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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 1, Number 1, January 2006
Contents
Antimalarial Drugs in Pregnancy: A Reviews Pp.1-15
François Nosten, Rose McGready, Umberto d’Alessandro,
Ana Bonell, Francine Verhoeff, Clara Menendez, Thenonest Mutabingwa
& Bernard Brabin
[Abstract] [Full
Text Article]
Safety of Selective Serotonin Reuptake Inhibitors
in Pregnancy Pp.17-24
Carlos De las Cuevas & Emilio J. Sanz
[Abstract] [Full
Text Article]
The Safety of Medications for the Treatment of
Bipolar Disorder During Pregnancy and the Puerperium Pp.25-33
Seetal Dodd & Michael Berk
[Abstract] [Full
Text Article]
The Role of Growth Factors in the Prevention and
Treatment of Chemotherapy-Induced Peripheral Neurotoxicity
Pp.35-42
Guido Cavaletti & Paola Marmiroli
[Abstract] [Full
Text Article]
Headache: One of the Most Common and Troublesome
Adverse Reactions to Drugs Pp.43-58
Anna Ferrari
[Abstract] [Full
Text Article]
SSRIs, Suicide and Violent Behavior: Is there
a Need for a Better Definition of the Depressive State? Pp.59-62
Chantal Henry & Jacques Demotes-Mainard
[Abstract] [Full
Text Article]
Hypnotics and Driving Safety: Meta-Analyses of
Randomized Controlled Trials Applying the on-the-Road Driving
Test Pp.63-71
Joris C. Verster, Dieuwke S. Veldhuijzen, Alain Patat,
Berend Olivier & Edmund R. Volkerts
[Abstract] [Full
Text Article]
Tolerability of Amine Uptake Inhibitors in Urologic
Diseases Pp.73-85
Martin C. Michel, Henricus G. Ruhe, Annemieke A. de Groot,
Ramiro Castro & Matthias Oelke
[Abstract] [Full
Text Article]
Role of Vitamin K2 in the Treatment
of Postmenopausal Osteoporosis Pp.87-97
Jun Iwamoto, Tsuyoshi Takeda & Yoshihiro Sato
[Abstract] [Full
Text Article]
The Clinical Development of γ-Hydroxybutyrate
(GHB) Pp.99-106
Gregory P. Wedin, Carl S. Hornfeldt & Lisa M. Ylitalo
[Abstract] [Full
Text Article]
Host Pharmacogenetics in the Treatment of HIV
and Cancer Pp.107-116
Alan Winston, Eleftheria Hatzimichael, Vanessa Marvin,
Justin Stebbing & Mark Bower
[Abstract] [Full
Text Article]
How Vaccine Safety can Become Political –
The Example of Polio in Nigeria Pp.117-119
Christopher J. Clements, Paul Greenough & Diana Shull
[Abstract] [Full
Text Article]
Informing People about the Risks and Benefits
of Medicines: Implications for the Safe and Effective Use
of Medicinal Products Pp.121-126
Dianne C. Berry
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Antimalarial Drugs in Pregnancy: A Reviews
François Nosten, Rose McGready, Umberto d’Alessandro,
Ana Bonell, Francine Verhoeff, Clara Menendez, Thenonest Mutabingwa
& Bernard Brabin
[Full Text Article]
In this review we examine the available information on the
safety of antimalarials in pregnancy, from both animal and
human studies. The antimalarials that can be used in pregnancy
include (1) chloroquine, (2) amodiaquine, (3) quinine, (4)
azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine,
(7) dapsone-chlorproguanil, (8) artemisinin derivatives, (9)
atovaquone-proguanil and (10) lumefantrine. Antimalarial drugs
that should not be used in pregnancy including (1) halofantrine,
(2) tetracycline/doxycycline, and (3) primaquine. There are
few studies in humans on the pharmacokinetics, safety and
efficacy of antimalarials in pregnancy. This is because pregnant
women are systematically excluded from clinical trials. The
absence of adequate safety data, especially in the first trimester,
is an important obstacle to developing treatment strategies.
The pharmacokinetics of most antimalarial drugs are also modified
in pregnancy and dosages will need to be adapted. Other factors,
including HIV status, drug interactions with antiretrovirals,
the influence of haematinics and host genetic polymorphisms
may influence safety and efficacy. For these reasons there
is an urgent need to assess the safety and efficacy of antimalarial
treatments in pregnancy, including artemisinin based combination
therapies.
