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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 2, Number 3, September 2007
Contents
Statin-Like Drugs for the Treatment of Brain
Cholesterol Loss in Alzheimer’s Disease Pp.
173-176
Biondi Elisa
[Abstract]
Drug Withdrawals in the United States: A Systematic
Review of the Evidence and Analysis of Trends Pp.
177-185
Amalia M. Issa, Kathryn A. Phillips, Stephanie Van Bebber,
Hima G. Nidamarthy, Karen E. Lasser, Jennifer S. Haas, Brian
K. Alldredge, Robert M. Wachter and David W. Bates
[Abstract]
The Potential of Selected Prostanoid Receptors as
Targets in a New Therapeutic Strategy for Allergy and Immune
Diseases Pp. 186-192
Kenji Kabashima and Yoshiki Tokura
[Abstract]
Human-Based In Vitro Experimental Systems
for the Evaluation of Human Drug Safety Pp. 193-199
Albert P. Li
[Abstract]
QT Prolongation and Safety in the Indian Population
Pp. 200-203
Jayesh Dabhi and Anita Mehta
[Abstract]
Oleamide Derivatives are Prototypical Anti - Metastasis
Drugs that Act by Inhibiting Connexin 26 Pp. 204-211
Hiroshi Nojima, Yusuke Ohba and Yasuyuki Kita
[Abstract]
Safety of Drug Eluting Stents: Current Concerns and
Controversies Pp. 212-219
Shahzad G. Raja and Geoffrey A. Berg
[Abstract]
Zolpidem and Traffic Safety - The Importance of Treatment
Compliance Pp. 220-226
Joris C. Verster, Edmund R. Volkerts, Berend Olivier,
William Johnson and Laura Liddicoat
[Abstract]
Drotrecogin Alfa (Activated) in the Treatment of Severe
Sepsis Pp. 227-231
Jean-Louis Vincent
[Abstract]
Desmopressin 30 Years in Clinical Use: A Safety Review
Pp. 232-238
Johan Vande Walle, Mette Stockner, Ann Raes and Jens P.
Nørgaard
[Abstract]
Abstracts
[Back to top]
Statin-Like Drugs for the Treatment of Brain Cholesterol Loss
in Alzheimer’s Disease
Biondi Elisa
Aging is one of the most significant risk factors for
neurological disorders including Alzheimer’s Disease
(late-onset AD and sporadic AD), the most common form of dementia.
AD is characterized by progressive atrophy and loss of neurons
resulting in cognitive deficits, confusion and dementia, culminating
in childlike helplessness and death. One of the major pathological
hallmarks of the disease are amyloid plaques, composed primarly
of insoluble fibrils of Aβ
peptide: this molecule derives from the processing of the
trans-membrane amyloid precursor protein (APP) by different
secretases and its production is a physiological event, but
the anormal increase in Aβ
levels appears to be toxic both in vitro and in
vivo. Being APP cleavage a membrane event the involvement
of lipids in alterations of this cleavage is assumable. Cholesterol
is the most abundant lipid in cellular membranes and is an
essential component of them, determining the fluidity and
biophysical properties.
In fact, genetic studies of the risk of AD have reported association
with polymorphism in some cholesterol related genes like the
allele ε4
of the apolipoprotein E, cholesterol 24-hydroxylase (CYP46A1),
ATP-binding cassette transporter a1 (ABCA1) and the lipoprotein
receptor-related protein (LRP).
Moreover a recent publication shows a downregulation of Seladin-1
(which catalyze the last step of cholesterol biosynthesis)
in affected neurons in Alzheimer’s Disease.
Post-mortem analysis of AD brains reveal a loss in cholesterol
content and this make the therapeutical use of statin-like
drugs quite a lot controversial. Taking together their clinical
trials results and the large body of literature regarding
lipid profile alterations in AD, it is actually unclear how
much these agents can be helpful or not for affected patients.
