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Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 4, Number 2, April 2006
Contents
The Management of Phosphodiesterase-5 (PDE5)
Inhibitor Failure Pp. 89-93
David H.W. Lau, Sashi Kommu, Faiz H. Mumtaz,
Robert J. Morgan, Cecil S. Thompson and Dimitri P. Mikhailidis
[Abstract]
Pharmacological Management of No Reflow During Percutaneous
Coronary Intervention Pp. 95-100
Italo Porto, Vaishali Ashar and Andrew R.J. Mitchell
[Abstract]
Plasminogen Activator System and Vascular Disease
Pp. 101-116
Suzanne M. Nicholl, Elisa Roztocil and Mark G. Davies
[Abstract]
Migraine: Current Therapeutic Targets and Future Avenues Pp.
117-128
D.K. Arulmozhi, A. Veeranjaneyulu and S.L. Bodhankar
[Abstract]
Pharmacotherapy of Abdominal Aortic Aneurysms
Pp. 129-149
Joe Dawson, Edward Choke, Saiqa Sayed, Gillian Cockerill,
Ian Loftus and Matt M. Thompson
[Abstract]
Fine Tuning Therapeutic Targeting of the Sphingolipid
Biosynthetic Pathway to Treat Atherosclerosis Pp.
151-154
W. Scott Kim, Charles E. Chalfant and Brett Garner
[Abstract]
Blood Pressure Reduction in the Primary and Secondary
Prevention of Stroke Pp. 155-160
Seth I. Sokol, John R. Kapoor and JoAnne M. Foody
[Abstract]
Postprandial Hypotension - Novel Insights into Pathophysiology
and Therapeutic Implications Pp. 161-171
Diana Gentilcore, Karen L. Jones, Deirdre G.
O’Donovan and
Michael Horowitz
[Abstract]
Abstracts
[Back to top]
The Management of Phosphodiesterase-5 (PDE5) Inhibitor
Failure
David H.W. Lau, Sashi Kommu, Faiz H. Mumtaz,
Robert J. Morgan, Cecil S. Thompson and Dimitri P. Mikhailidis
The oral phosphodiesterase type 5 (PDE5)
inhibitors have made a valuable contribution to the treatment
of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal
smooth muscle relaxation, vasodilatation and penile erection.
However, PDE5 inhibitors are not always effective. Decreased
efficacy, cost, incorrect administration, lack of sexual stimulation,
vascular risk factors associated with ED and vascular or neurogenic
diseases are causes of PDE5 inhibitor failure. Tachyphylaxis
may also occur. This is defined as reduced tissue responsiveness
to a drug in the presence of a constant concentration of this
drug.
Treatment failure may cause considerable distress. If dose
titration, more attempts and continuous dosing of PDE5 inhibitors
(taken on a daily basis) fail to resolve the initial PDE5
inhibitor failure, clinicians need to consider alternative
treatments. These include sublingual apomorphine, intracavernosal/intraurethral
pharmacotherapy, vacuum devices, the insertion of a prosthesis
and penile vascular surgery.
Combination therapy like prostaglandin E1 (PGE1)
with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan;
a 5-HT2 antagonist) as well as other pro-erection
agents, like Endothelin-1 antagonists, angiotensin II antagonists
(valsartan/losartan), adrenomedullin, Rho kinase inhibitors
and nitric oxide (NO) donors may be beneficial in the treatment
of ED. However, these combination therapies need to be validated.
Adding an androgen to a PDE5 inhibitor may help when circulatory
testosterone levels are low.
The early use of PDE5 inhibitors in patients with hypertension,
hyperlipidaemia or diabetes with concomitant ED and treating
these risk factors may improve corporeal blood flow and lead
to long-term preservation of cavernosal function. Therefore,
the efficacy of PDE5 inhibitors may be maintained.
Targeting the risk factors of ED (similar to those for arteriosclerosis)
in the early stages of the disease may prevent the development
or decrease the severity of ED.
