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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 1, Number 3, August 2006
Contents
NSAID Use and the Risk of Parkinson’s Disease
Pp. 223-225
Mahyar Etminan and Samy Suissa
[Abstract]
The Role of Atypical Antipsychotic Agents in the
Treatment of Schizophrenia and Schizoaffective Disorders in
the Elderly Pp. 227-241
Subramoniam Madhusoodanan, Abhishek Sinha, Martha Sajatovic,
Sanjay Gupta and Ronald Brenner
[Abstract]
Rapid Desensitization of Hypersensitivity Reactions
to Chemotherapy Agents Pp. 243-251
Mariana Castells
[Abstract]
Safety Profile of Plasmid/Liposomes and Virus
Vectors in Clinical Gene Therapy Pp. 253-257
Thomas Wirth, Marja Hedman, Kimmo Mäkinen, Hannu
Manninen, Arto Immonen, Matti Vapalahti and Seppo Ylä-Herttuala
[Abstract]
Adverse Dermatological Reactions in Rheumatoid
Arthritis Patients Treated with Etanercept, an Anti-TNFα
Drug Pp. 259-264
Shyra Rajakulendran and Chris Deighton
[Abstract]
Ciclesonide: A Closer Look at its Systemic and
Oropharyngeal Safety Profile Pp. 265-270
William E. Berger
[Abstract]
The Possible Adverse Effects of Intramuscular
Botulinum Toxin Injections and their Management Pp.
271-279
A. Magid O. Bakheit
[Abstract]
Oral Antiplatelet Agents and Bleeding Risk in
Relation to Major Cardiovascular Surgery Pp. 281-287
James McCaslin, Jonathan Smout, Patrick Kesteven and Gerard
Stansby
[Abstract]
Antiepileptic Drug-Induced Hypersensitivity Syndrome
Reactions Pp. 289-299
Norberto Krivoy, Masud Taer and Manuela G. Neuman
[Abstract]
Drug-Induced Hair Disorders Pp. 301-305
Bianca Maria Piraccini, Matilde Iorizzo, Giulia Rech and
Antonella Tosti
[Abstract]
Evaluating Drug Safety in Children and Adolescents
with Bipolar Disorder Pp. 307-318
Pamela C. Heaton, Colleen M. Garlick and Doan Tran
[Abstract]
Abstracts
[Back to top]
NSAID Use and the Risk of Parkinson’s Disease
Mahyar Etminan and Samy Suissa
Parkinson’s disease (PD) is a neurodegenerative
disease with limited pharmacologic therapies. Recent animal
studies and one large retrospective study have found NSAIDs
to be protective against the development of PD. We decided
to test this hypothesis by conducting a nested case-control
study using the Saskatchewan drug plan database. Entry to
the cohort was defined as the first prescription of an antihypertensive
agent between 1980 and 1987 and followed until 1999. Cases
were defined as those having received three prescriptions
for a dopamine agonist within a year. For each case, ten controls
were selected matched to the case by age, calendar time and
index date. Conditional logistic regression was used to estimate
rate ratios adjusting for gender, previous use of arthritis
medication and previous antipsychotic use.
Current users of NSAIDs had a slightly higher risk of developing
PD (RR=1.49 [95% CI, 1.11-2.01]). This effect was not seen
with past users (RR=1.18 [95% CI, 0.89-1.59]). Based on the
results of our study current users of NSAIDs may be at a slightly
higher risk of developing PD. More studies are needed to confirm
this finding.
[Back to top]
The Role of Atypical Antipsychotic Agents
in the Treatment of Schizophrenia and Schizoaffective Disorders
in the Elderly
Subramoniam Madhusoodanan, Abhishek Sinha, Martha
Sajatovic, Sanjay Gupta and Ronald Brenner
Schizophrenia and schizoaffective disorder are prevalent
in 1% of the adult population. The condition was thought to
predominantly affect the young however recent studies have
shown that the condition occurs in individuals throughout
the life-span. The aim of this review is to discuss the role
of atypical antipsychotics in treating schizoaffective disorder
and schizophrenia in the elderly. The advent of atypical antipsychotics
has made significant strides in the pharmacotherapy of schizophrenia
in the elderly. They are as efficacious as conventional agents
in reducing the positive symptoms, possibly some what more
efficacious in reducing negative symptoms and appear to have
a relatively safer adverse effect profile. However metabolic
side affects particularly glucose abnormalities and weight
gain, cerebrovascular effects, and mortality risk noted in
dementia patients are gaining increasing attention. Appropriate
monitoring for the metabolic side effects has been recommended
by agencies such as the FDA (United States Food and Drug Administration),
ADA (American Diabetic Association) and APA (American Psychiatric
Association). Treatment of elderly patients is complicated
by age related biological factors affecting drug response
and presence of comorbid medical conditions and concomitant
medication. Current research supports the role of atypical
antipsychotics in the treatment of schizophrenia and schizoaffective
disorder in the elderly. Despite advantages compared with
conventional agents, challenges to successful therapy remain,
even with these better tolerated agents.