[Back to top]
Safety of Selective Serotonin Reuptake Inhibitors
in Pregnancy
Carlos De las Cuevas & Emilio J. Sanz
[Full Text Article]
Psychiatric treatment with selective serotonin reuptake inhibitors
(SSRIs) may be desirable or necessary during pregnancy; however,
the benefit of these treatments must balance the benefits
to the mother with any risk to the developing foetus. At the
present time, the role of serotonin in normal central nervous
system development, as well as the effects of altering serotonin
transmission at critical periods of embryo development, remains
to be further clarified.
Depression has a high prevalence in pregnant women (around
10%) and approximately one-half of the pregnancies are unplanned,
making necessary that physicians have to know the risks associated
with the decision to use this kind of antidepressants during
pregnancy.
The effects of antidepressants in pregnancy could be classified
in several main categories: the teratogenic possible effects;
the effects on the normal development of the brain and neuropsychological
functions; the effects on birth weight and/or early delivery;
the risk of increased bleeding on the mother during delivery;
the neuropsychological behaviour and adaptation after delivery,
including not only neonatal withdrawal syndromes but also
pain reactivity and increased parasympathetic cardiac modulation
during recovery after an acute noxious event and in a wide
range of neurobehavioural outcomes; and medium- to long-term
effects in neurocognitive functions in those children.
These areas are reviewed according to the most recent published
cohort-controlled studies and prospective surveys regarding
SSRIs use in pregnancy. The review tries to clarify the blurred
aspects of the use of SSRI during pregnancy and to give sensible
and up-to-dated guidelines for the treatment of psychiatric
disorders with SSRI during pregnancy.
[Back to top]
The Safety of Medications for the Treatment of Bipolar
Disorder During Pregnancy and the Puerperium
Seetal Dodd & Michael Berk
[Full Text Article]
Risks associated with pharmacological treatment of bipolar
disorder are heightened during reproductive events. Treatments
need to be planned with the mutual agreement of both the treating
physician and the patient and tailored to the needs of the
individual so as to minimise risk while providing adequate
treatment. Conventional treatments have all been associated
with teratogeny in first trimester exposure, lithium with
cardiac malformation and valproate and carbamazepine with
neural tube malformations. There have been an insufficient
number of first trimester exposures to the newer anticonvulsant
mood stabilisers, lamotrigine and oxcarbazepine, to determine
whether there is a safety advantage in switching to these
agents. Increasingly, atypical antipsychotics are being suggested
as useful agents for the treatment of bipolar disorder. While
not known to be teratogenic, there are other reproductive
safety concerns associated with these agents. Bipolar disorder
patients may be prescribed antidepressants, and many of these
agents are associated with a low safety risk during reproductive
events, however data regarding use of these agents are currently
equivocal. Adverse outcomes from inadequate pharmacological
prophylaxis have been documented for both the mother and the
baby. Risks and benefits need to be carefully balanced based
on an accurate review of the evidence.
[Back to top]
The Role of Growth Factors in the Prevention and Treatment
of Chemotherapy-Induced Peripheral Neurotoxicity
Guido Cavaletti & Paola Marmiroli
[Full Text Article]
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a
major clinical problem since it is the dose-limiting side
effect of a significant number of antineoplastic drugs. The
incidence of CIPN varies depending on the conditions, but
severe neuropathy can occur in up to 40% of patients undergoing
a polichemotherapy regimen.
Moreover, even when CIPN is not a dose-limiting side effect,
its onset may severely affect the quality of life of cancer
patients and cause chronic discomfort. Currently, no treatment
is available which can significantly improve the clinical
signs and symptoms of CIPN. In recent years, new agents have
been proposed as neuroprotectants, and some of them have been
more specifically studied for CIPN. So far, the most interesting
results for future applications have been obtained in the
pre-clinical studies involving cytokines and growth factors.
For several of these drugs, in fact, sound hypotheses have
been formulated to support the idea of a protective role on
selected neuronal targets. However, this theoretical basis
has frequently failed to lead to consistent results in pre-clinical
and clinical applications. We will review the state-of-the-art
of CIPN treatment with growth factors and focus on the future
prospects opened up by the most recent pre-clinical and clinical
studies.
[Back to top]
Headache: One of the Most Common and Troublesome Adverse
Reactions to Drugs
Anna Ferrari
[Full Text Article]
It is difficult to attribute the diagnosis of adverse drug
reaction to a condition which is also a common symptom. The
decision might be arduous in the case of headache, because
this disorder is very frequent in the general population.