[Back to top]
Drug Withdrawals in the United States: A Systematic
Review of the Evidence and Analysis of Trends
Amalia M. Issa, Kathryn A. Phillips, Stephanie Van Bebber,
Hima G. Nidamarthy, Karen E. Lasser, Jennifer S. Haas, Brian
K. Alldredge, Robert M. Wachter and David W. Bates
There have been a number of highly publicized safety-based
drug withdrawals in the United States in recent years. We
conducted a review of drugs withdrawn since 1993 and examined
trends in drug withdrawals. Our objective was to determine
the frequency and characteristics of withdrawn drugs and trends
since 1993, and to discuss the implications of the findings.
We found that a mean of 1.5 drugs per year have been withdrawn
since 1993, and that the number of withdrawals has not increased
over time. However, some recent drug withdrawals have impacted
large numbers of people. The rate of withdrawals alone is
not an adequate measure of the status of drug safety in the
US, and there is a serious dearth of data that can be used
to examine the impact of drug withdrawals. Although drug withdrawals
are an important issue to address, drug safety policies need
to be developed within the broader context of drug safety
and effectiveness. A comprehensive approach will be needed
to address the improvement of drug safety. We propose improvements
to the evidence base to increase drug safety and assess how
new scientific evidence can be incorporated into drug safety
efforts.
[Back to top]
The Potential of Selected Prostanoid Receptors as
Targets in a New Therapeutic Strategy for Allergy and Immune
Diseases
Kenji Kabashima and Yoshiki Tokura
Allergy and immune diseases including asthma, atopic dermatitis,
rhinitis, and autoimmune diseases have been treated mainly
with steroid based therapy that has multiple side effects.
Even then, these allergic diseases are sometimes still not
easy to control. Therefore, new effective treatments with
fewer side effects are expected to be developed. Prostanoids
consisting of prostaglandins and thromboxane are cyclooxygenase
metabolites of arachidonic acid. They exert a range of actions
mediated through their respective receptors expressed in target
cells. In the skin, a wide variety of prostanoids and their
receptors are highly expressed under pathophysiological conditions.
However, their roles have not been well clarified. Recent
developments in molecular biology have enabled us to investigate
the physiological roles for each receptor via the
disruption of the respective gene in combination with receptor
selective compounds. It has been demonstrated that each prostanoid
receptor has multiple functions whose expression is regulated
in a context dependent manner, sometimes resulting in opposite,
excitatory and inhibitory, outcomes. The balance of prostanoid
production and receptor expression is important for homeostasis
of the human body. Here, we review new findings on the roles
of prostanoids in allergy and immune diseases, focusing on
skin disorders as a representative, and discuss the clinical
potentials of receptor-selective drugs.
[Back to top]
Human-Based In Vitro Experimental Systems
for the Evaluation of Human Drug Safety
Albert P. Li
Accurate prediction of human drug safety remains a major challenge
for drug development. Species-difference in drug toxicity
represents a main reason for the difficulty in the prediction
of human drug toxicity with nonhuman animal models. A combined
in vitro-in vivo strategy (IVIVS), using human-based
in vitro experimental systems to derive human-specific
information, and animal systems for in vivo variables,
may lead to a more accurate prediction of human in vivo
drug toxicity. The success of IVIVS requires in vitro
models with human-specific drug metabolism, appropriate target
cell populations, and relevant endpoints. A novel theory,
the Target Cell Initiation Theory for drug-induced organ failure
(TACIT), is proposed to support the IVIVS. Based on TACIT,
toxicity that requires chronic administration and multiple
secondary changes may be defined by the evaluation of changes
in target cells that initiate the cascade of secondary events.
A novel in vitro experimental system, the Integrated
Discrete Multiple Organ Co-culture (IdMOC) system, which allows
the evaluation of multiple organ toxicity under conditions
allowing multiple organ interactions, is described as a promising
technology.