[Back to top]
Rapid Desensitization of Hypersensitivity
Reactions to Chemotherapy Agents
Mariana Castells
All chemotherapy agents can cause hypersensitivity reactions,
which have limited the used of critical drugs in very sick
patients for fear of inducing a more severe reaction and possibly
death. The choice of an alternative chemotherapy regimen is
often limited by tumor sensitivity and, because of the increasing
number of cancer survivors, exposure to multiple courses of
the same or similar chemotherapy agents. Increased exposures
lead to sensitization and to hypersensitivity reactions in
an increasing patient population. The need to offer first
line therapy after cancer recurrence has spurred the clinical
development of rapid desensitizations, which allow patients
to be treated with medications to which they have presented
hypersensitivity reactions. Desensitization protocols are
available to treat hypersensitivity reactions to most chemotherapy
agents including taxenes, platinums, doxorubicin, monoclonal
antibodies and others, by gradual re-introduction of small
amounts of drug antigens up to full therapeutic doses. Candidate
patients include those who present mild to severe type I hypersensitivity,
mast cell/IgE dependent, reactions during the chemotherapy
infusion or shortly after. Symptoms include pruritus, flushing,
urticaria, angioedema, respiratory and gastrointestinal distress,
changes in blood pressure including hypotension, and shock
with anaphylaxis. Associated musculoskeletal symptoms and
pain can be present in patients reacting to taxenes as in
anaphylactoid reactions, in which mast cell/IgE mechanisms
cannot be demonstrated. There is now strong evidence that
anaphylactoid reactions are amendable to treatment with the
same rapid desensitization protocols as for type I hypersensitivity
reactions. Initial rapid desensitizations should only be performed
in settings with one on one nurse-patient care and where resuscitation
personnel and resources are readily available. Temporary tolerization
is achieved in a few hours. After the first desensitization,
standard protocols are available for safe, repeated desensitizations
in outpatient settings with similar conditions, which not
only provides flexibility, but allows patients to remain in
clinical studies. Breakthrough symptoms are less severe than
the initial hypersensitivity reaction in all series reviewed,
and deaths have not been reported. The aim of this review
is to familiarize the medical community with the type of hypersensitivity
reactions amendable to rapid desensitization and to review
protocols for chemotherapy desensitization that can be used
for most chemotherapy agents. Few studies have measured the
cancer response to the chemotherapy agents delivered through
rapid desensitizations. One patient population in which 26
patients were desensitized to carboplatin and 16 to paclitaxel
had similar rates of remission as for non-desensitized patients.
Education of nurses, pharmacists, oncology and allergy specialists
will lead to the universal use of rapid desensitization protocols
for all cancer patients with hypersensitivity reactions to
chemotherapy agents. Basic research is needed to uncover the
cellular and molecular mechanisms underlying the temporary
tolerization induced by rapid desensitization, so that pharmacological
interventions can improve its safety and efficacy.
[Back to top]
Safety Profile of Plasmid/Liposomes and Virus
Vectors in Clinical Gene Therapy
Thomas Wirth, Marja Hedman, Kimmo Mäkinen, Hannu
Manninen, Arto Immonen, Matti Vapalahti and Seppo Ylä-Herttuala
Despite of more than 500 gene therapy trials worldwide very
little systematic safety information is available from gene
therapy. Safety information was collected from 146 consecutive
patients who participated in three randomized, controlled
phase II gene therapy trials in cardiovascular diseases and
malignant glioma using adenoviruses, plasmid/liposomes and
retrovirus packaging cells. Total follow-up time of the patients
was 78794 days which equals 1.5 years per patient.
The main outcome measures were serious adverse events, other
adverse events and changes in general laboratory parameters.
Except fever and increases in CRP values plasmid/liposomes
were safe and well tolerated. The incidence of serious adverse
events in adenovirus-treated patients was 0.9 and 4.0/10000
patient days in cardiovascular and malignant glioma trials
as compared to 0.5 and 2.1 in randomized control patients,
respectively. Transient fever, leukopenia and increases in
CRP and liver enzymes were detected in virus-treated patients.
No deaths from side effects or no new cancers were associated
with gene therapy.
