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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 1, Number 2, May 2006
Contents
Evolving Paradigms in Pharmacovigilance Pp. 127-134
Wendy Brewster, Trevor Gibbs, Karol LaCroix, Alison
Murray, Michael Tydeman and June Almenoff
[Abstract]
Reducing False Positive Findings in Statistical Analysis
of Pharmacogenomic Biomarker Studies Using High-Throughput
Technologies Pp. 135-141
Shigeyuki Matsui
[Abstract]
Psychiatric Side Effects of Interferon Treatment
Pp. 143-150
Scott B. Patten
[Abstract]
Inhaled Insulin: A Novel and Non-Invasive Way for
Insulin Administration? Pp. 151-158
Teresa Quattrin
[Abstract]
Exogenous Surfactant in Paediatric Acute Lung Injury
and Acute Respiratory Distress Syndrome Pp. 159-168
Stephen D. Playfor and Venkata K.T. Nootigattu
[Abstract]
The Role of the New Zealand Intensive Medicines Monitoring
Programme in Identification of Previously Unrecognised Signals
of Adverse Drug Reactions Pp. 169-178
David W.J. Clark and Mira Harrison-Woolrych
[Abstract]
Sirolimus Early Graft Nephrotoxicity: Clinical and
Experimental Data Pp. 179-187
Nicolas Pallet, Eric Thervet, Christophe Legendre
and Dany Anglicheau
[Abstract]
The Safety and Efficacy of Parathyroid Hormone (PTH)
as a Biological Response Modifier for the Enhancement of Bone
Regeneration Pp. 189-203
Christopher C. Tzioupis and Peter V. Giannoudis
[Abstract]
The Safety of the Temozolomide in Patients with Malignant
Glioma Pp. 205-222
Alessandro Dario and Giustino Tomei
[Abstract]
Abstracts
[Back to top]
Evolving Paradigms in Pharmacovigilance
Wendy Brewster, Trevor Gibbs, Karol LaCroix, Alison
Murray, Michael Tydeman and June Almenoff
All medicines have adverse effects as well as benefits.
The aim of pharmacovigilance is to protect public health by
monitoring medicines to identify and evaluate issues and ensure
that the overall benefits outweigh the potential risks. The
tools and processes used in pharmacovigilance are continually
evolving.
Increasingly sophisticated tools are being designed to evaluate
safety data from clinical trials to enhance the likelihood
of detecting safety signals ahead of product registration.
Methods include integration of safety data throughout development,
meta-analytical techniques, quantitative and qualitative methods
for evaluation of adverse event data and graphical tools to
explore laboratory and biometric data. Electronic data capture
facilitates monitoring of ongoing studies so that it is possible
to promptly identify potential issues and manage patient safety.
In addition, GSK employs a number of proactive methods for
post-marketing signal detection and knowledge management using
state-of-the-art statistical and analytical tools. Using these
tools, together with safety data collected through pharmacoepidemiologic
studies, literature and spontaneous reporting, potential adverse
drug reactions can be better identified in marketed products.
In summary, the information outlined in this paper provides
a valuable benchmark for risk management and pharmacovigilance
in pharmaceutical development.
[Back to top]
Reducing False Positive Findings in Statistical
Analysis of Pharmacogenomic Biomarker Studies Using High-Throughput
Technologies
Shigeyuki Matsui
The promise of pharmacogenomics lies in the potential
to establish a personalized drug therapy with the intent of
maximizing effectiveness and minimizing risk, through development
of pharmacogenomics biomarkers. However, currently, most pharmacogenomic
measurements are not considered valid biomarkers with clear
clinical significance, thus this field is in early developmental
stages. Recently, the development of comprehensive, high-throughput
technologies such as gene expression microarrays has provided
powerful new tools for these stages. This technological transformation
is, at the same time, generating an increasing demand for
statistical analysis of large and complex multivariate datasets
from high-throughput assays. This article provides a review
of the key features to be observed in statistical analyses
of large amounts of data from pharmacogenomic biomarker studies
with high-throughput assays. The problem of false positive
can be very serious in such studies. The evaluation of stability
and reproducibility of the results of statistical analysis
are claimed to reduce chance that false positive findings
are subject to further investigation in subsequent studies.
[Back to top]
Psychiatric Side Effects of Interferon Treatment
Scott B. Patten
Background. Interferons are employed in the management
of multiple sclerosis, hepatitis C and certain malignancies.
Neuropsychiatric toxicity can interfere with the successful
use of these drugs.
Methods. This review was based on Medline literature
searches, supplemented by bibliographical citations in identified
papers. Information uncovered in the literature review was
interpreted in light of related pharmacoepidemiological and
psychiatric literature.
Results. Interferon-associated neurotoxicity does
not adhere closely to standard psychiatric syndromal and diagnostic
definitions. Delirium, depression, non-specific symptoms related
to sickness behavior and, rarely, manic and psychotic syndromes
are all potential adverse events during interferon treatment.
For depression, the evidence of increased risk is stronger
for interferon alpha than for interferon beta. The availability
of preventive and treatment interventions suggest that neuropsychiatric
toxicity can often be managed without needing to discontinue
the treatment.