[Back to top]
QT Prolongation and Safety in the Indian Population
Jayesh Dabhi and Anita Mehta
The QT interval in electrocardiogram (ECG) reflects the total
duration of ventricular myocardial depolarization and repolarization.
It has been well recognized that many condition may cause
QT interval prolongation. Unfortunately, numbers of cardiac
and non-cardiac drug prolong the QT interval and cause a distinctive
polymorphic ventricular tachy-cardia termed torsade de pointes
(TdP). TdP can degenerate into ventricular fibrillation, which
leads to sudden cardiac death. Recently various regulatory
and clinical bodies of Europe, USA, Canada and Australia have
made their focus on the drugs that induce prolongation of
QT interval. Committee for Proprietary Medicinal Products
(CPMP) of the European Agency issued a document entitled ‘Points
to Consider: The assessment of the potential for QT interval
prolongation by non-cardiovascular medicinal products’
[1, 2]. In addition, USFDA adopted the guideline ‘Clinical
evaluation of QT/QTc interval prolongation and proarrhythmic
potential for non-anti arrhythmic drugs’ [3]. These
documents and guidelines are primarily concern with development
of novel agents and the new use or new dose of already approved
drugs. The scope of this guideline is to study the effect
of drugs on QT prolongation and give idea of evaluation of
drug’s effects on QT prolongation. Today more than 50
available drugs (both old and new) have been identify, which
prolong the QT interval [1]. Several drugs have been withdrawn
from many countries on this basis but many of these drugs
are still available in Indian market and potentially creating
life-threatening arrhythmias. This article will focus on recommendation
of study on the normal limits of QT interval in Indian population
and preparation of the database, which can be helpful in withdrawal
of drugs from the market that produces QT prolongation.
[Back to top]
Oleamide Derivatives are Prototypical Anti - Metastasis
Drugs that Act by Inhibiting Connexin 26
Hiroshi Nojima, Yusuke Ohba and Yasuyuki Kita
Despite considerable research, metastasis remains a major
challenge in the clinical management of cancer. Recent reports
show that abnormally augmented expression of Cx26 is responsible
for the enhanced spontaneous metastasis of mouse BL6 melanoma
cells. The function of Cx26 appears to be responsible for
this phenotype since exogenous expression of a dominant-negative
form of Cx26 and oleamide derivatives called MI-18 and MI-22
that specifically inhibit Cx26-mediated gap junction-mediated
intercellular communications (GJIC) prevent the spontaneous
metastasis of BL6 cells. As expected from their structural
similarity to oleic acid (the major component of olive oil),
both MI-18 and MI-22 are safe drugs; nonetheless, they are
potent inhibitors of the spontaneous metastasis of BL6 mouse
melanoma cells. Thus, they are a novel prototype of an anti-metastasis
drug that has minimal side effects. While the primary tumors
do not necessarily show strong Cx26-immunostaining signals,
pronounced Cx26 expression is detected in the highly invasive
tumor regions; it is also more frequently observed in metastasized
tumors. Thus, Cx26 expression may be useful as a prognostic
tool that can predict the existence of highly metastatic cancer
cells in clinical samples.
[Back to top]
Safety of Drug Eluting Stents: Current Concerns and
Controversies
Shahzad G. Raja and Geoffrey A. Berg
Coronary artery stenting is currently the most frequently
performed percutaneous coronary intervention for the treatment
of coronary artery disease. Recently, drug- eluting stents,
loaded with anti-inflammatory, anti-migratory, anti-proliferative
or pro-healing drugs, have revolutionized the management of
coronary artery disease by markedly reducing instent restenosis.
Despite the excellent short- and mid-term results of randomized
controlled trials observed with drug-eluting stents, there
remain a number of unresolved issues and valid concerns about
long-term safety and efficacy of this revolutionary technology.
Important safety issues such as thrombosis, late stent malapposition,
aneurysm formation, edge effect, late inflammation due to
choice of polymer used to bind the drug, the release of toxins,
and potential interactions with brachytherapy and drugs have
not been completely addressed. This review article evaluates
current available scientific evidence on the various safety
issues related to the use of drug-eluting stents.