The drugs that more frequently induce headache belong to a
variety of therapeutic classes with different mechanisms of
action and different toxicity. In the majority of cases the
headache has not a typical feature, it is dosedependent, and
is associated to other symptoms of neurotoxicity. Some drugs
cause, instead, a specific headache: this is the case of NO
donors, which are also used in experimental studies in order
to induce headache.
This review describes the classes of drugs which induce
headache, analyzes the frequency of headache induction among
the drugs of the same class, and discusses the possible mechanisms
underlying headache induction. It is to be hoped that a better
awareness of this issue would help the physician to consider
it in the differential diagnosis of a recent-onset or changed
headache and to avoid prescription of drugs known to cause
headache to patients already suffering from this disorder.
[Back to top]
SSRIs, Suicide and Violent Behavior: Is there a Need
for a Better Definition of the Depressive State?
Chantal Henry & Jacques Demotes-Mainard
[Full Text Article]
To what extent do SSRIs increase the risk of suicide or violent
behavior? Recent data indicate that some SSRIs lack a favorable
'risk–benefit' profile for treating childhood and adolescent
depression. In addition, certain recent documents have cast
doubt on previous conclusions dissociating antidepressant
from violence.
Beyond the debate on the need for improved transparency
in clinical studies, this controversy raises other critical
issues of SSRI use that merit our consideration.
Firstly, is there an overuse of antidepressants, and does
the risk of suicide increase with the prescription of antidepressants
in the whole population? Secondly, is the response to antidepressants
modified during adolescence? If so, by what mechanisms? We
know that SSRI treatment can trigger mood changes in undiagnosed
young bipolar patients resulting in agitation and disinhibition,
and such effects may lead to suicide and violence.
Thirdly, recent extensive literature has shown that some
cases of depression are worsened by antidepressants and new
data has suggested that bipolar depression can be improved
by atypical antipsychotics. Finally, current criteria defining
the depressive state are very similar to those employed during
the 19th century, a pre-therapeutic period. Currently,
while it is recognised that depressive mood is a very broad
construct, there is still only one definition in international
classifications to describe a major depressive episode. There
is a clear need to develop an evidence-based approach to psychiatry
aiming at delineating diagnostic categories predictive of
the response to treatments.
[Back to top]
Hypnotics and Driving Safety: Meta-Analyses of Randomized
Controlled Trials Applying the on-the-Road Driving Test
Joris C. Verster, Dieuwke S. Veldhuijzen, Alain
Patat, Berend Olivier & Edmund R. Volkerts
[Full Text Article]
Background: Many people who use hypnotics are outpatients
and are likely to drive a car the day after drug intake. The
purpose of these meta-analyses was to determine whether or
not this is safe.
Methods: Placebo-controlled, randomized, double-blind
trials were selected if using the on-the-road driving test
to determine driving ability the day following one or two
nights of treatment administration. Primary outcome measure
of the driving test was the Standard Deviation of Lateral
Position (SDLP); i.e., the weaving of the car. Fixed effects
model meta-analyses were performed. Effect size (ES) was computed
using mean standardized (weighted) difference scores between
treatment and corresponding placebo SDLP values.
Results: Ten studies, published from 1984 to 2002
(207 subjects) were included in the meta-analyses. The morning
following bedtime administration, i.e. 10-11 hours after dosing,
significant driving impairment was found for the recommended
dose of various benzodiazepine hypnotics (ES=0.42; 95% Confidence
Interval (CI)=0.14 to 0.71). Twice the recommended dose impaired
driving both in the morning (ES=0.68;CI=0.39 to 0.97) and
afternoon, i.e. 16-17 hours after dosing (ES=0.57, CI=0.26
to 0.88). Zopiclone 7.5 mg also impaired driving in the morning
(ES=0.89;CI=0.54 to 1.23). Zaleplon (10 and 20 mg) and zolpidem
(10 mg) did not affect driving performance the morning after
dosing. Following middle-of-the-night administration, significantly
impaired driving performance was found for zopiclone 7.5 mg
(ES=1.51, CI=0.85 to 2.17), zolpidem 10 mg (ES=0.66, CI=0.13
to 1.19) and zolpidem 20 mg (ES=1.16, CI=0.60 to 1.72). Zaleplon
(10 and 20 mg) did not affect driving performance.
Conclusions: The analyses show that driving a car
the morning following nocturnal treatment with benzodiazepines
and zopiclone is unsafe, whereas the recommended dose of zolpidem
(10 mg) and zaleplon (10 mg) do not affect driving ability.