Conclusions. Safety can be maximized by organization
of health services in ways that enhance detection and management
of neuropsychiatric problems, and which support access to
basic and specialized mental health services.
[Back to top]
Inhaled Insulin: A Novel and Non-Invasive Way for
Insulin Administration?
Teresa Quattrin
Over the past few years significant steps forward have
been made towards the development of insulin formulations
suitable for inhalation via several delivery systems.
This innovative route of insulin delivery offers the potential
of administering pre-meal insulin in a non-invasive way to
patients currently receiving multiple daily injections. This
article describes the pharmacodynamic and pharmacokinetic
profiles and the efficacy and safety data of inhaled insulin
preparations. Particular emphasis is placed on Exubera, which
currently has the largest pool of efficacy and safety data.
In patients with type 1 diabetes 24-week trials have demonstrated
that inhaled insulin was equally efficacious to short acting
insulin (2-4 daily injections). Results of trials conducted
in type 2 diabetes showed inhaled insulin efficacy too, and
a potential role for inhaled insulin in patients failing oral
medications. Safety data have shown that the most common reported
adverse event is mild cough, which appears to be decreasing
in frequency during the course of therapy. Higher antibody
titers have been observed in patients treated with inhaled
insulin compared to subjects treated with sub-cutaneous insulin.
However, the titers do not present any association with clinical
correlates. The safety area in need of higher scrutiny is
naturally the area of pulmonary function tests (PFTs). A brief
synopsis of PFTs is followed by the review of PFTs data following
short and long term treatment with inhaled insulin. Two-year
data in type 2 diabetes showed a significant change in Forced
Expiratory Volume in 1 second (FEV1) after 6 months of treatment,
but not after 9, 12,18,24 months of treatment and 6 and 12
months of wash-out. In type 1 diabetes a significant change
in Diffusing Lung Capacity of Carbon Monoxide (DLCO) was observed
after 24 weeks of inhaled insulin therapy. Long-term data
in type 1 diabetes are only available as part of a pooled
sample composed of patients with both type 1 and type 2 diabetes.
In these patients, who had received inhaled insulin for at
least 4 years, annualized changes of FEV1 and DLCO were similar
in the group treated with inhaled insulin compared to the
group treated with sub-cutaneous insulin.
[Back to top]
Exogenous Surfactant in Paediatric Acute Lung Injury
and Acute Respiratory Distress Syndrome
Stephen D. Playfor and Venkata K.T. Nootigattu
Natural pulmonary surfactant is a complex mixture of
lipids and proteins with many biological functions. Surfactant
is responsible for lowering the surface tension within alveoli
and maintaining the functional integrity of the distal airways.
In addition to this function surfactant components represent
important elements of the host defence system of the lung.
Acute Respiratory Distress Syndrome (ARDS) and Acute Lung
Injury (ALI) are syndromes characterised by reduced pulmonary
gas exchange due to diffuse injury to the alveolar-capillary
barrier. The alveoli fill with proteinaceous fluid, and there
is a marked infiltrate of acute inflammatory cells. ARDS and
ALI may occur after both direct lung injury such smoke inhalation,
and after indirect lung injury such as in sepsis.
Qualitative and quantitative surfactant deficiencies are present
in individuals suffering from ARDS and ALI, and the role of
exogenous surfactant treatment in these conditions has attracted
considerable interest. Most clinical studies have shown only
improvements in the oxygenation of patients, but a recent
study has, for the first time, demonstrated a reduction in
the mortality of children with ARDS and ALI treated with exogenous
surfactant.
Given the differences that exist in surfactant composition,
dosing schedules and the pathological processes responsible
for ALI, it is clear that considerable work remains to be
done in this field.
[Back to top]
The Role of the New Zealand Intensive Medicines Monitoring
Programme in Identification of Previously Unrecognised Signals
of Adverse Drug Reactions
David W.J. Clark and Mira Harrison-Woolrych
The New Zealand Intensive Medicines Monitoring Programme
(IMMP) was established in 1977 to enhance monitoring for previously
unrecognised adverse drug reactions associated with selected
new medicines. This involved establishing cohorts from prescription
data and collection of event information: thus New Zealand
was a pioneer in the development of the methodology now known
as Prescription Event Monitoring (PEM). In the IMMP, PEM cohorts
are established using information, supplied by pharmacies,
from prescriptions for medicines that have been selected for
monitoring. Events are identified subsequently from follow-up
questionnaires to prescribing physicians and from other sources,
including spontaneous reporting of events.
The objective of this review is to illustrate how the IMMP
methodology enables identification of signals of previously
unrecognised adverse reactions. This is enhanced by high response
rates from pharmacists and prescribers in providing prescription
and event data respectively. In addition, high quality event
reports are obtained from multiple sources including follow-up
event returns from prescribers, reports received through the
national spontaneous reporting programme, prescription returns
and from record linkage to other databases. Collaboration
with other national centres and with the WHO Collaborating
centre for international drug monitoring in Uppsala, Sweden
(WHO-UMC) enables information on cases from their databases
to be used in validation of IMMP signals.
