NEWS & INSIGHTS AUGUST 2015

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2013 cholesterol
guidelines prove accurate
in predicting CV events

OBSTETRICS & NEWS

GYNAECOLOGY TNF blockade
FOCUS eases symptoms
in nonradiographic
World Breastfeeding
spondyloarthritis
Week

DRUG PROFILE CONFERENCE

Vortioxetine for COVERAGE
major depression See-sawing BP
should be target
of CVD treatment

2013 cholesterol guidelines prove
accurate in predicting CV events
RADHA CHITALE
T he 2013 American College of Cardiology/
American Heart Association (ACC/AHA)
guidelines for cholesterol management, which,
controversially, lowered the statin eligibility
threshold, proved superior to previous guide-
lines at identifying patients at risk for heart at-
tack, death from coronary heart disease (CHD),
and ischaemic stroke and more cost-effective,
according to two studies.
The ACC/AHA guidelines came under scru-
tiny because they broadened risk criteria for
statin eligibility beyond bad low-density lipo-
protein (LDL) levels to include age, smoking,
and diabetes, for example, and added stroke as
a primary endpoint event.
The new prediction model lowered the statin
treatment threshold from a 10 percent risk of an
atherosclerotic cardiovascular disease (ASCVD)
event within 10 years to 7.5 percent risk, which
could have put 8 to 12 million more people in the
US on statin therapy.
In this community-based primary prevention
cohort, the ACC/AHA guidelines for determin-
ing statin eligibility, compared with the [ATP III*],
were associated with greater accuracy and ef-
ficiency in identifying increased risk of incident
[cardiovascular disease (CVD)] and subclinical
coronary artery disease, particularly in interme-
diate-risk participants... the most challenging
group in clinical practice for whom to decide to
AUGUST 2015 2
initiate statin therapy, said investigators from
the efficacy study. [JAMA 2015;314:134-141]
The study included 2,435 patients (mean age
51 years, 56 percent women) who were treat-
ment-naive for lipid-lowering therapy whom the
researchers assessed using the 2013 ACC/AHA
guidelines and the 2008 ATP III guidelines.
Participants were checked for coronary ar-
tery calcification (CAC) between 2002 and 2005
and followed for a median 9.4 years for incident
CVD.
There were 40 nonfatal myocardial infarc-
tions, 31 nonfatal ischaemic strokes, and 3 fatal
coronary heart disease (CHD) events for a total
of 74 (3 percent) incident CVD events and 43
incident CHD (2 percent) events.
More patients could have received statin
therapy with the ACC/AHA guidelines (39 per-
cent) compared with the ATP III guidelines (14
percent).
Among those eligible or ineligible for statin
treatment, 7 vs 2 percent, respectively, devel-
oped incident CVD using the ATP III guidelines

compared with 6 vs 1 percent, respectively, us-
ing the ACC/AHA guidelines. The risk of incident
CVD among statin- eligible people was higher
when using the ATP III guidelines than with the
ACC/AHA guidelines (hazard ratio, 6.8 vs 3.1,
p<0.001). Statin eligibility was also more likely
for ACC/AHA-assessed patients than for ATP III-
assessed patients (p<0.001).
In assessing the cost efficiency, researchers
found that the 7.5 percent ASCVD threshold had
an incremental cost-effectiveness ratio (ICER) of
US$37,000 per quality-adjusted life-year (QALY)
compared to the 10 percent threshold. [JAMA
2015;314:142-150]
Lowering the statin eligibility further to 4 or
3 percent would cost US$81,000/QALY and
US$140,000/QALY,
respectively, and could
result in up to 160,000 CVD events averted.
There is no longer any question as to wheth-
AUGUST 2015 3
er to offer treatment with statins for patients
for primary prevention, and there should now
be fewer questions about how to treat and
in whom, said Dr. Philip Greenland of the
Northwestern University Feinberg School of
Medicine in Chicago, Illinois, US and Dr. Mi-
chael Lauer of the National Heart, Lung, and
Blood Institute in Bethesda, Maryland, US and
senior editor of the Journal of the American
Medical Association, in an accompanying edi-
torial. [JAMA 2015;314:127-128]
Although lifestyle interventions must be
employed across all segments of the popula-
tion, for many people a statin drug will also be
required to minimize risk.
*ATP III: US National Cholesterol Education Programs 2004 Up-
dated Third Report of the Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults

Solanezumab may delay Alzheimers
progression
ELVIRA MANZANO
T he amyloid-busting drug solanezumab of-
fers benefits in cognition and function when
given early, according to an ongoing extension
study of patients with Alzheimers disease. Tak-
ing solanezumab for longer time yielded greater
benefit.
We think there is a chance that solanezum-
ab will be the first disease-modifying medication
to be available, said Dr. Eric Siemers, a senior
medical director at Eli Lilly, which makes solan-
ezumab.
Two phase III trials of solanezumab (EXPEDI-
TION 1 and EXPEDITION 2) ended in failure in
2012. [N Engl J Med 2014;370:311-321]. How-
ever, the 2-year extension trial EXPEDITION-EXT
in patients with mild Alzheimers suggests that
solanezumab is able to slow disease progres-
sion over 3.5 years. At 7 months, differences in
cognition and function between patients treat-
ed early with solanezumab and those treated
late were statistically significant. [Alz & Dement
2015; doi:10/16/j.trci.2015.06.006]
A safety analysis showed that the drug was
well-tolerated.
EXPEDITION-EXT included 581 patients with
mild Alzheimers. One group (n=295) was treat-
ed with solanezumab 400 mg every month for
18 months, the other with placebo (n=286). Af-
ter 18 months, patients on placebo started treat-
ment with solanezumab while those in the origi-
AUGUST 2015 4
nal solanezumab arms continued to receive the
drug at the same dosing regimen. Both groups
were measured for cognition and daily function
scores using ADAS-Cog 14 and ADCS-iADL, re-
spectively. Primary analysis time point was 27
months.
We assessed if solanezumab had an ef-
fect that is consistent with slowing progression
of disease by modifying the underlying disease
progression, said study author Professor Hong
Liu-Seifert, medical director, Eli Lilly. Patients who
had the treatment delayed were unable to catch
up with those whose treatment began ear-
lier, suggesting that starting solanezumab early
could slow disease progression, not just reduce
symptoms.
There is persistence of treatment effect even
in placebo-treated patients given the drug 18
months later, said co-author Dr. Paul Aisen, di-
rector of the Alzheimers Therapeutic Research
Institute at the University of Southern California
in San Diego, California, US.
The findings are another piece of evidence
that solanezumab does have a disease-modify-
ing effect, said Siemers.
Experts not involved in the study said the
finding is an exciting step forward but cautioned
that the clinical effects of solanezumab remain
to be seen.
A follow-up trial in patients with mild disease
is expected to provide a more conclusive data
next year.
 AUGUST 2015 FO R U M 5

Childhood obesity arises from

obesogenic environments
Excerpted from a speech by Dr Margaret Chan, WHO director general, during the third
meeting of the Commission on Ending Childhood Obesity held recently in Hong Kong.

T he complexities of childhood obesity make it
an especially stubborn problem to address.
No stand-alone intervention or single-pronged
strategy will work.
Many of the factors that contribute to child-
hood obesity or stand in the way of its prevention
reside in non-health sectors. Persuading these
sectors to add health concerns to their mandates
is not easy, though our experiences with tobac-
co control show that it can be done. Compelling
evidence helps, especially when this evidence is
translated into a menu of feasible policy options.
The work of this Commission creates a high-
profile opportunity to communicate state-of-
the-art science, backed by your authority and
recommendations, directly to the policy-making
community.
I challenged the Commission on Ending Child-
hood Obesity to approach the huge problem of
childhood obesity with some new thinking. Given
the patchy and entirely inadequate progress to
date, I stressed the importance of coming up with
some novel approaches. The interim report deliv-
ered magnificently on all of these requests.

