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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 2, Number 1, January 2007
Contents
Editorial Pp.
1-4
Sildenafil is Well Tolerated by Erectile Dysfunction
Patients Taking Antihypertensive Medications, Including Those
on Multidrug Regimens Pp. 5-8
Marko Böhm, Martin Burkart and Gert Baumann
[Abstract] [Full
Text Article]
Adverse Reactions and Pathogen Safety of Intravenous
Immunoglobulin Pp. 9-18
Javier Carbone
[Abstract] [Full
Text Article]
Supervision in Primary Health Care – Can it
be Carried Out Effectively in Developing Countries?
Pp. 19-23
C. John Clements, Pieter H. Streefland and Clement Malau
[Abstract] [Full
Text Article]
Prevention of Emetic Episodes During Cesarean Delivery
Performed Under Regional Anesthesia in Parturients
Pp. 25-32
Yoshitaka Fujii
[Abstract] [Full
Text Article]
Attention Deficit and Hyperactivity Disorder: Controversies
of Diagnosis and Safety of Pharmacological and Nonpharmacological
Treatment Pp. 33-42
Shannon Benner-Davis and Pamela C. Heaton
[Abstract] [Full
Text Article]
Release of α-Glutathione
s-Transferase (α-GST)
and Hepatocellular Damage Induced by Helicobacter pylori
and Eradication Treatment Pp. 43-46
Bensu Karahalil, Seyhan Yagar and Yasemin Özin
[Abstract] [Full
Text Article]
Musculoskeletal Adverse Drug Reactions: A Review of
Literature and Data from ADR Spontaneous Reporting Databases
Pp. 47-63
Anita Conforti, Christian Chiamulera, Ugo Moretti, Sonia
Colcera, Guido Fumagalli and Roberto Leone
[Abstract] [Full
Text Article]
Rational Pharmacotherapy and Pharmacovigilance
Pp. 65-69
Ahmet Akici and Sule Oktay
[Abstract] [Full
Text Article]
The Risks and Benefits of Therapy with Aldosterone
Receptor Antagonist Therapy Pp. 71-77
Domenic A. Sica
[Abstract] [Full
Text Article]
Adverse Drug Reactions in Hospitals: A Narrative Review
Pp. 79-87
Emma C. Davies, Christopher F. Green David R. Mottram
and Munir Pirmohamed
[Abstract] [Full
Text Article]
Quality, Safety and Efficacy in the ‘Off-Label’
Use of Medicines Pp. 89-95
Therése Eileen Kairuz, Derryn Gargiulo, Craig Bunt
and Sanjay Garg
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Editorial
Is Current Drug Safety an Issue?
INTRODUCTION
At first sight the question: "Is current drug safety
an issue?" might appear to be unnecessary. On one hand,
it might be argued that drug safety is straightforward: all
the physician has to do is to consult his formulary and he
will have all the information he requires to use drugs safely.
On the other hand, the major clinical, medicolegal and financial
aspects of drug safety, together with the ever-increasing
store of knowledge and the burgeoning of scientific methods
applied to the subject, might be taken to imply that there
is no question about the fact that drug safety remains an
enormous issue.
Lazarou et al. [1] estimated that 2,216,000 hospitalised
patients had serious adverse drug reactions (ADRs) and 106,000
died in a single year in the USA. This implied that ADRs were
a major cause of fatality, ranking between four and six in
the list of most common causes of death. In a prospective
UK study, Pirmohamed et al. [2] found that ADRs accounted
for around 6.5% of hospital admissions, and 4% of the hospital
bed capacity. They concluded that most ADRs were predictable
from the known pharmacology of the drugs and many represented
known interactions that were probably preventable. The overall
mortality was 0.15%. The projected annual cost to the National
Health Service was £466 million or $847 million. These
papers lead to some unavoidable conclusions. The cost in human
terms is immeasurable. The cost in financial terms is very
high. Many would consider that the situation is unacceptable.
The need to take measures to reduce the distress, morbidity,
mortality and cost of ADRs is compelling.
