greater appreciation of how endothelial assessments are made in hypertension will have relevance for drug development and future management strategies.

The benefits of treating hypertension in terms of reduction of morbidity and mortality are well established. However, it is debatable whether this benefit is derived entirely from the effects of a reduced blood pressure or whether these agents exert effects over and above blood pressure reduction on the endothelium. Hypertension is associated with adverse changes (whether damage or dysfunction) in the endothelium. Indeed, endothelial damage / dysfunction has have been demonstrated to be a reliable prognostic indicator of future cardiovascular events in hypertension. Of the various drug classes, calcium channel blockers and the ACE inhibitors have significant direct effects on the endothelium. This is in contrast to the beta blockers and alpha adrenergic blockers that appear to indirectly influence endothelial function solely as a result of lowered blood pressure. Antioxidants may have a beneficial effect on endothelial function as well, although their clinical use does not seem to translate into clinical benefit.

Peripheral arterial disease (PAD) of the lower limbs is associated with a high cardiovascular morbidity and mortality. Intermittent claudication is the most common symptomatic manifestation of PAD, but is in its own value an important predictor of cardiovascular death, increasing it by three-fold, and increasing all-cause mortality by two-to-five fold. Hypertension is a risk factor for vascular disorders, including PAD. Of hypertensives at presentation, about 2-5% have intermittent claudication, with increasing prevalence with age. Otherwise, 35-55% of patients with PAD at presentation also show hypertension. Patients who suffer from hypertension with PAD have a greatly increased risk of myocardial infarction and stroke. There is no consensus on the specific treatment of hypertension in PAD because of the limited controlled studies on antihypertensive therapy in such specific PAD population. There is an obvious need of such outcome studies, especially since the two conditions are frequently encountered together. However, as risk is high in all PAD patients, the most important goal remains to decrease the global cardiovascular risk in such patients rather than to focus on the control of blood pressure only and on the reduction of symptoms of PAD. Therefore, treatment with antiplatelet drugs, ACE-inhibitors and statins should be considered.

Excess weight gain accounts for as much as 65-75% of the risk for essential hypertension and also greatly increases the risk for end stage renal disease (ESRD). Obesity raises blood pressure by increasing renal tubular reabsorption, impairing pressure natriuresis, and causing volume expansion due to activation of the sympathetic nervous system (SNS) and renin-angiotensin aldosterone system (RAAS), and by physical compression of the kidneys, especially when visceral obesity is present. The mechanisms of SNS activation in obesity are still unclear but may be due, in part, to hyperleptinemia that stimulates the hypothalamic pro-opiomelanocortin (POMC) pathway. With prolonged obesity, there may be a gradual loss of kidney function that worsens with time, exacerbates hypertension, and makes blood pressure more difficult to control. Lifestyle modifications, including weight reduction and increased physical activity, are essential first steps in the management of obesity hypertension and renal disease. Anti-obesity drugs offer potential pharmacotherapy for obesity hypertension, but current drugs are very limited and additional long-term studies are needed to test their safety and efficacy. Clinical trials are also needed to determine the most effective antihypertensive drugs for obese hypertensive patients. Special considerations for the obese patient, in addition to adequately controlling the blood pressure, include correcting the metabolic abnormalities and protecting the kidneys from further injury.

Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent which is widely used for the induction and maintenance of anesthesia and for sedation in the intensive care unit. Propofol is an oil at room temperature and insoluble in aqueous solution. Present formulations consists of 1% or 2% (w / v) propofol, 10% soyabean oil, 2.25% glycerol, and 1.2% egg phosphatide. Disodium edetate (EDTA) or metabisulfite is added to retard bacterial and fungal growth. Propofol is a global central nervous system depressant. It directly activates GABAA receptors. In addition, propofol inhibits the NMDA receptor and modulates calcium influx through slow calcium ion channels. Propofol has a rapid onset of action with a dose-related hypnotic effect. Recovery is rapid even after prolonged use. Propofol decreases cerebral oxygen consumption, reduces intracranial pressure and has potent anti-convulsant properties. It is a potent antioxidant, has anti-inflammatory properties and is a bronchodilator. As a consequence of these properties propofol is being increasingly used in the management of traumatic head injury, status epilepticus, delirium tremens, status asthmaticus and in critically ill septic patients. Propofol has a remarkable safety profile. Dose dependent hypotension is the commonest complication; particularly in volume depleted patients. Hypertriglyceridemia and pancreatitis are uncommon complications. Allergic complications, which may include bronchospasm, have been reported with the formulation containing metabisulfite. In addition, this formulation has been demonstrated to result in the generation of oxygen free radicals. High dose propofol infusions have been associated with the “propofol syndrome”; this is a potentially fatal complication characterized by severe metabolic acidosis and circulatory collapse. This is a rare complication first reported in pediatric patients and believed to be due to decreased transmembrane electrical potential and alteration of electron transport across the inner mitochondrial membrane.