That report cleared the air, and settled some
controversies, in a number of areas.
You spelled out the rationale for focusing on
childhood obesity and tracked the spillover ben-
efits this has for society at large. You also cited
evidence that the negative health consequences
of childhood obesity can persist, even if normal
weight is attained in adulthood. In other words,
childhood obesity can leave a permanent im-
print. Who would want to see a person perma-
nently impaired so early in life?
You adopted a life-course approach as a nov-
el way to tackle a risk that tends to be passed on
from one generation to the next. You recognized
that different life-course groups require packages
of specific, coordinated interventions that should
be applied in sequence, with a cumulative effect.
Adoption of the life-course approach also led
to some startling observations. For example,
some children are on the pathway to obesity
from the day they are born, or even before they
are born, as the emerging evidence shows.
You introduced some new concepts. Risks
once thought to be either genetic or acquired
may be a combination of both. This is important
as some epigenetic changes can be modified or
reversed through appropriate interventions.
You clarified the scale of the challenge by
stressing the need for a multi-pronged ap-
proach that engages multiple non-health sec-
tors. Addressing the obesogenic environment
is not enough, but no approach that fails to
address this environment can be successful.
You sounded the alarm, time and time again.
Childhood obesity can erode the benefits that
arrive with social and economic progress. Child-
AUGUST 2015 F O R U M 6
hood obesity must be accepted as a significant
and urgent threat to health that is relevant in all
countries. Governments must take the lead.
You signalled the group of countries at great-
est risk: those undergoing rapid socioeconomic
and nutritional transitions, where evidence on ef-
fective interventions is often patchy or non-exis-
tent.
You placed things in perspective. You iden-
tified many factors that help explain why the
prevalence of infant, childhood, and adolescent
obesity is increasing in all countries, but you sin-
gled out one particularly pervasive driving force:
the globalized marketing of unhealthy foods and
beverages. In fact, you described the evidence
of its impact on childhood obesity as unequivo-
cal. That, too, clears the air.
You pointed the finger at the larger role played
by food, trade, and investment policies, and by
trade and agriculture agreements.
You reminded everyone that real progress
depends on establishing constructive, transpar-
ent engagement with the private sector, and en-
couraging policies that support the production of
healthier foods.
But you also issued a warning: voluntary ini-
tiatives are not likely to be sufficient. To be suc-
cessful, efforts aimed at reducing the marketing
of unhealthy foods and beverages need support
from regulatory and statutory approaches.
As noted, the impact of taxation measures on
purchasing behaviour is well-supported by the
evidence.
You included novel policy options, such as
zoning around schools to curtail the sale of un-
healthy foods and beverages.

Finally, and perhaps most importantly, you
defined a moral responsibility and stated where
it must lie. None of the factors that cause obesity
are under the control of the child.
Childhood obesity does not arise from lifestyle
choices made by the child. It arises from environ-
ments created by society and supported by gov-
ernment policies. The argument that obesity is
the result of personal lifestyle choices, often used
to excuse governments from any responsibility
to intervene, cannot apply to childhood obesity.
As stated in the report, This singular conclu-
sion places a moral responsibility on all societies
to act on the childs behalf to reduce the risk of
obesity through a variety of actions.
This, in my view, is one of the Commissions
most compelling conclusions.
The Interim Report provided the basis for a pub-
lic consultation. The task now before you is to turn
the best science and new thinking into further rec-
ommendations and menus of policy options. Your
recommendations need to be appropriate to the
magnitude of the crisis and have the best chance
of making a difference in a diversity of settings.
During the May World Health Assembly,
reaching agreement on how WHO should en-
gage with non-state actors was one of the most
difficult issues in an especially challenging ses-
sion. In particular, in engaging with industry, two
red lines must not be crossed, as I have stressed
time and time again.
AUGUST 2015 FO R U M 7
Industry must have no say on the technical
guidance issued by WHO. And industry cannot
participate in the formulation of public health pol-
icies. Both areas are prone to conflicts of interest.
Both must be protected from influence by indus-
tries with a vested interest.
Combatting obesity involves many indus-
tries, including the sports industry. We must
get the targets right, and here the Interim Re-
port helps again.
The biggest harm comes from the market-
ing of sugar-rich non-alcoholic beverages and
ultra-processed, energy-dense, and nutrient-
poor foods, which are often the cheapest and
most readily available, especially in poorer
communities.
As noted in the report, these industries seek
voluntary agreements and strongly oppose regu-
latory approaches. Both industries are powerful
economic operators. Economic power readily
translates into political power.
Let them make their promises. Welcome their
proposals to reformulate their products. Then
watch very closely and hold them accountable
for what actually happens.
This is the approach being followed by some
countries. Give these industries enough rope to
hang themselves if they fail to deliver on volun-
tary agreements and marketing codes. But we
cannot exclude them from the outset without giv-
ing them a chance.
 AUGUST 2015 N E W S 8

Some antidepressants linked

to increased risk of birth defects
ROSHINI C.

