Current Pharmaceutical Design - Volume 13, Issue 25, 2007

This issue of Current Pharmaceutical Design, for which I have the honour to be Executive Guest Editor, addresses issues relating to the clinical management and treatment of hypertension, its pathophysiology and the clinical use of antihypertensive drugs. Goon et al. [1] discuss hypertension, anti-hypertensive therapy and neoplasia, providing an overview establishing the strengths and weaknesses of the arguments presented and highlighting possible pharmacophysiological pathways involved. Aidietis et al. [2] then address the role of hypertension in the pathogenesis of cardiac arrhythmias. Kuhl et al. [3] then address the important issue of the management of hypertension in relation to acute coronary syndromes and revascularisation. Their review discusses the frequency of hypertension and acute coronary syndromes as single clinical conditions, as well as their combined presentations, which necessitates a pragmatic management approach. Karthikeyan and Lip [4] then address the area of hypertension in pregnancy, where information on pathophysiology is everexpanding, as well as new insights into management strategies. Finally, we end on a more controversial note, where Lim and Lip [5] provide a viewpoint on metabolic syndrome and the continuum with diabetes. Indeed, the increased risk of cardiovascular complications may not be related to diabetes status per se but the frequent association of diabetes with a high-risk phenotype, now recognised as the so-called ‘metabolic syndrome’. 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] Goon PKY, Stonelake PS, Lip GYH. Hypertension, anti-hypertensive therapy and neoplasia. Curr Pharm Des 2007; 13(25): 2539-2544. [2] Aidietis A, Laucevicius A, Marinskis G. Hypertension and cardiac arrhythmias. Curr Pharm Des 2007; 13(25): 2545- 2555. [3] Kühl M, Lip GYH, Varma C. Management of hypertension in relation to acute coronary syndromes and revascularisation. Curr Pharm Des 2007; 13(25): 2556-2566. [4] Karthikeyan VJ, Lip GYH. Hypertension in pregnancy: pathophysiology & management strategies. Curr Pharm Des 2007; 13(25): 2567-2579. [5] Lim HS, Lip GYH. From diabetes to metabolic syndrome: a view point on an evolving concept. Curr Pharm Des 2007; 13(25): 2580-2583.

The link between cancer, hypertension and anti-hypertensive drug treatment is controversial. Despite numerous studies looking either directly or indirectly at cancer and hypertension, the results are often conflicting and do little to answer the dominant questions of cause and effect. Also, the treatment of hypertension has continued to evolve, with newer therapies being made available including angiotensin- converting enzyme inhibitors. Whilst the potential link with cancer is thought to be small at worst, with the overall benefits of hypertension faroutweighing its negative impacts, the suggestion of a carcinogenic role for either hypertension or its treatment continues to be an emotive issue, and needs firm answers. In this review, we provide an overview establishing the strengths and weaknesses of the arguments presented and highlight possible pharmacophysiological pathways involved.

Arterial hypertension is a widespread disease and one of important yet under-recognized and under-treated causes of atrial and ventricular arrhythmias. Hypertrophy of cardiac muscle in hypertensive patients is characterized not only by increased myocardial mass, but also by proliferation of fibrous tissue and decreased intercellular coupling, that lead to inhomogeneity of electrical properties and propensity to various arrhythmias. Many trials show the importance of treating hypertension in order to restore normal myocardial function and decrease the number of premature beats, runs of ventricular tachycardia, and attacks of atrial fibrillation. To date, the most convincing data are collected regarding the importance of blockade of renin-angiotensin-aldosterone system (RAAS) in order to avoid arrhythmias in arterial hypertension. Other antihypertensive drug classes (eg beta-blockers, calcium antagonists) are also useful, and investigational compounds that aim at regression of hypertrophy are under search. Polymorphism of genes coding the function of RAAS, pathways of synthesis and degradation of proteins and other cardiac and extracardiac systems involved in regulation of blood pressure, are recognized as promising targets for research.