What are the issues in the field of drug safety and how do
they differ in the 21st century from those that were prevalent
from the earliest times that medicinal preparations were used
to treat an illness? Some of the issues are similar but others
are very different. In particular, advances in genetics and
other scientific methods hold great promise for avoiding,
or at least reducing, ADRs. Some sceptics within the field
of medicine, when speaking of genetics generally, would say
that the geneticists claim to have all the answers, but not
quite yet. There is, however, no denying that there have been
extraordinary developments in this field as far as drug safety
is concerned. A whole new vocabulary has developed, including
terms such as: pharmacogenomics, theragenomics, toxicogenomics,
chemogenomics, metabonomics, chemometrics, transcriptome analysis
and many others.
It is interesting and perhaps ironic to note that, despite
all these advances, disasters in the testing of new drugs
can still occur. A recent dramatic episode illustrated this
all too well [3]. Eight healthy volunteers took part in the
first human phase I trial of a monoclonal T cell agonist,
TGN1412, intended to treat autoimmune and immunodeficiency
disease. The trial took place in a unit at Northwick Park
Hospital, London. The six men who received the active component
rapidly developed very serious multisystem failure. There
was grave concern that some of the men might not survive.
The safety aspects of this trial will certainly have far-reaching
consequences.
A number of specific areas are worthy of attention when considering
the area of drug safety. The following selection is not intended
to be comprehensive but might give some indication of why
drug safety remains such a major field of interest.
Population and Individual Characteristics
Some of the more obvious factors that need to be taken into
account when prescribing medication include age, gender, race
and comorbid medical conditions such as renal impairment.
Lifestyle issues such as smoking, alcohol intake and diet
can also affect drug metabolism to a great degree. There has
been an increasing recognition of the importance of individual
variation in factors such as the activity of certain isoenzymes,
not only including the cytochrome P-450 family but also the
UGT (uridine diphosphate glucuronosyltransferase) group. Some
individuals appear to be remarkably resistant to medication
and this has led to an interest in multidrug resistance (MDR)
and the role of specific proteins such as P-glycoprotein (PGP)
or MDR-1. Knowledge of the activity of these substances in
an individual could lead to the avoidance of undertreatment
on one hand and toxicity on the other. There is a particular
interest in this area with regard to anti-cancer drugs but
there has also been emerging attention to the possibility
that multidrug resistance proteins might be responsible for
some cases of drug-resistant epilepsy.
Drug development is costly and is potentially fraught with
risk. New methods might reduce both the costs and the risk
significantly. Searfoss et al. [4] have commented:
“Nowhere in the role of drug development has the expectation
of the impact of transcriptome analysis been greater than
in the area of pre-clinical toxicology". Sasseville et
al. [5] have estimated that a reduction of drug development
attrition by 10% would result in an increase in value by $100
million.
The recognition that age is a factor in drug adverse effects
has led to a number of papers examining these issues in the
elderly. There has been much less attention to the issues
affecting neonates, children and teenagers. Recently, attention
was drawn to a concern about the use of antidepressants in
teenagers. Unfortunately, in the opinion of the current author,
this matter was managed very poorly (see later) [6].
Other Medication Dose Issues
The classical example of the right dose being given by the
wrong route is that of intrathecal penicillin. The dose that
would be appropriate for intravenous or intramuscular administration
may be fatal if given into the CSF during lumbar puncture.
This is an example of a therapeutic preparation being highly
toxic when given in the wrong dose. A very interesting situation
arises when a highly toxic agent given in the right dose can
be therapeutic. The outstanding recent example has been the
very beneficial use of what is reputed to be one of the most
toxic substances known to man, namely botulinum toxin. Although
much of the publicity has been around the cosmetic use of
this agent, it has proved to be of particular benefit in other
situations, for example the treatment of spasticity in people
with cerebral palsy or the treatment of excessive drooling
in people with mental retardation. These examples illustrate
the fact that correct use of pharmaceutical agents can be
of great benefit, while incorrect use can be disastrous.
Large doses of oral steroids given over long periods are associated
with very serious adverse effects. This well-established fact
appears to have made some people reluctant to accept low-dose
inhaled steroids for the treatment of asthma, even though
this treatment can be highly beneficial, usually with few,
if any, adverse effects.