It is concluded that gene therapy, like any other therapy,
is associated with side effects which depend on the administered
vector, dose, and route of delivery and properties of the
transgene. However, given the limitations of this study and
length of the follow-up, the safety profile of gene therapy
seems to be acceptable for the treatment of severe human diseases.
[Back to top]
Adverse Dermatological Reactions in Rheumatoid
Arthritis Patients Treated with Etanercept, an Anti-TNFαDrug
Shyra Rajakulendran and Chris Deighton
Etanercept is an anti-TNF drug with marked efficacy in
inflammatory arthritis. This review addresses dermatological
side effects that have been encountered in our 85 patients
on the drug for rheumatoid arthritis, and reviews other reported
cutaneous adverse events. Injection site reactions are common
and usually self-limiting. We and others have encountered
patients with recall site reactions where the four rotated
injection sites simultaneously develop a hypersensitivity
reaction. In all cases, the rash has responded to antihistamines
and the etanercept was thereby continued. Other injection
site reactions include discoid lupus and cutaneous vasculitis
that respond to cessation of treatment and appropriate therapy.
Skin reactions more distant from the injection site are also
reviewed, with erythema nodosum, widespread lupus rashes,
infections and skin tumours summarised. A patient who developed
a purpuric rash at the site of last injection with a drug
induced worsening of thrombocytopaenia is described. Although
the therapeutic advantages of etanercept outweigh the side
effects, clinicians need to be aware of the adverse reactions
of these drugs with their increasing use.
[Back to top]
Ciclesonide: A Closer Look at its Systemic
and Oropharyngeal Safety Profile
William E. Berger
Inhaled corticosteroids (ICS) are recommended first-line
therapy for patients with asthma of all severities. Prolonged
exposure to high-dose ICS can cause systemic and oropharyngeal
adverse events. Minimizing ICS-related adverse events by selecting
an ICS with an improved safety profile may increase patients’
adherence to their asthma treatment. Ciclesonide, a novel
ICS currently under development, is a parent compound that
is converted in the lungs by endogenous esterases to its active
metabolite, desisobutyryl-ciclesonide. Reported data suggest
that ciclesonide is well tolerated, with no observed effect
on hypothalamic-pituitary-adrenal (HPA)-axis function and
a low incidence of oropharyngeal adverse events (comparable
with placebo). These safety benefits, observed in children
and adults with asthma, may be due to ciclesonide’s
favorable pharmacokinetic/pharmacodynamic properties. The
lack of HPA-axis function suppression may be due to the low
oral bioavailability, high serum protein binding and rapid
apparent systemic clearance reported with desisobutyryl-ciclesonide.
The low incidence of oropharyngeal adverse events may be attributed
to the low oral deposition of ciclesonide in the oropharynx
and its limited conversion to desisobutyryl-ciclesonide. The
favorable safety profile of ciclesonide suggests a conferred
benefit to asthma patients treated with this novel ICS.
[Back to top]
The Possible Adverse Effects of Intramuscular
Botulinum Toxin Injections and their Management
A. Magid O. Bakheit
In the last two decades or so the intramuscular administration
of botulinum toxin type A, and more recently type B, has become
an established first line treatment of many neurological and
other medical disorders. So far, the toxin has been used mainly
by experienced researchers and clinicians with extensive knowledge
of its mode of action and potential adverse effects. However,
in the foreseeable future it is likely that this treatment
will be provided by more medical practitioners and in different
clinical settings, especially as the range of its clinical
indications increases.
Botulinum toxin, in therapeutic doses, is a remarkably safe
drug with relatively few adverse effects. The commonest adverse
effects are muscle weakness, fatigue, flu-like symptoms, a
dry mouth, dizziness and a skin rash. Nonetheless, serious
adverse events may occur, albeit rarely, and it is imperative
that prescribers of this treatment are thoroughly familiar
with its potential risks. The purpose of this article is to
review the possible adverse effects of botulinum toxin intramuscular
injections, to describe the factors that might predispose
to them and to summarise the strategies for their prevention
and treatment.
[Back to top]
Oral Antiplatelet Agents and Bleeding Risk
in Relation to Major Cardiovascular Surgery
James McCaslin, Jonathan Smout, Patrick Kesteven and
Gerard Stansby
Introduction: Patients requiring major cardiovascular
surgery are likely to be prescribed antiplatelet agents either
alone or in combination. By virtue of antiplatelet agent effect,
they can potentially increase bleeding complications, especially
if used in combination. This article aims to review the evidence
and make appropriate recommendations regarding these agents.
Aspirin: 16 papers are reviewed which concern surgery
whilst taking aspirin. The bulk of the evidence is from the
coronary bypass setting.