[Back to top]
Zolpidem and Traffic Safety - The Importance of Treatment
Compliance
Joris C. Verster, Edmund R. Volkerts, Berend Olivier,
William Johnson and Laura Liddicoat
Zolpidem is among the most frequently prescribed hypnotic
drugs for those who suffer from insomnia. Recent media reports
drew attention to driving impairment after zolpidem misuse.
This review summarizes the available data on the effects of
recommended use and misuse of zolpidem on driving ability
and traffic safety. Both experimental studies and roadside
evidence were taken into account. From these studies it must
be concluded that patients should fully comply with the prescription
instructions of zolpidem, i.e. to take the medication just
prior to a full 8 hours of uninterrupted sleep. If this strategy
is adopted, zolpidem is a safe alternative to benzodiazpine
hypnotics and zopiclone who do show significant driving impairment
the morning following bedtime administration. However, to
ensure traffic safety higher dosages than recommended (10
mg) or allowing less than 8 hours between zolpidem intake
and actual operation of a motor vehicle should be avoided.
[Back to top]
Drotrecogin Alfa (Activated) in the Treatment of Severe
Sepsis
Jean-Louis Vincent
Severe sepsis and septic shock are common in the critically
ill patient and account for considerable morbidity and mortality
not to mention the high associated costs. Advances in our
understanding of sepsis pathophysiology and in the important
link between the inflammatory response to sepsis and activation
of coagulation led to the development and licensing of the
first ever, specific, immunomodulatory anti-sepsis drug. Drotrecogin
alfa (activated), a recombinant version of activated protein
C, was shown in a large randomized controlled clinical trial
to reduce mortality rates from 30.8% in the placebo group
to 24.7% in the treatment group, which equated to one additional
life saved for every 16 patients treated. Vasopressor requirements
and duration of mechanical ventilation were also reduced.
Apart from an expected increased risk of severe bleeding,
mostly associated with interventions, drotrecogin alfa (activated)
was not associated with any other adverse reactions. In this
article, I will briefly summarize the events leading to the
development of drotrecogin alfa (activated) including aspects
of sepsis epidemiology and pathophysiology and the results
of early animal and clinical studies. The results of the large
multicenter phase III PROWESS study will then be reviewed,
along with results from subsequent open-label studies. Finally,
I will focus on the key side effect issue with drotrecogin
alfa (activated), that of increased bleeding, drawing data
from the available clinical studies, and highlighting the
contraindications and precautions when prescribing this drug.
[Back to top]
Desmopressin 30 Years in Clinical Use: A Safety Review
Johan Vande Walle, Mette Stockner, Ann Raes and Jens P.
Nørgaard
Desmopressin acetate is the synthetic analogue of the
antidiuretic hormone arginine vasopressin. It has been employed
clinically for >30 years in a range of formulations: intranasal
solution (since 1972), injectable solution (since 1981), tablets
(since 1987), and most recently, an oral lyophilisate (since
2005). The antidiuretic properties of desmopressin have led
to its use in polyuric conditions including primary nocturnal
enuresis, nocturia, and diabetes insipidus. While a large
body of clinical data is available for desmopressin, and despite
its widespread use, comprehensive reviews of the safety of
desmopressin are lacking (although some case series have attempted
to correlate patient and/or dosing characteristics with the
occurrence of adverse reactions). The purpose of this paper
is to review the safety of desmopressin, based on analyses
of both published data (MedLine) and of adverse reactions
reported to Ferring Pharmaceuticals, the major manufacturer
of desmopressin. Based on the findings, suggested strategies
to reduce the risk of adverse reactions are proposed. Treatment
with intranasal and oral formulations of desmopressin is generally
well tolerated, and side effects are usually minor. The risk
of hyponatraemia, although small, can be reduced by adhering
to the indications, dosing recommendations and precautions
when prescribing desmopressin.
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