Adverse Drug Interactions
In addition to the adverse drug reactions that can occur with
individual drugs, there are very many adverse drug interactions
that can occur when more than one drug is prescribed to an
individual. One of the drug interactions that has rightly
attracted attention is the risk of life-threatening cardiac
arrhythmias. For example, torsades de pointes may occur when
CYP3A4 inhibitors are taken with the CYP3A4 substrates terfenadine,
cisapride or astemizole [7]. There are many other examples
of adverse drug interactions. The current author has a particular
interest in the adverse interactions between antiepileptic
drugs and antipsychotic medication [8].
Inappropriate Use of Medication
There has been much interest in the prescription of medication
for situations that should have been managed using other strategies.
For example, sedative or antipsychotic medication has sometimes
been prescribed for people with learning disability and behavioural
disturbance when alterations in management strategies or changes
in the environment would have been much more appropriate.
Morbidity or mortality associated with the prescription of
such medication would be hard to justify.
Another interesting situation that arises is that of misdiagnosis.
It is estimated that approximately 25% of people with a diagnosis
of epilepsy do not have the condition. This implies that many
of them will be treated inappropriately with antiepileptic
medication and will not be receiving treatment for whatever
condition they do have. Again, if such patients have ADRs,
the prescribing physician could find himself in a difficult
situation.
The Role of the Media
The role of the media in drug safety issues can easily be
underestimated. Two examples follow.
The possibility that the combined measles mumps and rubella
(MMR) immunisation might cause autism received much publicity.
Some parents understandably refused to allow their children
to have this immunisation. The result has been an increase
in measles in young children, an infection that can be associated
with serious consequences in a few cases. Mumps can also have
significant sequelae. Rubella can cause major handicaps if
the foetus is exposed to the infection in utero. Subsequent
studies found no evidence for an association between autism
and the MMR immunisation. Even with the wisdom of hindsight
it is difficult to know how the media might have managed this
situation better.
More recently, there has been a suggestion that the use of
selective serotonin reuptake inhibitors in teenagers with
depression might be associated with an increase in suicides.
As already stated, in the opinion of the current author, the
situation was managed badly [6]. The regulatory agencies gave
confusing and misleading information. A leading daily newspaper
printed an article on the front page drawing attention to
the possible association between the use of these drugs and
suicidality in teenagers. The treatment of depression is a
particularly interesting therapeutic situation; drug trials
almost invariably show a very high placebo response. Against
this background what reaction might be expected from a teenager
or a member of their family reading a report suggesting that
the medication might be harmful? Not only would the placebo
effect be lost but there would actually be a "negative
placebo effect"; the medication may be perceived as being
harmful even if it were not. What were population effects
of this increased morbidity? What additional distress, worsening
depression or even suicide were precipitated as a result?
Some might consider reporting of this nature to be unwise.
Newspaper editors might be well advised to be very cautious
about reporting mental health stories in a way that might
cause harm. A careful examination of all the available data
suggested that the initial reports of increased suicidality
were exaggerated.
Risk-Benefit Considerations
Some drugs are now used in very large numbers of people. Examples
include antihypertensive agents and statins. A low incidence
of very serious adverse effects might be unacceptable in these
circumstances. In contrast, a higher risk of serious adverse
effects might be acceptable when treating potentially life-threatening
conditions such as cancer or HIV-AIDS. These concepts are
generally well understood. However, it is not only life-threatening
conditions in which a higher risk of serious adverse effects
might be acceptable. A good example is the reintroduction
of clozapine for the treatment of schizophrenia that has been
resistant to treatment with other agents. Although the mortality
in this condition, particularly from suicide [9], is raised,
it is not considered to be a directly life-threatening condition
like most cases of untreated cancer or HIV-AIDS. Clozapine
was withdrawn in many parts of the world because of reports
of potentially fatal bone-marrow depression. However, when
relatives of patients with schizophrenia that had failed to
respond to any other medication were informed that there might
be a significant chance of a serious life-threatening adverse
effect, they reasoned that the relatively small risk of a
very serious adverse effect was more acceptable than the 100%
risk of the ongoing devastating symptoms of schizophrenia.