S ome antidepressants may increase the

risk of birth defects among babies born
to mothers who took the medications early in
pregnancy, a study has shown. However, re-
searchers said the results should be interpreted
with caution as the overall risk is relatively small
and there is no definitive proof that the medica-
tions caused birth defects in newborns.
Researchers analyzed data on 38,000 wom-
en who gave birth between 1997 and 2009 and
found that certain birth defects were more com-
mon among women treated with certain selec-
tive serotonin reuptake inhibitors (SSRIs). Fluox-
etine and paroxetine, for example, were linked to
right ventricular outflow tract obstruction cardiac
defects. Paroxetine was also associated with or without cleft palate, oesophageal atresia, anal
anencephaly and atrial septal defects. However, atresia, hypospadias, limb reduction defects,
there was no association between sertraline use craniosynostosis, gastroschisis, and omphalo-
and birth defects. There was also no increased cele) among newborns and asked their mothers
risk of birth defects with citalopram and escitalo- about antidepressant use prior to getting preg-
pram. [BMJ 2015, 350:h3190] nant or during the first trimester of pregnancy.
The primary objective of the study was to Those who had taken citalopram, escitalo-
identify if previously reported links between birth pram, fluoxetine, paroxetine, or setraline were
defects and SSRIs were supported by data from included in the study. Women with known
the US National Birth Defects Prevention Study, chromosomal or monogenic disorders, with
a population-based, case-control study. The pregestational diabetes or using misoprostol,
researchers looked at the birth defects (neural methotrexate, mycophenolate mofetil, thalido-
tube defects, anencephaly, all septal defects, mide and isotretinoin were excluded from the
ventricular septal defects, right ventricular out- analysis as well as those with depression, anxi-
flow tract obstructions, cleft palate, cleft lip with ety, bipolar disorder, or obsessive compulsive

disorder who did not use antidepressants, and
those who did not consume antidepressants
from 3 months prior through to the end of preg-
nancy.
The results of the study highlighted the im-
portance of identifying the links between specific
Intrahepatic cholestasis of pregnancy
raises risk of multiple diseases later
in life
SARAS RAMIYA
I ntrahepatic cholestasis of pregnancy (ICP) in-
creases the risk of hepatobiliary cancer and
immune-mediated and cardiovascular diseases
later in life, shows a study conducted in Swe-
den.
The new study involving more than 125,000
pregnant women was conducted to determine
the risks of ICP in expectant mothers. ICP is
found in 0.4 to 1.5 percent of pregnancies. Symp-
toms include unexplained itching with increased
levels of serum bile acids and/or liver enzymes
in the second and third trimester. Although ICP
may lead to preterm delivery and stillbirth, it was
previously not regarded as a serious condition in
mothers because it spontaneously resolves after
delivery. [J Hepatol 2015 Mar 12. doi: 10.1016/j.
jhep.2015.03.010]
This large population-based study in
women with ICP found increased risks of later
AUGUST 2015 N E W S 9
antidepressants and birth defects, as opposed
to associating risk with classes of drugs, said the
authors. They also acknowledged that the birth
defects could be linked to factors other than ma-
ternal antidepressant use, such as underlying
medical conditions.
hepatobiliary cancer and immune-mediated
diseases and a small increased risk of later car-
diovascular disease, said principal investiga-
tor Dr. Hanns-Ulrich Marschall of Sahlgrenska
Academy, Institute of Medicine, Department of
Molecular and Clinical Medicine, University of
Gothenburg, Sweden.
Investigators identified 11,388 women with
ICP and 113,893 matched women without ICP
from the Swedish Medical Birth Register and the
Swedish Patient Register. These women deliv-
ered between 1973 and 2009. The Patient Regis-

