| Current
Drug Therapy
ISSN: 1574-8855
Current Drug Therapy
Volume 1, Number 3, September 2006
Contents
Effect of Antipsychotic Drugs on Cerebrovascular
Morbidity and Mortality: A Systematic Review
Pp. 241-248
S. Mazzucco, A. Cipriani, C. Lintas and C. Barbui
[Abstract]
Antiplatelet Therapy and Oral Anticoagulation
for Prevention of Ischemic Stroke Pp. 249-256
C. Weimar and H.-C. Diener
[Abstract]
Drug Targeting in Bronchial Asthma: Inhaled Corticosteroids
Should Reach the Peripheral Airways Pp. 257-261
P.N.R. Dekhuijzen
[Abstract]
An Increasing Incidence of Treatment Resistance
in Hypertension? Pp. 263-272
I.K. Eide
[Abstract]
Use of Topiceuticals (Topically Applied, Peripherally
Acting Drugs) in the Treatment of Chronic Pain Pp.
273-282
B.S. Galer and A.R. Gammaitoni
[Abstract]
Topical Anesthetics for Procedural Pain in Children:
What Does the Future Hold? Pp. 283-290
W.T. Zempsky
[Abstract]
Multidrug-Resistance (MDR) Proteins Develops Refractory
Epilepsy Phenotype: Clinical and Experimental Evidences Pp.
291-309
A. Lazarowski, L. Czornyj, F. Lubieniecki, S.
Vazquez, C. D’Giano, G. Sevlever, A.L. Taratuto, A.
Brusco and E. Girardi
[Abstract]
Update on Anti-TNF-Alpha Treatment in Rheumatic
Diseases Pp. 311-318
M. Massarotti, A. Ferrara and B. Marasini
[Abstract]
Colloidal and Pharmacological Activity of Albumin
in Clinical Fluid Management: Recent Developments Pp.
319-328
C.J. Wiedermann
[Abstract]
Abstracts
[Back to top]
Effect of Antipsychotic Drugs on Cerebrovascular Morbidity
and Mortality: A Systematic Review
S. Mazzucco, A. Cipriani, C. Lintas and C.
Barbui
Background: Since 2002, there has been contrasting
evidence indicating an increased risk of adverse cerebrovascular
outcomes in people treated with the two most commonly prescribed
atypical antipsychotics, risperidone and olanzapine.
Objective: The objective of this systematic review
is to examine the evidence of the correlation between antipsychotic
drug use and the risk of cerebrovascular diseases.
Method: We used the Medline computer database to
search the relevant papers published in English from January
1966 to October 2005. We used the following key words: antipsychotic
agents, transient ischaemic attack, cerebrovascular accident,
stroke, vascular diseases, risk factors and mortality. Articles
that investigated the relationship between antipsychotic drug
exposure and subsequent cerebrovascular morbidity and mortality
were collected and reviewed.
Results: We found one meta-analysis based on a systematic
review of randomised controlled trials (RCTs), 4 pooled analyses
of RCTs, 4 database analyses, 1 case-control study and 1 cross-sectional
study. A total of 11 RCTs suggested that 48 out of 2187 (2.2%)
subjects exposed to antipsychotics experienced cerebrovascular
adverse events, compared with 10 out of 1190 (0.8%) placebo-treated
subjects. In terms of risks, the relative risk was statistically
significant for risperidone (3.2, 95% Confidence Interval
(CI) 1.4 to 7.2) but not for olanzapine 1.8 (95% Confidence
Interval (CI) 0.5 to 6.3). In general, data from large observational
administrative databases suggested no increased risk of cerebrovascular
events with the atypical antipsychotics, compared with typical
antipsychotics, although the evidence seems still inconclusive.
Conclusion: So far, randomised and non-randomised
studies provided contrasting findings on the risk of cerebrovascular
accidents in subjects exposed to antipsychotic drugs. Individual
patient data metaanalyses, carried out by independent organisations,
are urgently needed to systematically summarise factors associated
with cerebrovascular morbidity and mortality in individuals
treated with first and second-generation antipsychotic drug.
[Back to top]
Antiplatelet Therapy and Oral Anticoagulation
for Prevention of Ischemic Stroke
C. Weimar and H.-C. Diener
Purpose of Review: To provide an update on
stroke prevention strategies with oral anticoagulants (vitamin
K antagonists) and platelet inhibitors.
Recent Findings: In asymptomatic women, aspirin reduces
the risk of stroke but not of myocardial infarction while
in men only the risk of myocardial infarction but not stroke
could be significantly reduced.
No benefit of oral anticoagulants could be shown in patients
with non-cardioembolic stroke. Patients with symptomatic intracranial
stenosis had a higher risk of intracerebral bleeding with
oral anticoagulation compared to high dose aspirin.
The combination of aspirin plus extended-release dipyridamole
significantly reduces the risk of recurrent stroke as well
as the risk of a combined cardiovascular outcome compared
to aspirin alone. The combination of aspirin plus clopidogrel
did not reduce the risk of stroke in patients with non-cardioembolic
ischemic events compared to clopidogrel monotherapy.