It is interesting to note that similar reasoning has not necessarily
been applied to other analogous situations. The use of the
antiepileptic drug felbamate fell sharply when reports of
potentially-fatal aplastic anaemia and hepatotoxicity emerged.
The risk appeared to be one in a few thousand. Some patients
with severe uncontrolled epilepsy, perhaps associated with
frequent falls and in a twilight state of impaired awareness,
have a greatly reduced quality of life. Would the risks of
a drug such as felbamate be acceptable in such circumstances?
Scientific endeavours to reduce one risk sometimes result
in another. Specific cyclo-oxygenase-2 (COX-2) inhibitors
were developed in an attempt to produce an anti-inflammatory/analgesic
agent without the adverse effects of gastrointestinal bleeding.
However, an increased risk of myocardial infarction has emerged,
leading to the withdrawal of these drugs in many countries
[10-12].
Pharmacovigilance has a very important role to play in providing
the necessary data to assist in the assessment of such risk-benefit
considerations. The collection of prospective data, for example,
pregnancy registers in women treated with antiepileptic drugs,
are proving to be of great value in assessing the risk of
seizures during pregnancy on one hand and foetal adverse effects
of the medication on the other hand. Collecting prospective
data in this way is certainly to be encouraged.
Final Thoughts
In this brief editorial, I have hardly scratched the surface
of the enormous topic of current drug safety issues. When
I accepted the post of Editor-in-Chief of this journal, I
did so with some trepidation, recognizing that it was not
a task I could undertake without considerable assistance.
The success of this journal is totally dependent on the combined
efforts of an outstanding editorial board, world-class peer
reviewers, papers contributed by leaders in the field, constructive
critical comment from colleagues, and the support of very
helpful editorial staff.
There is much talk of teamwork in medical practice and research.
This is entirely appropriate. The area of drug safety provides
an excellent example of the value of such teamwork. In my
own experience close collaboration with other disciplines
has been of enormous benefit both in my clinical and research
work. The aim of this journal is to provide the right balance
between basic and clinical science so that the enormous morbidity
and significant mortality associated with drug treatment can
be reduced in the future. It is only through the close collaboration
between chemists, basic scientists and clinicians that the
risks can be reduced and that medication can be used to full
advantage for the benefit of the patients under our care.
REFERENCES
[1] Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse
drug reactions in hospitalized patients: a meta-analysis of
prospective studies. JAMA 1998; 279(15): 1200-5.
[2] Pirmohamed M, James S, Meakin S, et al. Adverse
drug reactions as cause of admission to hospital: prospective
analysis of 18 820 patients. BMJ 2004; 329(7456): 15-9.
[3] Goodyear MD. Further lessons from the TGN1412 tragedy.
BMJ 2006; 333(7562): 270-1.
[4] Searfoss GH, Ryan TP, Jolly RA. The role of transcriptome
analysis in pre-clinical toxicology. Curr Mol Med 2005; 5(1):
53-64.
[5] Sasseville VG, Lane JH, Kadambi VJ, et al. Testing
paradigm for prediction of development-limiting barriers and
human drug toxicity. Chem Biol Interact 2004; 150(1): 9-25.
[6] Wong IC, Besag FM, Santosh PJ, Murray ML. Use of selective
serotonin reuptake inhibitors in children and adolescents.
Drug Saf 2004; 27(13): 991-1000.
[7] Zhou S, Yung CS, Cher GB, et al. Mechanism-based
inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin
Pharmacokinet 2005; 44(3): 279-304.
[8] Besag FM, Berry D. Interactions between antiepileptic
and antipsychotic drugs. Drug Saf 2006; 29(2): 95-118.
[9] Osby U, Correia N, Brandt L, Ekbom A, Sparen P. Mortality
and causes of death in schizophrenia in Stockholm county,
Sweden. Schizophrenia Res 2000; 45(1-2): 21-8.