[Back to top]
Pharmacological Management of No Reflow During Percutaneous
Coronary Intervention
Italo Porto, Vaishali Ashar and Andrew R.J. Mitchell
Angiographic no reflow is a recognized phenomenon
during percutaneous coronary intervention (PCI). It usually
follows successful lesion dilation and, by definition, it
represents a reduction in epicardial coronary blood flow in
the absence of identifiable dissection, obstruction or distal
vessel cut off (indicative of distal embolisation). No reflow
appears to be more commonly associated with PCI for acute
myocardial infarction and PCI for saphenous vein graft occlusions.
While the exact mechanism of no reflow is unknown, theoretical
causes include local humoral and microembolic effects leading
to microcirculatory dysfunction. As the process is multifactorial,
various therapeutic strategies are required in different situations.
The present day pharmacological management involves the use
of vasodilators including nitrates, verapamil, papaverine,
adenosine, nicardipine and sodium nitroprusside, but interestingly
a vasoconstrictor like epinephrine may also have a role. Glycoprotein
IIb/IIIa platelet receptors antagonist have shown a powerful
de-thrombotic effect, and the intracoronary administration
appears to be particularly promising. We review the pathogenesis
of a reduced epicardial flow during PCI and focus on those
drugs that have been studied for the treatment of no reflow.
Although no double blind, randomized trial has been conducted
to assess any of these agents, or to determine the appropriate
dosage, we try to identify some useful conclusions from the
published evidence.
[Back to top]
Plasminogen Activator System and Vascular Disease
Suzanne M. Nicholl, Elisa Roztocil and Mark G. Davies
Vascular diseases, such as atherosclerosis,
thromboembolic disorders and stroke, in addition to surgical
procedures such as restenosis, all share the plasminogen activator
system as a central component in the pathogenesis of vascular
injury. Since the development of plasminogen deficient mice
our knowledge of the effects of this proteolytic system in
cardiovascular disease has vastly increased. The plasminogen
activator system plays a key role in vascular homeostasis
and constitutes a critical response mechanism to cardiovascular
injury. The central components of the PA system are the proteolytic
activators, urokinase-plasminogen activator (u-PA) and tissue-type
plasminogen activator (t-PA), plasminogen (plg) and its degradation
product, plasmin, together with the major inhibitors of this
system, plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2).
An extensive network of additional proteases, inhibitors,
receptors and modulators directly associate and are influenced
by the PA system, the largest group being the Matrix Metalloproteinases
(MMPs) and their respective inhibitors the Tissue inhibitors
of MMPs (TIMPS).
[Back to top]
Migraine: Current Therapeutic Targets and Future Avenues
D.K. Arulmozhi, A. Veeranjaneyulu and S.L. Bodhankar
TMigraine is characterized by attacks of
intense pulsatile and throbbing headache, typically unilateral
in nature with or without aura. Migraine affects a substantial
fraction (10-20 %) of the world population (more women than
men). With regard to the pathophysiology of migraine, several
theories have been proposed; the major three are vascular
(due to cerebral vasodilatation), neurological (abnormal neurological
firing) and neurogenic dural inflammation (release of inflammatory
neuropeptides).
The drugs used to treat migraine can be divided into two groups:
agents that abolish the acute migraine headache and agents
aimed at prevention. The acutely acting antimigraine agents
(5-HT1B/1D receptor agonists) stimulated
research interest in the field of migraine. Currently prophylactic
treatments for migraine include calcium channel blockers,
5-HT2 receptor antagonists, beta-adrenoceptor blockers
and γ-amino
butyric acid (GABA) agonists. Unfortunately, many of these
treatments are non-specific and not always effective. Despite
progress, the complex etiology of migraine requires further
research, the condition often remains undiagnosed and available
therapies are underused.
In this review, the evidence that linked the different theories
of migraine with its pathophysiology is considered. Furthermore,
the present therapeutic targets and future approaches for
the acute and prophylactic treatment of migraine are critically
evaluated.
[Back to top]
Pharmacotherapy of Abdominal Aortic Aneurysms
Joe Dawson, Edward Choke, Saiqa Sayed, Gillian Cockerill,
Ian Loftus and Matt M. Thompson
Aortic aneurysms account for 10,000
deaths annually in the UK, due to rupture. At present the
only effective therapeutic strategy to treat abdominal aortic
aneurysms is to surgically repair them; this carries an elective
mortality of up to 10%.