Clopidogrel: 14 papers are reviewed which concern
surgery whilst taking clopidogrel.
Dipyridamole: 2 papers are reviewed concerning dipyridamole.
Cilostazol: No trials are available concerning surgery
and cilostazol. Several relevant publications are reviewed.
Conclusion: It is the recommendation of the authors
that aspirin should usually be continued perioperatively,
whilst clopidogrel should be stopped for seven days prior
to surgery if at all possible.
[Back to top]
Antiepileptic Drug-Induced Hypersensitivity
Syndrome Reactions
Norberto Krivoy, Masud Taer and Manuela G. Neuman
Host dependent idiosyncratic drug reactions, otherwise
known as unpredictable type B reactions, are of a major concern
in clinical practice and drug development. Hypersensitivity
syndrome reactions are idiosyncratic in nature and may be
induced by a variety of agents including antiepileptic drugs
(AEDs). The AEDs hypersensitivity syndrome is a rare but potentially
life-threatening syndrome that occurs after exposure to phenytoin,
carbamazepine or phenobarbital. Phenobarbital, phenytoin and
carbamazepine, have shown cross-reactivity; while, no evidence
of cross reactivity between other antiepileptic drugs such
as valproic acid, gabapentin or lamotrigine has been observed.
True hypersensitivity reaction is a systemic disease
defined by the triad of fever, skin eruption and multi-organ
involvement that occurs 1-8 weeks after exposure to a
drug . Because most reactions occur within two months of treatment
initiation, it is likely that the true incidence of the syndrome
is underestimated. It was hypothesized that reactive metabolite/s
(RM) rather than the parent drug, is/are responsible for initiating
the sequence of toxic and immunological events that culminate
clinically in a drug hypersensitivity syndrome reaction. Cells
that possess surface antigens for which T cells have specific
receptors then present this antigen. Exanthemas are related
to delayed T- cell hypersensitivity so it has been hypothesized
that memory T cells might subsequently increase in number
in the most severely affected cutaneous sites. To manage hypersensitivity
syndrome successfully, the symptoms must recognized early,
the use of the offending drug must be terminated immediately,
and alternative antiepileptic medication should be prescribed.
Currently, the diagnosis of AEDs-induced hypersensitivity
syndromes is based on clinical grounds and on in vitro
testing. In the field of pharmacogenetics, we bare witness
to how effectively the combination of effective screening
methods and understanding of the role of genetic polymorphisms
play in the metabolic pathways of AEDs facilitating new therapies
that allow scientists and physicians to better diagnose and
treat patients.
[Back to top]
Drug-Induced Hair Disorders
Bianca Maria Piraccini, Matilde Iorizzo, Giulia Rech and
Antonella Tosti
Drugs may induce hair loss, stimulate hair growth or,
more rarely, induce changes in the hair shape and colour.
Drug-induced hair loss is usually completely reversible and
is, in most cases, a consequence of a toxic effect of the
drug on the hair follicle matrix. In rare cases alopecia may
be permanent.
Depending on type of drug, dosage and patient susceptibility,
hair loss presents as telogen effluvium, anagen effluvium
or both. Telogen effluvium is also commonly observed after
discontinuation of drugs that prolong anagen, such as topical
minoxidil and oral contraceptives.
Although a large number of drugs have been occasionally reported
to produce hair loss, only for a few drugs the relation between
drug intake and hair loss has been proven.
[Back to top]
Evaluating Drug Safety in Children and Adolescents
with Bipolar Disorder
Pamela C. Heaton, Colleen M. Garlick and Doan Tran
The safety of the use of medications in adolescents and
children to treat bipolar disorder has not been extensively
studied. The prevalence of bipolar disorder in children and
adolescents is unknown due to the lack of completed large-scale
epidemiological studies. In addition, the diagnosis of this
disorder is still questionable in this age group because the
same explicit diagnostic criteria used in adults potentially
cannot be applied to children and adolescents since the early-onset
symptoms often overlap with other disorders such as attention-deficit
disorder. The safety of drugs used to treat bipolar disorder
is of growing concern, particularly because this population
usually requires more than one psychotropic medication to
manage the disease. Common side effects seen with several
agents, particularly antipsychotics, are somnolence, weight
gain, extrapyramidal symptoms, dyslipidemia, type-2 diabetes,
and hyperprolactinemia. This review will discuss the most
advanced practice guidelines in assessing and treating bipolar
disorder in children and adolescents, the safety and effectiveness
of the drugs currently used based on clinical trials and post-marketing
surveillance, and the risks versus benefits associated with
their use.
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