ter provided information on diagnoses of cancer
and immune-mediated and cardiovascular dis-
eases both before and after delivery.
The study showed that women who had
experienced ICP were at 2.5 times higher risk
of cancer in the biliary tree and 3.5 times in-
creased risk of liver cancer later in life com-
pared with matched controls. Even after adjust-
ing for a diagnosis of hepatitis C, which is very
strongly associated with liver cancer, women
with ICP were still at 2.5-times increased risk of
liver cancer.
The data indicate that patients with ICP
have an increased risk of a variety of immune-
AUGUST 2015 N E W S 10
mediated diseases, such as thyroid disease
(30 percent higher than pregnant controls),
diabetes (47 percent), psoriasis (27 percent),
and Crohns disease (55 percent). Investiga-
tors also found a slightly increased risk of future
cardiovascular disease, but only in women with
both ICP and pre-eclampsia during pregnancy.
We strongly recommend a follow-up of
serum liver tests 6 to 12 weeks after delivery
in all women with ICP, with and without per-
sisting pruritus, and if serum liver test results
are elevated, further evaluation by a hepa-
tologist, said Marschall and his co-inves-
tigators.

Simple sniffing test can help screen
for autism
DR MARIA KATRINA FLORCRUZ
A simple sniffing test can help detect autism
spectrum disorder (ASD) in nonverbal chil-
dren, according to a recent study.
Researchers exposed children to unpleasant
smells such as rotten fish and milk and pleasant
smells such as shampoo or flowers. They found
that children without autism would inhale the nic-
er scents to a much greater extent than the less
pleasant odours. However, children with ASD
had aberrant sniffing response regardless of the
odour. Altered sniffing was associated with the
severity of ASD (r=-0.75, p<0.001) and social
impairment (r=0.72, p<0.001). [Current Biology
2015; doi:/10.1016/j.cub.2015.05.048]
The study included 18 children with ASD
(mean age 7 + 2.3 years) and 18 matched
healthy controls (mean age 6.7 + 2.1 years).
Children with organic olfactory disturbance,
acute respiratory infection, and social com-
munication
questionnaire score above 11
were excluded. Sniff response was measured
using a computer-controlled olfactometer. A
custom paediatric nasal cannula delivered
odour while measuring nasal airflow. The
children were seated and watching a cartoon
during the 10-minute procedure.
Based on sniff parameters and traces, there
was a significant increase in sniffing for pleasant
versus unpleasant odours among children with-
out ASD. This group also adjusted their sniffing
AUGUST 2015 N E W S 11
to account for odour detection within 305 ms of
odour onset. On the other hand, children with
ASD did not significantly change their sniffing re-
gardless of the odour.
Analysis of three-way interaction among sniff
parameters, odorant valance and group showed
that children without ASD had adult-like sniff re-
sponse. ASD children, on the other hand,did
not adjust their sniff according to odorant prop-
erties, indicating that they did not activate their
olfactory internal action model.
Furthermore, sniff response parameters,
notably sniff duration, was strongly correlated
with autism severity on Autism Diagnosis Ob-
servation Schedule (ADOS). This suggests
an association between olfaction and ADOS
scores. Sniff response was also correlated with
the social affect component of ADOS, but not
motor impairment.
Moving forward, the researchers intend to
do further studies to test the specificity of the
sniff-response pattern to autism, or if similar
association is present in other neurodevelop-
mental conditions.
 AUGUST 2015 N E W S 12