Recent advances in vascular biology have led to a greater
understanding of the pathophysiological process that causes
aortic aneurysms to expand and rupture. Key pathological processes
include widespread aortic inflammation, proteolytic degradation
of the extracellular matrix, neovascularisation and generation
of reactive oxygen species. Identification of these processes
has lead to pharmacological strategies to prevent aneurysm
expansion and rupture. Many of these strategies have undergone
proof of concept in animal models and some have now entered
clinical trials.
This review outlines current thinking regarding the molecular
events leading to aneurysm expansion and explains how these
processes may be inhibited. Experimental data on agents retarding
aneurysm expansion in animal models are discussed. A significant
proportion of the review details pharmacological agents that
have undergone or are undergoing clinical trials.
Pharmacological treatment for abdominal aneurysms is urgently
required given the number of small aneurysms being diagnosed
by screening programmes. This is a rapidly evolving field
and one in which translation from experimental research to
clinical practice is anticipated within 5 years.
[Back to top]
Fine Tuning Therapeutic Targeting of the Sphingolipid
Biosynthetic Pathway to Treat Atherosclerosis
W. Scott Kim, Charles E. Chalfant and Brett
Garner
The accumulation of sphingolipids, including sphingomyelin
and glycosphingolipids, in atherosclerotic lesions is well
known. Plasma sphingomyelin concentration is correlated with
atherosclerosis development and is an independent predictor
of coronary artery disease. Similarly, plasma glycosphingolipid
levels are increased in conditions associated with atherosclerosis
risk. Recent studies have focused on understanding the mechanisms
by which specific intermediates and end-products of the sphingolipid
biosynthetic pathway, such as sphingomyelin, glycosphingolipids,
ceramide and sphingosine-1-phosphate may modulate vascular
biology and atherosclerosis. Here we focus on recent work
indicating that pharmacological modulation of the sphingolipid
biosynthetic pathway could offer a novel treatment for atherosclerosis
or, at the very least, provide mechanistic insights concerning
the eitiology of this disease which is the major cause of
death in developed countries.
[Back to top]
Blood Pressure Reduction in the Primary and Secondary
Prevention of Stroke
Seth I. Sokol, John R. Kapoor and JoAnne
M. Foody
Control of hypertension is well established for the primary
prevention of stroke. Prior studies, on the other hand, conflict
over whether hypertension remains a risk factor for recurrent
stroke and if blood pressure reduction is associated with
better outcomes in this subset of patients. We review current
evidence regarding the role of BP lowering for primary and
secondary prevention of stroke. Current evidence amassed from
both primary and secondary prevention trials demonstrate that
BP reduction is a crucial common element in overall reduction
of stroke risk.
[Back to top]
Postprandial Hypotension - Novel Insights into Pathophysiology
and Therapeutic Implications
Diana Gentilcore, Karen L. Jones, Deirdre
G. O’Donovan and Michael Horowitz
Postprandial hypotension is a frequent disorder, occurring
in ~ 40% of nursing-home residents, and represents a major
cause of morbidity and mortality. Current approaches to management
are suboptimal. While it has been generally assumed that ingestion
of carbohydrate has the greatest effect, the fall in blood
pressure (BP) does not appear to be mediated by the consequent
elevations in blood glucose and insulin. Moreover, there is
evidence that fat may decrease BP to a comparable extent to
carbohydrate, although onset of the response may be slower,
and that the response is affected by the type of carbohydrate.
It has recently been established that the rate of nutrient
delivery from the stomach into the small intestine is an important
determinant of the hypotensive response to carbohydrate, so
that the magnitude of the fall in BP and rise in heart rate
is greater when gastric emptying is relatively more rapid.
In both healthy elderly subjects and patients with type 2
diabetes, the fall in BP is attenuated when gastric emptying
and small intestinal carbohydrate absorption are slowed by
dietary (e.g. guar) or pharmacological (e.g. acarbose) means.
Conversely, gastric distension attenuates the postprandial
fall in BP. Strategies for the treatment of postprandial hypotension
should, therefore, potentially be directed at (i) meal composition,
particularly carbohydrate type and content, (ii) slowing gastric
emptying and/or small intestinal carbohydrate absorption and/or
(iii) increasing postprandial gastric distension.
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