[10] Bombardier C, Laine L, Reicin A, et al. Comparison
of upper gastrointestinal toxicity of rofecoxib and naproxen
in patients with rheumatoid arthritis. VIGOR Study Group.
N Eng J Med 2002; 343(21): 1520-8.
[11] Drazen JM. COX-2 inhibitors-a lesson in unexpected problems.
N Eng J Med 2005; 352(11): 1131-2.
[12] Kearney PM, Baigent C, Godwin J, Emberson JR, Patrono
C. Do coxibs and traditional non-steroidal anti-inflammatory
drugs increase the risk of atherothrombosis? Meta-analysis
of randomised trials. Br Med J 2006; 332: 1302-5.
Frank M.C. Besag
(Editor-in-Chief)
Specialist Medical Department
Twinwoods Health Resource Centre
Milton Road
Bedfordshire ?MK41 6AT
UK
E-mail: FBesag@aol.com
[Back to top]
Sildenafil is Well Tolerated by Erectile Dysfunction
Patients Taking Antihypertensive Medications, Including Those
on Multidrug Regimens
Marko Böhm, Martin Burkart and Gert Baumann
[Full
Text Article]
Erectile dysfunction occurs extensively among patients
with arterial hypertension. We investigated the safety of
sildenafil for patients with and without antihypertensive
medication. Our study included data from 35 double-blind,
placebo-controlled, and randomized investigations, with a
total of 8115 patients. The term of therapy was between 6
weeks and 6 months, for both the sildenafil group (5-200 mg,
n = 4819) as well as the placebo group (n
= 3296). We studied the adverse events in the men who received
1 or more hypertensives (n = 2388), and in those
who took no antihypertensive medication (n = 5727).
Our findings disclosed equal frequency of adverse events in
both groups, without influence by the number of different
antihypertensives administered. The occurrence of AEs associated
with blood pressure was slight, and was comparable between
the individual groups. These results support the conclusion
that sildenafil is also well tolerated by patients taking
one or more antihypertensives. Patients being treated with
alpha blockers should be stable on this therapy in order to
minimize the possibility of orthostatic hypotension. An initial
dose of 25 mg should furthermore be considered for these patients.
[Back to top]
Adverse Reactions and Pathogen Safety of Intravenous
Immunoglobulin
Javier Carbone
[Full
Text Article]
The range of diseases in which intravenous immunoglobulin
(IVIG) is effective has expanded significantly since its initial
use in primary antibody deficiency. This biological medicine
must comply with three conditions: therapeutic efficacy, clinical
tolerance and viral safety. Factors relevant to the viral
safety of IVIG include: effective use of donor exclusion criteria,
screening of donations in order to exclude potentially infectious
donations, testing of plasma pools for evidence of viral infection,
validated steps for removal and/or inactivation of potentially
present infectious agents, equipment cleaning, traceability
of lots, and post-marketing follow-up of patients. Variables
potentially affecting the risk and intensity of adverse events
associated with administration of IVIG include: patient age,
underlying condition, dose, concentration, IgA content, stabilizing
agent and rate of infusion. Mild adverse reactions (headache,
flushing, low backache, nausea) are often associated with
a fast infusion rate, and respond rapidly on slowing the infusion.
Very rare serious and potentially fatal side effects include:
anaphylactic reactions, aseptic meningitis, acute renal failure,
and thrombotic complications. Many of these serious adverse
reactions have occurred in patients who had significant risk
factors or underlying disease states. Clinicians should pay
close attention to patient selection and consider the potential
risk/benefit ratio versus alternate therapies.
[Back to top]
Supervision in Primary Health Care – Can it
be Carried Out Effectively in Developing Countries?
C. John Clements, Pieter H. Streefland and Clement Malau
[Full
Text Article]
There is nothing new about supervision in primary health care
service delivery. Supervision was even conducted by the Egyptian
pyramid builders. Those supervising have often favoured ridicule
and discipline to push individuals and communities to perform
their duties. A traditional form of supervision, based on
a top-down colonial model, was originally attempted as a tool
to improve health service staff performance. This has recently
been replaced by a more liberal “supportive supervision”.