Glucagon-like peptide-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPP IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, (iv) potency as insulin secretagogues, and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.

Many genetic disorders are reported to cause irreversible damage to the fetus before birth. In utero gene therapy may be an effective tool for correction of genetic disorders by replacing defective gene with normal one. There are many reasons for moving forward with in utero gene therapy. The most important reason is to provide early intervention as to prevent or slow dysfunction and morbidity. This approach may prove to be advantageous in rapidly replicating fetal cells, and less sensitive to immune response to vector or transgene product due to underdeveloped immune system. In addition, the developing fetus may be a better candidate for gene therapy than the adult because gene engraftment may be more feasible in early fetal life, where stem cells or pleuripotent progenitor cells are more accessible to vectors. Some reports are available on successful in utero gene transfer in animal models but many questions remain to be answered before in utero gene therapy can be considered a viable solution to human. The real moral challenge facing in utero gene therapy is finding ways to insure that the review of protocols is adequate, and that those undertaking trials are competent to do so. Present review article analyzes the overall progress of the field, and the research that still needs to be performed before it can be considered to human clinical trials.

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF gene superfamily, which induces apoptosis through engagement of death receptors. TRAIL is unusual as compared to the other cytokines of this family, as it interacts with a complex system of receptors consisting of two pro-apoptotic death receptors (TRAIL-R1 and TRAILR2) and three decoy receptors (TRAIL-R3, TRAIL-R4 and osteoprotegerin). Moreover, with respect to other members of the TNF superfamily, such as CD95L and TNF-α, TRAIL has generated great interest as a potential tumor-specific cancer therapeutic because as a stable soluble trimer it selectively induces apoptosis in many transformed cells but not in normal cells. Of note, TRAIL cytotoxicity is at least partially independent of the major systems involved in resistance to chemotherapy, such as p53 wild-type function and multidrug resistance (MDR) genes. Since one fundamental problem of most cancers is the development of multiple mechanisms of resistance, which progressively reduce or suppress the therapeutic efficacy of conventional chemotherapy, new therapeutic approaches that either restore the pro-apoptotic activity of chemotherapeutic drugs or by-pass the mechanisms of resistance are highly desirable. This review will focus on the potential of TRAIL for its application in the therapy of hematological malignancies, used either alone or in combination with chemotherapy. The scenario emerging from the literature is that the treatment and management of hematological malignancies will require the rational combination of TRAIL plus conventional or new drugs in a regimen that would optimize the anti-neoplastic activity in malignant cells resistant to chemotherapy through restoration of the proapoptotic activity of TRAIL.

Aberrations in nitrergic neurotransmission, due to a decrease in neuronal nitric oxide (NO) synthase (nNOS) protein, play an important role in the pathogenesis of autonomic neuropathy in diabetes. Until recently the mechanism of the decrease in nNOS protein content in nitrergic nerves during diabetes was debated. Two different views were prevailing, one attributing the nNOS decrease to nitrergic nerve degeneration, the other to an alteration in nNOS expression. Our recent study in which we showed that nitrergic nerves undergo a degenerative process in two phases might bring a solution to this debate. Our model suggests that, in the early stages of diabetes, nNOS expression is decreased in the nitrergic axons while nNOS levels are unaffected in the cell bodies, most probably due to a defect in axonal transport. This decrease is reversible with insulin treatment. As the diabetes progresses, nNOS starts to accumulate in the cell bodies since it cannot be transported down to the axons. Increased nNOS protein and NO production coincide with accumulation of advanced glycation endproducts (AGEs) in the blood and tissues. Synergistic action of AGEs and endogenous NO leads to increased oxidative stress within the cell bodies, resulting in apoptosis. This degenerative phase of nitrergic neuropathy is not reversible with insulin treatment. This suggests a point of no return for autonomic nerves after which the degenerative changes become irreversible. Future therapeutic approaches could target the defective axonal transport and prevention of AGEs accumulation before this point of no return. In the later stages, reduction of AGEs, replenishment of lost nitrergic neurons and restoration of function are putative therapeutic targets.