The NZ IMMP methodology and signals of previously unrecognised
adverse drug reactions arising from the IMMP databases are
reviewed. Recent signals include amnesia and QTc prolongation
with sibutramine; pain activation with sumatriptan; epistaxis
with risperidone; psychiatric and visual disturbances with
the COX-2 inhibitors celecoxib and rofecoxib and psoriasis
with rofecoxib. In addition, other types of investigation
are discussed along with the importance of rapid communication
to prescribers of new information concerning the risks of
medications. The IMMP has features that differ from those
of other centres that incorporate PEM methodology. New Zealand
is a small country (approximately 4 million) and thus communication
is relatively easy. This facilitates good rapport with prescribing
doctors. However, mainly because of the small population,
several years may be required to achieve a large cohort. Although
this has drawbacks in terms of rapid results, it enables a
longitudinal approach to prescription data analysis, including
aspects of prescribing such as reasons for cessation of therapy
and changes in prescribing practise.
Although not specifically reviewed in this article, the programme
has also made significant contributions in determining the
incidence of certain adverse drug reactions and in carrying
out in-depth epidemiological investigations relating to the
safe use of medicines. Through these activities, the New Zealand
IMMP provides an ongoing contribution to safety in the use
of medicines.
[Back to top]
Sirolimus Early Graft Nephrotoxicity: Clinical and
Experimental Data
Nicolas Pallet, Eric Thervet, Christophe Legendre
and Dany Anglicheau
Sirolimus (SRL) is a recently available immunosuppressive
agent. SRL, is a macrolide isolated from Streptomyces
hydroscopicus that, in complex with its cellular receptor,
FK binding protein, potently inhibits downstream signaling
by the mammalian target of rapamycin (mTOR). It has been shown
to reduce the incidence of acute rejection episode after renal
transplantation.
SRL by itself does not seem to cause significant nephrotoxicity
in most animals and human studies in normal conditions. However,
when combined with calcineurin inhibitors, serum creatinine
levels often increase. The mechanisms for the synergism of
this side-effect are still discussed. Furthermore, recent
clinical data have shown that the administration of SRL immediately
after renal transplant delay the recovery from delayed graft
function. This effect may be secondary to the inhibition of
the proliferation of the renal tubular cells which is a normal
process for tubular repair. Some experimental data have confirmed
this hypothesis. Finally, in the long-term, SRL use has been
associated with a significant increase of proteinuria which
may in the long-term increase the risk of graft loss of cardio-vascular
morbio-mortality.
For all these reasons, SRL nephrotoxicty has become an important
issue after renal transplantation. The review will discuss
the clinical and the experimental data regarding this complication,
which has been underestimated.
[Back to top]
The Safety and Efficacy of Parathyroid Hormone (PTH)
as a Biological Response Modifier for the Enhancement of Bone
Regeneration
Christopher C. Tzioupis and Peter V. Giannoudis
Osteoporosis is characterized by low bone mineral density
and deterioration in the microarchitecture of bone that increases
its fracture vulnerability. The mainstay of therapy for osteoporosis
is anti-resorptive in mechanism. Parathyroid hormone (PTH)
is the most recently approved anabolic agent for osteoporosis.
The mechanism of PTH’s skeleton anabolic action is composite
involving pathways linked to common signalling peptides that
affect gene osteoblast transcription. A number of animal studies
and clinical trials have demonstrated that intermittent PTH
administration induces anabolic effects on both cancellous
and cortical bone, enhances bone mass and increases mechanical
bone strength, increasing spine and hip bone mineral density
and reducing fragility fractures. Preclinical studies investigating
the effect of PTH on fracture healing show an increase in
bone density and strength indicating an enhancement of this
biological cascade. Preclinical and clinical safety assessments
have revealed little evidence of toxic effects and there have
been few reports of adverse events related to their use. An
increase in osteosarcoma in rats probably is not prognostic
of an equivalent possibility in humans. In summary, parathyroid
hormone is a major advance in the treatment of osteoporosis.
Additional studies addressing long-term clinical safety are
needed. However the current evidence is very promising.
[Back to top]
The Safety of the Temozolomide in Patients with Malignant
Glioma
Alessandro Dario and Giustino Tomei
The temozolomide is a promising orally cytotoxic agent
used in malignant glioma. The survival curve improvement after
drug administration appears to be statistically significant.
The review of temozolomide side effects is carried out by
search on literature data found on web and is divided on the
4 grades of toxicity according to the National Cancer Institute
Common Toxicity Criteria, version 2.0. The adverse effects
related with TMZ administration are divided in three categories:
myelosuppression, non haematologic toxicity, and infections.
The main adverse effect is the myelosuppression that appears
to be rather low and reversible as well as the vomiting or
nausea. The different schedules of administration are analysed.
The frequency of concomitant infections is underlined. In
particular, if available, the relationship between temozolomide
and other cytotoxic agents or anticonvulsivant drugs is analysed
to clarify the possibility of increase of toxicity. The temozolomide
is used also in children but the toxicity could be more frequent.
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