While it is undoubtedly an improvement on the traditional
model, we believe that even this version will not succeed
to any great extent until there is a better understanding
of the human interactions involved in supervision. Tremendous
cultural differences exist over the globe regarding the acceptability
of this form of management. While it is clear that health
services in many countries have benefited from supervision
of one sort or another, it is equally clear that in some countries,
supervision is not carried out, or when carried out, is done
inadequately. In some countries it may be culturally inappropriate,
and may even be impossible to carry out supervision at all.
We examine this issue with particular reference to immunization
and other primary health care services in developing countries.
Supported by field observations in Papua New Guinea, we conclude
that supervision and its failure should be understood in a
social and cultural context, being a far more complex activity
than has so far been acknowledged. Social science-based research
is needed to enable a third generation of culture-sensitive
ideas to be developed that will improve staff performance
in the field.
[Back to top]
Prevention of Emetic Episodes During Cesarean Delivery
Performed Under Regional Anesthesia in Parturients
Yoshitaka Fujii
[Full
Text Article]
Nausea, retching, and vomiting are common in parturients undergoing
cesarean delivery performed under regional anesthesia. These
emetic episodes are distressing to the parturient and disturbing
to the surgeon. Numerous antiemetics have been studied for
the prevention of these emetic episodes in parturients scheduled
for cesarean delivery. Traditional antiemetics, including
butyrophenones (e.g., dropertidol), benzamide (e.g., metoclopramide),
and anticholinergics (e.g., glycopyrrolate), are used for
the control of these emetic episodes. Non-traditional antiemetics,
propofol and dexamethasone, are available for the prevention
of these emetic episodes. Serotonin receptor antagonists,
ondansetron and granisetron, are more effective than traditional
antiemetics for the prophylaxis against these emetic episodes.
None of the available antiemetics are entirely effective,
perhaps because most of them act through the blockade on one
type of receptor. There is a possibility that combined antiemetics
with different sites of activity would be more effective than
one drug alone for the prevention of these emetic episodes.
Antiemetic therapy with combined granisetron and dexamethasone
or combined propofol and dexamethasone is highly effective
for the prevention of these emetic episodes in parturients
scheduled for cesarean delivery. Non-pharmacological technique
includes acupressure at P6 (Nei-Kuwan) point. Overall, these
pharmacological and non-pharmacological therapy reduces emetic
episodes in parturients undergoing regional anesthesia for
cesarean delivery.
The clinician must weight the benefit of using pharmacological
and non-pharmacological techniques for nausea, retching, and
vomiting in parturients undergoing cesarean delivery performed
under regional anesthesia.
[Back to top]
Attention Deficit and Hyperactivity Disorder: Controversies
of Diagnosis and Safety of Pharmacological and Nonpharmacological
Treatment
Shannon Benner-Davis and Pamela C. Heaton
[Full
Text Article]
Attention-Deficit and Hyperactivity Disorder (ADHD) is a condition
that presents with a variety of behavioral and social problems.
The objective of this review was to examine the evidence concerning
the controversies surrounding the diagnosis of ADHD and the
safety of pharmacological and nonpharmacological treatment.
A MEDLINE search was conducted using MeSH terms ADHD, children,
treatments or behavioral therapy. The search was limited to
January 1990 to present, randomized clinical trials, retrospective
studies and English. Fifty-seven articles were selected for
review. Controversies exist regarding the diagnosis: variations
exist by gender, across countries and by method of diagnosis.
These issues are currently unresolved. The interventions with
the most data concerning their safety and efficacy in children
were stimulant medications. Children with ADHD who took stimulant
medications showed the greatest improvement in behavior when
compared to other interventions such as behavior therapy or
family counseling. Limitations of behavior therapy included
that it is often a difficult process to continue on an ongoing
basis and only a portion of the therapy stimulated the child’s
natural reward system. However, a combination of both stimulant
medication and behavior therapy demonstrated synergistic efficacy.
Care must be taken to insure that issues of gender and race,
as well as the adverse effects of treatment options, are adequately
taken into account by the treating clinician.