Summary: For primary prevention
in patients <65 years without risk factors, no antithrombotic
treatment should be given. The choice between oral anticoagulants
and antiplatelet agents depends on the stroke etiology and
individual risk factor profile. Patients with non-cardioembolic
stroke generally are candidates for antiplatelet therapy.
New anticoagulation strategies will facilitate dosing and
may reduce under-use in patients with atrial fibrillation
and clear indications for oral anticoagulation.
[Back to top]
Drug Targeting in Bronchial Asthma:
Inhaled Corticosteroids Should Reach the Peripheral Airways
P.N.R. Dekhuijzen
Bronchial asthma is characterised by an eosinophilic inflammatory
process in the airways, and manifests itself functionally
by bronchial hyperresponsiveness and variable airflow obstruction.
In the past this inflammatory process was presumed to be predominantly
present in the large and intermediate airways. This is not
surprising since functional abnormalities in the small airways
(or so-called silent zone) are much more difficult to establish
in comparison to changes in the larger airways. As a consequence,
changes in airway calibre and bronchial hyperresponsiveness
are mainly measured in the central part of the lung, i.e.
by means of the FEV1 at rest or after challenge with bronchoconstrictive
stimuli like histamine and methacholine.
Recently, advanced physiological, radiological and morphological
studies show that the inflammatory process extends to the
peripheral airways and even the alveolar compartment. This
so-called peripheral inflammation is related to the clinical
manifestation of the severity of asthma.
Targeting the small airways with new inhaled corticosteroids
with a small particle size and a high peripheral deposition
may result in better control of the disease.
The presence and clinical consequences of peripheral inflammation
and its therapeutic approach are discussed in this review.
[Back to top]
An Increasing Incidence of Treatment
Resistance in Hypertension?
I.K. Eide
According to recent experience there is an unexpected high
prevalence of treatment resistance in hypertension, i.e. an
inefficiency of even complex treatment modalities, increasing
the need for multi-drug regimens. Mostly, this applies to
systolic hypertension which over the years was found to cause
at least as much target organ damage as diastolic. In view
of the high prevalence of hypertension, such resistance may
be a rising concern. This might not only be due to inefficiency
of drugs, but also to low blood pressure levels as treatment
goals and to increasing patient age with more systolic hypertension.
Over the past few years, some new evidence has accumulated
that will contribute to a break-down of the complex of treatment
resistance into several categories of both primary and secondary
hypertension, the most important may be the high frequency
of white-coat hypertension, aldosteronism, low-renin hypertension
and adiposity. In turn, the new evidence may lead to effective
treatment for nearly every patient suffering therapy resistance.
Such efficiency is all the more wanted since blood pressures
in these patients are often severe and fraught with serious
complications.
[Back to top]
Use of Topiceuticals (Topically Applied,
Peripherally Acting Drugs) in the Treatment of Chronic Pain
B.S. Galer and A.R. Gammaitoni
Due to partial efficacy and adverse-event burdens, limited
success has been achieved in the treatment of many chronic
pain conditions with traditional, systemically administered
analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs),
COX-2 inhibitors, opioids, antidepressants, and anticonvulsants.
Additionally, it is not uncommon for patients suffering from
chronic pain to have complex medication regimens to treat
their pain and other medical conditions and yet still experience
both their pain and bothersome medication adverse events.
An alternative to systemic analgesics for the treatment of
chronic pain is the use of analgesics applied directly to
the site of pain on the skin, ie, topically, that possess
a peripheral mechanism of action. Apparent clinical advantages
of topical drug delivery include significant reduction of
systemic adverse events secondary to extremely low systemic
exposure to medication, minimized risk of drug interactions,
and elimination of what can often be a lengthy dose titration
period. Over the past decade, further knowledge of the anatomy
and neurochemistry of peripheral nociceptors has identified
a number of viable targets for topically applied analgesics
(topiceuticals). Moreover, studies in both inflammatory nociceptor
and neuropathic pain models have clearly demonstrated pain
behaviors can be significantly reduced by blocking or dampening
pain generation in the periphery. We provide here some background
on the physiology and pathophysiology of peripheral nociceptive
afferents and the mechanisms of action of various topical
analgesics. Over the past decade, there has been a significant
increase in the use of topiceutical analgesic drugs worldwide
and a growing body of evidence for their efficacy, safety,
and tolerability. A review of the clinical data on the treatment
of chronic pain with topical analgesics is also presented.
[Back to top]
Topical Anesthetics for Procedural
Pain in Children: What Does the Future Hold?
W.T. Zempsky
Minor procedures are a major source of pain and anxiety for
children. Topical anesthetics are one component of a systematic
approach to procedural pain in children. Topical anesthetics
are underutilized due to inconvenience, slow onset, cost and
inconsistent efficacy. New topical anesthetic systems are
available or under investigation which may reduce the barriers
to topical anesthetic use. These include systems which utilize
technologies such as iontophoresis, ultrasound, lasers, heat
and pressurized delivery. Hopefully, the advent of new topical
anesthetic systems will contribute to a comprehensive effort
to decrease procedural pain in children.