In patients with acute coronary syndromes (ACS), hypertension is common. The type of ACS and severity of hypertension would determine the treatment algorithm. In ST elevation myocardial infarction (MI), time to reperfusion is essential whereas in malignant hypertension the reduction of blood pressure to prevent end organ damage is the priority. Many therapeutic drugs available for ACS and hypertension are commonly used to treat both these conditions simultaneously. Once the ACS is treated medically, revascularization therapy is likely to be considered. Importantly, optimization of hypertension management may prevent subsequent complications. In this review, we discuss the frequency of hypertension and ACS as single clinical conditions, as well as combined presentations. The pathophysiology of myocardial perfusion in hypertensive patients and the effect of blood pressure (BP) normalization is discussed. This review focuses on treatment strategies from a non-interventional and interventional perspective. Finally, current medications used in treating hypertension in ACS will be compared with regards to their mode of action and prognostic value.

Hypertension is the most common medical condition encountered in and complicating pregnancy, with significant implications on maternal and perinatal morbidity and mortality. It is also one of the areas of clinical practice that has been studied extensively, yet less well understood. The hypertensive disorders of pregnancy are a spectrum of conditions that are classified into 4 categories based upon recommendations of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. This article provides an overview of the pathophysiology and current pharmacologic management of hypertension in pregnancy.

The current diagnostic threshold for diabetes mellitus is imposed on a continuous distribution of blood glucose measurement. A more clinical approach estimates a threshold above which the rate of diabetes-specific complications rises steeply. However, the diagnostic threshold for diabetes is essentially established on the risk of microvascular and not cardiovascular complications. Indeed, while there appears to be a continuous relationship between blood glucose, cardiovascular risk and overall mortality, this association extends into the sub-diabetic range, with no threshold identified. In this regard, the assumption that the diagnosis of diabetes can effectively identify patients at elevated risk of cardiovascular morbidity and mortality is potentially flawed, and questions the utility of diabetes status (as a dichotomous variable) for the assessment and management of cardiovascular risk. Indeed, the increased risk of cardiovascular complications may not be related to diabetes status per se but the frequent association of diabetes with a high-risk phenotype, now recognised as the so-called ‘metabolic syndrome’. By implication, cardiovascular disease prevention should not be dominated by a drive for the prevention of diabetes, but this broader clinical syndrome of increased cardiovascular risk.

Protein acetylation, catalyzed by the opposing activities of histone deacetylases (HDAC) and histone acetyltransferases, is now recognized to be an important epigenetic modulator of gene transcriptional activity and cell function. As a result of the intense search for HDAC inhibitors (HDACi) during the past fifteen years, a large number of structurally divergent classes with variable potencies and isoenzyme selectivities have been identified. They occupy an important and promising position in a number of therapeutic areas. Several HDACi are under clinical evaluation as tumor cell-selective chemotherapeutics, and show great promise for the treatment of inflammatory disorders, neurodegenerative diseases, protozoal and latent viral infections, and (fibro)proliferative disorders. Recently, it was discovered that they might be used as enhancers of differentiation in stem cell therapy, and as medium supplements that stabilize the phenotype of primary cells in culture. Next to biological activity, the pharmaceutical potential of a compound is also dependent on the adequate translation of in vitro potency into in vivo efficacy whilst maintaining an acceptable safety profile. Therefore, this review will not only address the formerly mentioned applications, but will also deal with the pharmacokinetic and toxicological properties of currently available HDACi. Several compounds exert potent activities in vitro, but have been shown to be of limited therapeutic value due to rapid biotransformation, and thus poor in vivo bioavailability. The first attempts to improve the metabolic properties of HDACi have been made and will be discussed. In contrast to conventional chemotherapeutics, HDACi exert no drastic side effects at therapeutically effective doses. Although a bulk effect on histone acetylation is observed, HDACi display a remarkable tumor cell-selective toxicity. The mechanisms underlying these cell typedependent differences in sensitivity to HDACi-mediated effects, however, remain largely elusive.

Serotonin (5-HT) receptors are part of the G protein-coupled and ligand-gated ion channel families. 5-HT exerts its diverse actions by binding to cell surface receptors which can be classified into seven distinct families (5-HT1 to 5- HT7) according to their structural diversity and mode of action. Some of the 5-HT families are comprised of multiple receptors which share similar structural and mechanistic properties but display very different operational profiles. Evidence continues to mount in support of the important roles of the 5-HT receptors in various neuropsychiatric disorders such as anxiety, depression, schizophrenia, migraine and drug addiction. The 5-HT receptors may also play an important role in obesity, aggression, sexual behaviour and cardiovascular disorders. A number of selective/non-selective 5-HT agonist and antagonist ligands (drugs) have been developed to challenge many of these disease states.