[Back to top]
Tolerability of Amine Uptake Inhibitors in Urologic
Diseases
Martin C. Michel, Henricus G. Ruhe, Annemieke
A. de Groot, Ramiro Castro & Matthias Oelke
[Full Text Article]
Inhibitors of serotonin (5-HT) and/or noradrenaline (NA)
reuptake have been developed for pharmacological treatment
of major depressive disorder. Insights in the role of 5-HT
and NA in the neurological control of the lower urinary tract
have also lead to their application in common urological conditions
such as stress urinary incontinence (SUI), nocturnal enuresis
and ejaculatory disorders.
The European approval of the 5-HT and NA reuptake inhibitor
(SNRI) duloxetine for treatment of SUI underlines the importance
of a new approach in SUI, but has also given rise to questions
about the safety of antidepressants in urology. This paper
reviews the safety of 5-HT and NA reuptake inhibitors in their
on-and off-label use in urology. A systematic Medline search
was performed for randomised controlled trials, meta-analyses
and practice guidelines dealing with antidepressants in urology.
The safety profiles of the drugs in the urological population
were compared with data from psychiatric populations.
Tricyclic antidepressants are associated with serious cardiovascular
side effects. In addition, anticholinergic and antihistaminic
side effects are common. Although recently questions have
been raised regarding the cardiovascular safety profile of
venlafaxine, most selective 5-HT reuptake inhibitors and SNRI
have not been associated with serious cardiovascular effects.
Their most common side effect is nausea. However, nausea tends
to be mild and, importantly, transient. Patient counselling
about side effects and up-titrating doses may be useful strategies
for minimising discomfort and withdrawals.
[Back to top]
Role of Vitamin K2 in the Treatment
of Postmenopausal Osteoporosis
Jun Iwamoto, Tsuyoshi Takeda & Yoshihiro
Sato
[Full Text Article]
Vitamin K2, raloxifene, and bisphosphonates,
such as etidronate, alendronate, and risedronate, are widely
used in the treatment of postmenopausal osteoporosis in Japan.
A meta-analysis study has demonstrated the efficacy of anti-resorptive
agents: raloxifene and etidronate have been shown to reduce
the incidence of vertebral fractures, and alendronate and
risedronate have been shown to reduce the incidence of both
vertebral and hip fractures. Furthermore, a report of the
World Health Organization (WHO) has provided evidence from
a randomized controlled trial suggesting that vitamin K2,
which may stimulate bone formation via γ-carboxylation
of osteocalcin and/or steroid and xenobiotic receptors (SXRs),
reduces the incidence of vertebral fractures, despite having
only modest effects on the bone mineral density (BMD). Based
on the weight of the currently available evidence, it i s
recommended that alendronate and risedronate, rather than
vitamin K2, should be chosen initially
for the treatment of postmenopausal osteoporosis, because
these agents have been shown to be the most efficacious for
reducing the incidence of both vertebral and hip fractures
among the current range of commercially available agents.
However, the more potent anti-fracture efficacy of combined
treatment with the anti-resorptive and commercially available
anabolic agents may need to be established. Some studies have
shown that combined treatment with a bisphosphonate and vitamin
K2 may be more effective than treatment
with a bisphosphonate alone in preventing vertebral fractures.
On the other hand, the results of a preclinical study do suggest
the possible efficacy of combined treatment with vitamin K2
and raloxifene in the prevention of vertebral and hip fractures
in postmenopausal women, although no clinical studies have
reported on the effects of combined treatment with vitamin
K2 and raloxifene in postmenopausal
women with osteoporosis. Vitamin K deficiency, as indicated
by high serum levels of undercarboxylated osteocalcin, has
been shown to contribute to the occurrence of hip fractures
in elderly women. Thus, we propose that the important role
of vitamin K2 used in combination with
bisphosphonates or raloxifene should not be underestimated
in the prevention of fractures in postmenopausal women with
osteoporosis with vitamin K deficiency.
[Back to top]
The Clinical Development of γ-Hydroxybutyrate
(GHB)
Gregory P. Wedin, Carl S. Hornfeldt & Lisa
M. Ylitalo
[Full Text Article]
The discovery of gamma-hydroxybutyrate (GHB) over 40 years
ago led to its immediate use as a general anesthetic agent.
