Professional Documents
Culture Documents
Pharmacology
DOI:10.1111/bcp.12303
Editors pick
Department of Clinical Pharmacology, School of Medicine (Cardiovascular Division) Kings College London, London, 2School of Medicine, University of
East Anglia, Norwich, UK, 3Section of Clinical Pharmacology, Department of Medicine, Dartmouth Medical School &Dartmouth-Hitchcock Medical
Center, Lebanon, NH, USA, 4Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia and 5Centre for Human
Drug Research, Leiden, the Netherlands
Themed issues
This Journal continues to publish a mix of original
research and review articles on all aspects of drug action
in man in categories identified by the authors, sometimes grouped into themed issues or sections. The first
themed section of 2013 was on nutraceuticals a term
that has caused some dismay among purists, representing as it does a field awash with marketing hype for products that are chemically incompletely defined and with
little, and very often no, scientific basis. Nevertheless
there is an emerging body of evidence to support the
therapeutic use of several such products and we recall
that the founding fathers of pharmacology were prepared to use incompletely characterized extracts of
spleen, prostate or fungus (e.g. ergot) to probe physiological function and to advance therapeutics. We
explored this young branch of our discipline in this collection of articles. We wished in particular to highlight
that an evidence-based approach to such products,
underpinned by good science, can make important contributions to public health, in addition to, not instead of,
pharmaceutical therapies see for example [1].
August saw an issue on biologics. The history of these
dates back at least 200 years and includes the development of the smallpox vaccine following on from Edward
Jenners work at St Georges Hospital in London, as well as
the use of blood transfusion. Biologics have very much
come to the fore in recent years and such therapies have
mushroomed (currently approximately 30% of new drugs
licensed per annum in Europe and the USA). We
overviewed the current status of biologics in a number of
disease areas (and also an article on a potential nontherapeutic application of the future: gene doping in sport
[2]), and touched on how the conduct of early phase trials
has evolved since the supervised simultaneous megaoverdose of a whole cohort of subjects with TGN1412,
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Br J Clin Pharmacol
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Editors pick
Therapeutic matters
Dosing regimens need to be adjusted according to renal
function, so it is no surprise that clinical pharmacologists
have a keen interest in the comparative performance of
different formulae for estimating the glomerular filtration
rate (GFR). In a study of 16 older patients, Drenth-Van
Mareen and colleagues found that the CockcroftGault
equation based on ideal body weight is the most reliable
option [5]. However, caution is required since misclassification of chronic kidney disease potentially occurred in
up to one in four patients, even with the best performing
formula.
Errors in classification also occur when computerized
diagnostic codes (recorded by general practitioners) are
used to identify suicide and self-harm. Thomas and colleagues found that only just over a quarter of suicides
(identified from the gold standard national statistics database) were correctly identified using diagnostic codes in
the Clinical Practice Research Database, and that the
general practice codes also grossly underestimated the
incidence of self-harm [6]. Data linkage of general practice
records with government mortality databases will help to
address these gaps, which are particularly important for
pharmaco-epidemiological research into drug-related selfharm and suicide.
Research may also shake some therapeutic preconceptions. Melatonin, a non-prescription drug widely used for
sleep problems, was investigated in patients receiving
chronic haemodialysis (a procedure that can interfere with
sleep) by Rusccher and colleagues [7]. These authors found
some benefit from 3 month melatonin treatment, but no
demonstrable improvement in quality of life or sleep with
use up to 12 months. The case for long term use of
melatonin remains unproven.
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Br J Clin Pharmacol
Topical vs. oral administration of non-steroidal antiinflammatory drugs (NSAIDs) reduces the incidence and
severity of harmful effects but can be equally effective for
soft tissue pain and inflammation. Diclofenac is formulated
as a gel and is available without prescription, but concerns
remain regarding its COX2 inhibition. Hence, there is the
need to evaluate other NSAIDs. The tissue rather than
plasma pharmacokinetics of these topical formulations are
the optimal bioavailability assessment, but which tissue is
the subject of debate. Kai and colleagues conducted
a pharmacokinetic study in 16 patients scheduled to
undergo anterior cruciate ligament reconstruction [15].
Oral flurbiprofen (as tablets) was given to seven patients
twice daily and, flurbiprofen as a proprietary tape (immediate release transdermal delivery) on the medial and
lateral aspects of the knee at 14 and 2 h prior to surgery to
another nine patients, with blood, subcutaneous fat, sartorius muscle, tendon and peri-osteal tissue and drilledbone tissue collected for flurbiprofen concentration
assessment. Whereas the transdermal : oral concentration
ratio was about 6 for fat, tendon and muscle, it was only 2
for peri-osteal tissue and 0.5 for bone. Somewhat surprising was that the plasma concentration for the transdermal
formulation was 40% that of plasma. Although these
values were only at one time point, they indicate that a
substantial amount of the drug can diffuse into the blood
stream and that just sampling one tissue (for example the
tendon) may lead one to conclude erroneously that other
local tissues, such as the peri-osteum, will have the same
pharmacokinetic profile.
Allopurinol has stood the test of time (it is listed twice
in the WHO list of Essential Medicines), having been
discovered and investigated in the mid 1950s by Nobel
laureates Gertrude Elion and George Hitchings. It was
approved in 1966 for hyperuricaemia, but still holds some
secrets, including what factors determine the substantial
inter-individual variation in responsiveness to this drug.
Graham and colleagues [16] tackled this by examining
doseresponse relationships in patients with gout, using a
modelling approach with plasma urate as the response
metric. It is under-appreciated that for individuals there is
a plasma urate concentration beyond which the value
cannot be reduced further by allopurinol, the apparent
resistant plasma urate concentration. By collating data
from two patient cohorts (total 47 patients), these authors
developed an equation that relates dose, plasma urate
concentration before and during allopurinol treatment to
steady-state and ID50 (allopurinol dose to reduce the
inhibitable plasma urate concentration by 50%). The equation fitted the data with an r2 of 0.74. Somewhat surprisingly creatinine clearance did not improve the fit, but the
authors rightly argue that it should nonetheless be used to
determine the starting dose. They confirmed that a higher
baseline plasma urate requires a higher maintenance dose
and (less well appreciated) that not everyone needs the
usual fixed dose of 300 mg daily.
Editors pick
Table 1
Distribution of articles by category in 2013 (1st Jan31st Oct)
Article category
Number
Percentage
Review
Pharmacokinetics (PK)
67
28
24.7
10.3
Letter
Clinical trials
26
23
9.6
8.5
Drug safety
Drug interactions
14
13
5.2
4.8
PKPD relationships
Pharmacoepidemiology
11
10
4.1
3.7
Supplement article
Pharmacodynamics (PD)
10
9
3.7
3.3
Pharmacogenetics
Methods in clinical pharmacology
8
7
3.0
2.6
7
6
2.6
2.2
Systematic review
Meta-analysis
6
4
2.2
1.5
Therapeutics
Drugs in pregnancy and lactation
4
3
1.5
1.1
Translational research
1.1
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2 Gould D. Gene doping: gene delivery for olympic victory.
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6 Thomas KH, Davies N, Metcalfe C, Windmeijer F, Martin RM,
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