[Back to top]
Release of α-Glutathione
s-Transferase (α-GST)
and Hepatocellular Damage Induced by Helicobacter pylori
and Eradication Treatment
Bensu Karahalil, Seyhan Yagar and Yasemin Özin
[Full
Text Article]
Helicobacter pylori (H. pylori) is a gram
negative, spiral, microaerophylic bacterium that infects the
stomach of more than 50% of the human population worldwide.
H. pylori is well recognized as a critical factor
in the majority of patients with peptic ulcer disease and
successful treatment results in cure of the disease. On the
other hand, H. pylori infection has been associated
with several extra-intestinal diseases such as hepatic encephalopathy.
In this study, a triple treatment was used in management and
eradication of H. pylori infection. We hypothesized
that H. pylori infection and/or eradication treatment
increased the releasing of α-glutathione
S-transferase (α-GST).
We also investigated whether α-GST
is a more sensitive marker than aminotransferases (traditional
liver function tests) for hepatocellular damage. However,
we did not find any association between both H. pylori
infection and eradication treatment and α-GST
levels. According to our data, eradication treatment did not
cause hepatocellular damage.
[Back to top]
Musculoskeletal Adverse Drug Reactions: A Review of
Literature and Data from ADR Spontaneous Reporting Databases
Anita Conforti, Christian Chiamulera, Ugo Moretti, Sonia
Colcera, Guido Fumagalli and Roberto Leone
[Full
Text Article]
The musculoskeletal system can be a target organ for adverse
drug reactions (ADRs). Drug-induced muscle, bone or connective
tissue injuries may be due to, i), primary direct drug action,
or, ii), undirected consequence of generalized drug-induced
disease. Musculoskeletal ADRs may be only temporarily disabling,
such as muscle cramps, as well as in other cases may be serious
and life-threatening, such as rhabdomyolysis. In the last
few years there has been an increasing awareness of musculoskeletal
ADRs. Some recent drug safety issues dealt with serious or
uncommon musculoskeletal reactions like rhabdomyolysis associated
to statins and tendon rupture associated to fluoroquinolones.
In this review, we firstly selected those drug classes having
a significantly high percentage of musculoskeletal disorder
reports in the WHO adverse drug reaction database, maintained
by the Uppsala Monitoring Centre. Secondly, the different
musculoskeletal ADRs were closely analyzed through the data
obtained from an Italian interregional ADRs spontaneous reporting
data-base. The findings on drugs associated to different musculoskeletal
disorders, have been integrated with a review of the epidemiological
data available in the literature. For the most involved drugs
(HMG-CoA reductase inhibitors, fluoroquinolones, corticosteroids,
bisphosphonates, retinoids) the underlying musculoskeletal
ADR mechanisms were also reviewed and discussed.
[Back to top]
Rational Pharmacotherapy and Pharmacovigilance
Ahmet Akici and Sule Oktay
[Full
Text Article]
Pharmacovigilance is defined as “the detection, evaluation,
understanding and prevention of adverse drug reactions (ADRs)”.
The ultimate aim of pharmacovigilance is the optimization
of the risk-benefit ratio of marketed drugs at the individual
level (i.e. the choice of the most suitable treatment for
a given patient) and at the population level (i.e. main-tenance
or removal of a drug from the market, informing prescribers
of its potential risks, etc.). Prevalence of drug-related
morbidity and mortality increase in correlation with the increase
in drug use. Both physicians and patients prefer polypharmacy
because of different reasons such as insufficient knowledge,
lack of enough time for the patients, being misled by non-scientific
newspaper / TV news, etc. Polypharmacy is among the major
causes of drug-related morbidity and requires additional medication
as treatment. On the other hand, adverse reactions might be
minimized by adequate knowledge and rational prescribing,
simply by reducing inappropriate polypharmacy. Therefore,
physicians’ prescribing habits based on rational pharmacotherapy
processes which include choosing suitable drug(s), at an optimum
dose and duration of use, among the effective and safe treatment
alternatives, and informing patients about the diagnosis and
treatment, can be a major contribution to optimize the risk-benefit
ratio of drugs. As an essential step in the rational pharmacotherapy
process, giving adequate information to the patients about
their treatment (i.e. dosage, use instructions, warnings,
effects, side effects, etc.) may prevent some of the drug-related
problems. In addition, informed patients are more likely to
seek advice from their physicians to seek advice for ADRs.
