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RESEARCH NEWS
New
research from the Centre
Glubb,
D.M., McHugh, P.C., Deng, S., Joyce,P.R., Kennedy,
M.A. (2009) Association of a functional polymorphism
in the adrenomedullin gene (ADM) with response to paroxetine.
Pharmacogenomics Journal. [Epub ahead of print]. In this
work we describe gene expression changes induced by
an antidepressant in a cultured neural cells. One of
the most interesting expression changes observed was
for a small protein hormone called adrenomedullin. Further
investigation showed the gene for this protein may have
a modest effect on patient responses to this antidepressant.
McHugh, P.M., Rogers, G.R., Glubb, D.M., Allington, M.,
Joyce, P.R., Kennedy, M.A. (2009) Proteomic analysis of rat hippocampus
exposed to the antidepressant paroxetine. J Psychopharmacol.
Apr 3. [Epub ahead of print].
This work is a preliminary exploration of the effect
on protein patterns in the hippocampus after exposure
to the antidepressant paroxetine. We identified a range of proteins
that showed upregulation
or downregulation of several proteins. The functions
of these proteins may inform about aspects of antdidepressant action
in the brain.
Glubb,
D.M., Joyce, P.R., Kennedy, M.A. (2009) Expression
and association analyses of promoter variants of
the neurogenic gene HES6, a candidate gene for
mood disorder susceptibility and antidepressant
response. Neurosci. Let. 460, 1985-190. This study
further explored a gene that showed expression
changes in cultured brain cells exposed to the
antidepressant paroxetine. We found that genetic
variability in the control regions of the gene
affected expression, but that these variants were
not associated with risk of mood disorders or response
to antidepressant drugs.
Sharp CF, Gardiner SJ, Jensen BP, Roberts RL, Troughton RW, Lainchbury JG, Begg, EJ.(2009) CYP2D6 genotype and its relationship with metoprolol dose,
concentrations and effect in patients with systolic heart failure. Pharmacogenomics J 9:175-184.
The beta-blocker drug metoprolol is often used to
treat systolic heart failure. The drug is broken
down by a liver enzyme called CYP2D6, which displays
signficiant genetic variability. The effect of these
CYP2D6 gene variants on dose of the drug and clinical
measures of treatment was examined in heart failure
patients. A clear effect of gene variation on drug
levels
in patient blood was observed, although no clinical
effects were obvious.
McHugh,
P.M., Rogers,G.M., Glubb, D.M., Allington, M.D.,
Hughes, M., Joyce,
P.R., and Kennedy, M.A. (2008) Downregulation
of Cyclin D1 (Ccnd1) and Hairy Enhancer of Split
6 (Hes6)
in rat hippocampus after chronic exposure to the
antidepressant paroxetine. Acta Neuropsychiatrica
20, 307-313.
This study explored gene expression changes in the
brain induced by an antidepressant drugs, and identified
two genes of possible importance to the action of
these drugs.
Clark, DWJ, Ashton,
JA, Wallace, AK, Zhou, L, Kennedy, MA. (2008) Pharmacogenetic
investigation using a pharmacovigilance database.
PharmacoVigilance Review 2, 9-13. David Clark and colleagues
describe a pilot pharmacogenetic study in the pharmacovigilance
database of the New Zealand Intensive Medicines Monitoring
Programme.
Roberts,R.L,
Gearry,R., Sies,C., George,P., Burt,M., Marinaki,A.,
Barclay,M.,
Kennedy, M.A. (2008). Trinucleotide repeat variants
in the promoter of the thiopurine S-methyltransferase
gene of patients exhibiting ultra-high enzyme activity.
Pharmacogenetics and Genomics 18, 434-438. Genetic
analysis of rare patients showing very high
activity of an enzyme called TPMT, important in breaking
down drugs used in treatment of inflammatory bowel
disease and leukaemia, uncovered a subtle difference
in the gene sequence which appears to result in high
activity.
18 Jun 2009. FDA updates plavix (clopidogrel) label with pharmacogenetic data
The US Food and Drug Administration has updated the label for Plavix with pharmacogenetic data informing doctors and patients of diminished response to the drug and increased risk of heart attack in patients with reduced CYP2C19 function.
The new label acknowledges that mutations which affect the CYP2C19 gene are associated with reduced response to clopidogrel, and that pharmacogenetic testing can identify the mutations that cause variability in CYP2C19 activity. However, the FDA does not formally recommend or require testing for the CYP2C19 genetic variants proir to treatment, nor does it provide any dosing advice for patients with the mutations.
"The optimal dose regimen for poor metabolizers has yet to be determined," the new label states.
19 Feb 2009. Important
paper on estimation of warfarin dose published
in NEJM. A large international
consortium today published its findings on a study
of over 5000 patients prescribed warfarin. The group
showed that by combining clinical data with pharmacogenetic
information on
the genes CYP2C9 and VKORC1, a stable therapeutic
dose could be more rapidly acheived. They found the
greatest benefits were in the 46% of patients that
require relatively low or high doses; patients who
require intermediate doses acheived little benefit
from the addition of pharmacogenetic
data.
29 Oct 2008. Wisconsin
Brings Together Four Institutions For Personalized
Medicine Initiative.
Wisconsin has launched a new project that brings together
four state research institutions with the aim of studying
20,000 patient samples for 1 million genetic markers
to eventually translate personalized healthcare research
into real-world medical practice.
29 Mar 2007. Realizing
the Promise of Pharmacogenomics: Opportunities
and Challenges. Comprehensive draft document
on pharmacogenomic released by the NIH Secretary’s
Advisory Committee on
Genetics, Health, and Society (USA). Provides an up to date, thorough assessment
of the state of pharmacogenomics knowledge, practice, and the challenges
ahead. This 128 page document is open for public comment until 1 June 2007.
26 Aug 2007. FDA
approves encourages genetic tests for guiding initial
warfarin dosage. The FDA announced today the approval
of updated labeling for the widely used blood-thinning
drug, Coumadin, to explain that people's genetic makeup
may influence how they respond to the drug. About one
third of patients receiving warfarin metabolize it quite
differently
than expected. Research has shown that some of the unexpected
response to warfarin depends on a patient's variants
of the genes CYP2C9 and VKORC1. These tests are not yet
widely available, and more research is required to confirm
the value and appropriateness of the tests.
29 Mar 2007. Realizing
the Promise of Pharmacogenomics: Opportunities
and Challenges. Comprehensive draft document
on pharmacogenomic released by the NIH Secretary’s
Advisory Committee on
Genetics, Health, and Society (USA). Provides an up to date, thorough assessment
of the state of pharmacogenomics knowledge, practice, and the challenges
ahead. This 128 page document is open for public comment until 1 June 2007.
New
research from the Centre
