Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 25, 2007
Contents
The Clinical Management and Treatment of Hypertension,
Its Pathophysiology and the Clinical Use of Antihypertensive
Drugs
Executive Editor: Gregory Y.H. Lip
Editorial Pp. 2538
Hypertension, Anti-Hypertensive Therapy and Neoplasia
Pp. 2539-2544
P.K.Y. Goon, P.S. Stonelake and G.Y.H. Lip
[Abstract]
Hypertension and Cardiac Arrhythmias Pp.
2545-2555
A. Aidietis, A. Laucevicius and G. Marinskis
[Abstract]
Management of Hypertension in Relation to Acute Coronary
Syndromes and Revascularisation Pp. 2556-2566
M. Kühl, G.Y.H. Lip and C. Varma
[Abstract]
Hypertension in Pregnancy: Pathophysiology & Management
Strategies Pp. 2567-2579
V.J. Karthikeyan and G.Y.H. Lip
[Abstract]
From Diabetes to Metabolic Syndrome: A View Point
on An Evolving Concept Pp. 2580-2583
H.S. Lim and G.Y.H. Lip
[Abstract]
General Articles
The Pharmaceutical Potential of Histone Deacetylase Inhibitors
Pp. 2584-2620
G. Elaut, V. Rogiers and T. Vanhaecke
[Abstract]
5-Hydroxytryptamine (5-HT) Receptor Ligands
Pp. 2621-2637
S.L. Kitson
[Abstract]
Abstracts
[Back to top]
Editorial: The Clinical Management and Treatment of
Hypertension, Its Pathophysiology and the Clinical Use of
Antihypertensive Drugs
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 ever-expanding,
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.
Gregory Y.H. Lip
Professor of Cardiovascular Medicine
University Department of Medicine
City Hospital
Birmingham B18 7QH
England UK
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Hypertension, Anti-Hypertensive Therapy and Neoplasia
P.K.Y. Goon, P.S. Stonelake and G.Y.H. Lip
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.
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Hypertension and Cardiac Arrhythmias
A. Aidietis, A. Laucevicius and G. Marinskis
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.
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Management of Hypertension in Relation to Acute Coronary
Syndromes and Revascularisation
M. Kühl, G.Y.H. Lip and C. Varma
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.
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Hypertension in Pregnancy: Pathophysiology & Management
Strategies
V.J. Karthikeyan and G.Y.H. Lip
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.
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From Diabetes to Metabolic Syndrome: A View Point
on An Evolving Concept
H.S. Lim and G.Y.H. Lip
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.
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The Pharmaceutical Potential of Histone Deacetylase Inhibitors
G. Elaut, V. Rogiers and T. Vanhaecke
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 pheno-type 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 type-dependent differences in sensitivity to HDACi-mediated
effects, however, remain largely elusive.
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5-Hydroxytryptamine (5-HT) Receptor Ligands
S.L. Kitson
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.
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