In this review article, therefore, the influence of rational
pharmacotherapy training on the pharmacovigilance of drugs
will be discussed.
[Back to top]
The Risks and Benefits of Therapy with Aldosterone
Receptor Antagonist Therapy
Domenic A. Sica
[Full
Text Article]
Spironolacotone and eplerenone are mineralocorticoid-blocking
agents. These compounds block both the epithelial and non-epithelial
actions of aldosterone with the latter assuming increasing
clinical importance. Spironolactone and eplerenone both effectively
reduce blood pressure either as mono- or add-on therapy; moreover,
they each offer survival benefits in diverse circumstances
of heart failure and the potential for renal protection in
proteinuric chronic kidney disease. However, as the use of
mineralocorticoid-blocking agents has increased the hazards
inherent to use of such drugs has become more apparent. Whereas;
the endocrine side-effects of spironolactone are in most cases
little more than a cosmetic annoyance the potassium-sparing
effects of both spironolactone and eplerenone can prove fatal
if sufficient degrees of hyperkalemia develop. However, for
most patients the risk of developing hyperkalemia in and of
itself should not discourage the sensible clinician from bringing
these compounds into play. Hyperkalemia should always be considered
as a possibility in any patient receiving one or the other
of these medications. As such, steps should be taken to lessen
the likelihood of its occurring if therapy is being contemplated
with agents in this class.
[Back to top]
Adverse Drug Reactions in Hospitals: A Narrative Review
Emma C. Davies, Christopher F. Green David R. Mottram
and Munir Pirmohamed
[Full
Text Article]
The serious nature of adverse drug reactions (ADRs) has been
highlighted in a number of instances over the last forty years,
the most recent of these being the occurrence of serious thrombotic
events with the use of COX-2 inhibitors. ADRs are estimated
to be between the 4th and 6th leading
cause of death in the USA, with fatal ADRs occurring in 0.32%
of patients. A recent UK study showed that 6.5% of hospital
admissions were related to ADRs. ADRs can therefore be regarded
as a significant public health and economic problem. There
is an urgent need to develop better preventive strategies
to reduce the burden of ADRs. Because ADRs can affect any
bodily system, can have many different clinical presentations,
and are of widely variable severity, prevention will not be
easy and will have to be multifactorial in its approach. This
paper reviews the epidemiology of ADRs in hospitals and evaluates
the research that has been undertaken to date to prevent ADRs.
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Quality, Safety and Efficacy in the ‘Off-Label’
Use of Medicines
Therése Eileen Kairuz, Derryn Gargiulo, Craig Bunt
and Sanjay Garg
[Full
Text Article]
Suitable dosage forms are not always available for specific
patient populations and must be extemporaneously compounded.
Extemporaneous preparation is the manipulation of drugs and
excipients for a particular patient using traditional compounding
techniques; these are referred to as ‘off-label’
and ‘unlicensed’ medicines. Off-label use can
include altered doses, dosage forms or indications for use.
Registered medicines are produced to internationally recognized
standards of Good Manufacturing Practices. Within the pharmaceutical
manufacturing industry, quality, safety and efficacy are enforced
by regulatory legislations. In contrast, the responsibility
for acceptable standards for the compounding of ‘off-label’
medicines falls on the prescriber, pharmacist or hospital
nurse. Studies have been conducted by researchers from Australia
and throughout Europe, highlighting the frequency of off-label
use for paediatrics, with one study reporting that most extemporaneous
preparations (29.6%) were for drugs required to treat metabolic
diseases. Risks include compounding errors, adverse reactions
to ingredients and excipients, and non-validated stability
of the product. Sterile compounded products, including products
for ophthalmic and palliative care, carry additional risks
in these vulnerable patients.
This paper provides an overview of off-label medicines highlighting
biopharmaceutical, quality, safety and efficacy issues important
to medical and allied health professionals.
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