Non-viral gene therapy benefits

patients with cystic fibrosis
DR MARIA KATRINA FLORCRUZ

L ung delivery of plasmid DNA encoding the

cystic fibrosis transmembrane conductence
regulator (CFTR) gene complexed with a cat-
ionic liposome, helped improve lung function
in patients with cystic fibrosis (CF), a phase IIb
randomized controlled trial has shown.
At 12-month follow-up, there was a significant
but modest treatment effect on the forced expi-
ratory volume in 1 second (FEV1) in the treat-
ment group compared with the placebo group
(3.7 percent, 95 percent CI, 0.17.3; p=0.046).
This result suggests stabilization in lung function
in the gene therapy group versus a decline in
the placebo group. [Lancet Respir Med2015;
doi/10.1016/S2213-2600(15)00245-3]
The trial was conducted in two CF centres
at 18 sites in the UK. Participants were eligible
if they were ages 12 years, had a predicted
FEV1 of 5090 percent, and had any combina-
tion of CFTR gene mutations. The treatment
group (n=78) received nebulised pGM169/
GL67Ageneliposome complex 5 ml or placebo
(n=62) every 28 days. Routine treatments were
continued while DNase was withheld for 24 hours
before and after dosing.
A total of 140 CF patients participated in the
study, 116 of which were included in the per-
protocol analysis. Relative differences in FEV1
after 12 months of treatment were -0.4 percent
(95 percent CI, 2.8 to 2.1) in the treatment
group vs 4.0 percent (95 percent CI, 6.6 to
1.4) in the placebo group. Further analysis
showed that 15 patients in the therapy group
and 6 in the control group had an improvement
of 5 percent or more in the percent predicted
FEV1 from baseline values. There was no differ-
ence in treatment-attributable adverse events
between the two groups.
Previous trials using viral vectors to deliv-
er CFTR gene into respiratory epithelial cells
have resulted in inefficient transduction. This
study proved for the first time that copies of
the normal CF gene delivered by aerosol inha-
lation can have a measurable beneficial effect
on lung function. Whether increased or more
frequent dosing or combining gene therapy
with other basic treatments would increase
benefits has yet to be determined in larger tri-
als, researchers said.

Empowering women through
contraception may reduce healthcare
burden
KAVITHA G. SHEKAR
E mpowering women through better access
to contraception could improve socioeco-
nomic status, promote human development
and reduce healthcare burden, paving the way
to gender equality, says an expert during an ob-
stetrics and gynaecology conference in Kuch-
ing, Malaysia.
To prove his point, Professor Alokendu Chat-
terjee, president of the South Asian Federation of
Obstetrics and Gynaecology (SAFOG), Kolkata,
India cited five key points from the 2014 WHO
guidelines and recommendations on Human
rights in the provision of contraceptive informa-
tion and services. These are non-discrimination,
availability, accessibility, quality of contraceptive
information and services, and informed decision-
making.
He said family planning (FP) services should
be provided equally to everyone voluntarily,
free of discrimination, coercion or violence. All
FP methods, including emergency contracep-
tion, should be made available within essential
medicine supply chain to increase availability
to women. In addition to that, gender sensi-
tive counselling and current evidence based
information on FP should be provided to meet
womens specific needs. Governments should
ensure that healthcare facilities, commodities
AUGUST 2015 N E W S 13
and services are of medically appropriate stan-
dards. Client feedback must be incorporated
into contraceptive programmes. Informed deci-
sion-making, on the other hand, would include
respecting the right to privacy, confidentiality,
participation, and accountability of women.
Physicians and healthcare providers should
offer a wide range of evidence-based and safe
contraceptive methods like emergency contra-
ception, short-acting, long-acting and perma-
nent FP methods to ensure womens ability to
make an informed choice.
Womens access to modern methods of
contraception would prevent 54 million un-
intended pregnancies, 26 million abortions,
7 million miscarriages, nearly 80,000 cases
of maternal mortality, and 1.1 million infant
deaths, Chatterjee said. This would partic-
ularly benefit adolescent girls who are often
forced to make compromises in education
and employment leading to poverty and lower
 AUGUST 2015 N E W S 14

educational attainment. balances out any damaging information youth

Educating adolescents on sexuality and
various contraceptive methods meanwhile in-
culcates responsible reproductive health be-
haviour and could delay the onset of sexual
activity leading to fewer sexual partners. Ac-
curate, good-quality, non-judgmental, age-ap-
propriate information on sexuality benefits and
may receive from their peers or various media
platforms. [2009 International technical guide-
lines on sexuality education. Paris: United Na-
tions Educational, Scientific and Cultural Orga-
nization (UNESCO). Available at http://unesdoc.
unesco.org/images/0018/001832/183281e.pdf.
Accessed on 25 June 2015]