[Back to top]
Multidrug-Resistance (MDR) Proteins
Develops Refractory Epilepsy Phenotype: Clinical and Experimental
Evidences
A. Lazarowski, L. Czornyj, F. Lubieniecki, S.
Vazquez, C. D’Giano, G. Sevlever, A.L. Taratuto, A.
Brusco and E. Girardi
Epilepsy affects approximately 3% of the population.
Majority of epileptic patients may control their crisis with
anticonvulsant drugs, however, 30%-40% became refractory to
pharmacological therapies and could require surgical treatment.
The causes of pharmacological refractoriness are poorly understood.
Multidrug-resistance (MDR) mechanisms observed in cancer,
could be also present in Refractory Epilepsy (RE). The ATP-binding-cassette
(ABC) transporters may develop MDR phenotype preventing anti-epileptic
drugs (AEDs) to reach their parenchyma brain targets. MDR-1
gene encoded P-glycoprotein (P-gp), is constitutively expressed
in excretory tissues, including vascular endothelial cells
(VEC) of the blood-brain-barrier. Here, we describe several
MDR proteins over-expressed in VEC, astrocytes and neurons
from adults and pediatric RE patients. Surgically treated
cases showed brain P-gp over-expression with persistent plasmatic
low levels of AEDs, and/or accelerated 99mTc-MIBI
hepatic-clearance. Experimentally, we observed that a sequential
and progressive seizures-induced P-gp over-expression from
VEC astrocytesneurons
correlated with increasing refractoriness to phenytoin treatment.
Clinically and experimentally, we observed that nimodipine
reverts RE phenotype.
Because P-gp depolarizes potential membrane of P-gp-expressing
tumor-cells, we hypothesized that weaker glutamic stimulation
may totally depolarizes to P-gp-expressing neurons, inducing
persistent low convulsive-threshold and playing a role in
epileptogenesis mechanisms Pharmacological control of ABC-transporters
could avoid the current invasive surgical treatments for Refractory
Epilepsy.
[Back to top]
Update on Anti-TNF-Alpha Treatment
in Rheumatic Diseases
M. Massarotti, A. Ferrara and B. Marasini
The development of inhibitors of Tumor Necrosis
Factor (TNF) α,
a pro-inflammatory cytokine playing a pivotal role in chronic
inflammatory diseases, represents a milestone in the therapy
of several rheumatic diseases. Currently, three TNFα-blocking
drugs are available for clinical use in rheumatic diseases:
infliximab, etanercept and adalimumab. These drugs rapidly
reduce disease activity and probably change the poor outcome
of several chronic rheumatic diseases, by preventing the development
of bone erosions, joint deformity and disability. Although
these drugs have proved to be effective and well tolerated
in the short period, some concerns exist about long-term safety
and efficacy. In fact, the long-term use of inhibitors of
TNFα,
a pivotal cytokine in host defense, might result in the development
of infections and neoplasms, therefore the long-term safety
has to be defined. The most frightening infection to date
is tuberculosis, and guidelines for the screening of patient
candidates to biological treatment has significantly reduced
the risk. Parasitic and viral infections do not contraindicate
biological therapy. Lymphoma has been reported in association
with TNFα
antagonists, but whether or not there is a causal relationship
is still debated.
The use of biological agents in other rheumatic inflammatory
conditions is rapidly increasing, but their cost poses a considerable
financial burden on healthcare systems and a careful economic
evaluation is needed.
[Back to top]
Colloidal and Pharmacological Activity
of Albumin in Clinical Fluid Management: Recent Developments
C.J. Wiedermann
Human albumin is extensively used and investigated in clinical
fluid management. Whether albumin confers sufficient benefit
to justify its cost has been a subject of enduring controversy.
A 2003 systematic review assembled evidence of benefit, but
uncertainty has persisted. Abundant additional data have been
newly reported, and this review provides an update. Major
recent developments include the largest ever single randomized
trial in the field of fluid management as well as the largest
ever meta-analysis of randomized trials in the field. The
randomized trial confirmed the safety of albumin in intensive
care unit patients, while the meta-analysis demonstrated that
albumin administration reduces morbidity in broad populations
of acutely ill hospitalized patients. In liver disease, new
randomized trials have shown that albumin can reduce morbidity
as an adjunct to paracentesis and improve circulatory function
in spontaneous bacterial peritonitis. Large observational
studies have provided evidence of a survival advantage among
cardiac surgery patients receiving albumin rather than artificial
colloids. For extracorporeal circuit priming during cardiopulmonary
bypass, albumin was found in a meta-analysis to maintain platelet
counts and fluid balance more effectively than crystalloid.
Randomized trials in both cardiac and noncardiac surgery indicated
less impairment of coagulation by albumin than hydroxyethyl
starch. Improved oxygenation, augmented loss of excess fluid
and reduced morbidity after albumin supplementation were demonstrated
in a randomized trial of hypoalbuminemic patients. A large-scale
pharmacovigilance study showed serious adverse events in albumin
recipients to be rare. Emerging evidence has further supported
many of the current uses of albumin in fluid management.
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