Subsequent research demonstrated that GHB is an endogenous
compound in the mammalian brain and current research suggests
that GHB is a probable neurotransmitter. In the United States,
reports of anabolic effects lead to its misuse among body
builders during the 1980’s while the intoxicating properties
of the drug lead to its popularization as a substance of abuse
during the 1990’s. GHB became associated with reports
of drug-facilitated sexual assault and cases of physical dependence
and withdrawal. Efforts to ban GHB caused increased use of
GHB analogues and pro-drugs. Against this backdrop, GHB was
being developed for the treatment of narcolepsy, leading to
the approval of Xyrem® (sodium oxybate) oral solution
in 2002 for the treatment of cataplexy in patients with narcolepsy.
A risk management program permits the safe handling and distribution
of the approved product, minimizes the risk for diversion,
provides professional and patient education about the risks
and benefits of sodium oxybate, and includes physician and
patient registries. Post-marketing surveillance indicates
sodium oxybate has an acceptable safety profile and presents
minimal risk for the development of physical dependence.
[Back to top]
Host Pharmacogenetics in the Treatment of HIV and
Cancer
Alan Winston, Eleftheria Hatzimichael, Vanessa
Marvin, Justin Stebbing & Mark Bower
[Full Text Article]
Physicians prescribing drugs are routinely confronted with
the balance between efficacy and toxicity. Pharmacogenetics
involves the study of how inheritance influences response
to drugs, and its goal is to enable the appropriate selection
of these individuals, thus eliminating unpredictable responses.
Pharmacogenetics can be used to identify target populations
that either will have minimal benefit or a better outcome
including better survival or improvement in surrogate end
points. As we move towards common use of targeted therapies,
the future of medicine will involve an examination of the
interplay between multiple genetic factors, as the response
to drugs is likely to be complex and polyfactorial especially
in chronic diseases. There has already been some success in
situations where single genes play a large role in the overall
drug response, and this is discussed with reference to commonly
used cytotoxics and antiretrovirals, encompassing the major
principles of pharmacogenetics.
[Back to top]
How Vaccine Safety can Become Political – The
Example of Polio in Nigeria
Christopher J. Clements, Paul Greenough &
Diana Shull
[Full Text Article]
Vaccine safety is increasingly a major aspect of immunization
programmes. Parents are becoming more aware of safety issues
relating to vaccines their babies might receive. As a consequence,
public health initiatives have had to take note of pressures
brought to bear by individual parents and groups. Now we document
a new phase in vaccine safety where it has been used to achieve
political objectives. In 1988, the World Health Assembly declared
its intention to eradicate poliomyelitis from the globe by
the year 2000. This goal had to be postponed to 2005 for a
number of reasons. Although the progress has been spectacular
in achieving eradication in almost all nations and areas,
the goal has been tantalizingly elusive.
But arguably the most difficult country from which to eradicate
the virus has been Nigeria. Over the past two years, tension
has arisen in the north against immunizing against polio using
the oral polio vaccine (OPV). Although this vaccine has been
used in every other country in the world including other Muslim
states, some religious leaders in the north found reason in
August 2003 to advise their followers not to have their children
vaccinated with OPV. Subsequent to this boycott, which the
Kano governor had endorsed for a year and then ended in July
2004, cases of polio occurred in African nations previously
free of the virus, and the DNA finger-print of the virus indicated
it had came from Nigeria. In other words, Nigeria became a
net exporter of polio virus to its African neighbours and
beyond. Now the disease has spread to about a dozen formerly
polio-free countries, including Sudan and Indonesia. We show
that, while the outward manifestations of the northern Nigerian
intransigence were that of distrust of vaccine, the underlying
problem was actually part of a longstanding dispute about
political and religious power vis a vis
Abuja. It is unlikely that polio transmission will be interrupted
by 2005 if this dispute is allowed to run its course.
[Back to top]
Informing People about the Risks and Benefits of Medicines:
Implications for the Safe and Effective Use of Medicinal Products
Dianne C. Berry
[Full Text Article]
Providing effective information about drug risks and benefits
has become a major challenge for health professionals, as
many people are ill equipped to understand, retain and use
the information effectively. This paper reviews the growing
evidence that people’s understanding (and health behaviour)
is not only affected by the content of medicines information,
but also by the particular way in which it is presented. Such
presentational factors include whether information is presented
verbally or numerically, framed positively or negatively,
whether risk reductions are described in relative or absolute
terms (and baseline information included), and whether information
is personalised or tailored in any way. It also looks at how
understanding is affected by the order in which information
is presented, and the way in which it is processed. The paper
concludes by making a number of recommendations for providers
of medicines information, about both the content and presentation
of such information, that should enhance safe and effective
medicines usage.
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