TNF blockade eases symptoms in

nonradiographic spondyloarthritis
ELVIRA MANZANO

S ubcutaneous injections of the TNF- block-

er golimumab provide significant relief in pa-
tients with severe axial spondyloarthritis (axSpA)
but no apparent spinal radiographic changes on
MRI scan, according to the phase III, multicentre
GO-AHEAD* study.
After just one injection, the significant chang-
es in the BASDAI and ASDAS scores [two dis-
ease activity measures] were already appar-
ent, said lead author Dr. Joachim Sieper of the
University Clinic Benjamin Franklin in Berlin,
Germany. Patients on golimumab also had sig-
nificantly greater improvements in physical func-
tion, inflammation, range of motion, and health- inflammatory drugs (NSAIDs). The patients were
related quality of life versus those on placebo. randomize d to once monthly subcutaneous
The two-part GO-AHEAD study included 198 injections of golimumab 50 mg (n=98) or place-
patients (18-45 years) who had active nonra- bo (n=100). [Arthritis Rheum 2015;doi:10.1002/
diographic-axSpA and high disease activity de- art.39257]
spite first-line treatment with nonsteroidal anti- The same regimen will be extended by 11

months of open-label follow-up, results of which
will be reported separately.
At 1 month of treatment, 71 percent of pa-
tients on golimumab had achieved an Assess-
ment of SpondyloArthritis International Society
(ASAS) 20 response, defined as 20 percent
improvement or at least 10 unit reduction in
3 of 4 domains (patient global assessment,
pain, physical function and inflammation), with
no worsening in the fourth, compared with 40
percent for placebo (p<0.0001). Similarly, there
was a higher ASAS 40 response with golimum-
ab (56.7 versus 23 percent; p<0.0001).
Significant benefits for golimumab were also
seen on other secondary endpoints such as the
BASDAI 50, (p<0.0001) and ASAS partial re-
mission or low disease activity (p=0.0136).
Overall, golimumab was well tolerated with
slightly fewer patients reporting any adverse
events compared with placebo (41.2 vs 47
percent). There were no cases of serious in-
fections, serious opportunistic infections, ac-
AUGUST 2015 N E W S 15
tive tuberculosis, malignancies, serious sys-
temic hypersensitivity reactions, or death. No
new safety signals were also identified with the
treatment.
The GO-AHEAD study provides additional
evidence of the safety and efficacy of TNF-
blockade with golimumab in axSpA patients
who had inadequate response or intolerance to
NSAIDs.
However, in 20 percent of patients with no
positive MRI or elevated C-reactive protein,
there were no differences in the efficacy end-
points, suggesting that this subgroup of pa-
tients may not be candidates for treatment with
golimumab, said Sieper. As short study dura-
tion was considered a caveat of GO-AHEAD 1,
results from the extended study will establish if
there is continued reduction of symptoms with
longer follow-up for golimumab.
*GO-AHEAD: Golimumab in Participants with Active Axial Spondy-
loarthritis
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Uric acid enhances thrombolytic
treatment in women with acute
ischaemic stroke
ROSHINI C.
T reatment with uric acid (UA) and recom-
binant tissue plasminogen activator (rtPA)
alteplase improves clinical outcomes in wom-
en with acute ischaemic stroke, a study has
shown.
Uric acid therapy doubled the effect of pla-
cebo to achieve an excellent outcome in wom-
en (p=0.036), but not in men (p=0.997), who
had acute ischaemic stroke. Excellent outcome
was defined as a modified Rankin scale (mRS)
score of 0-1, or 2, if premorbid score was 2.
Reanalyzing results of the Efficacy Study of
Combined Treatment with Uric Acid and rtPA in
Acute Ischemic Stroke (URICO-ICTUS) trial, a
multi-centre, double-blind study in which 411
stroke patients were treated with alteplase and
UA or placebo, researchers found that 47 of 111
women treated with UA achieved an excellent
outcome at 90 days compared with 28 of 95 wom-
en treated with placebo. By contrast, 36 of 100
men treated with UA and 38 of 105 treated with
placebo achieved excellent outcome. [Stroke
2015; doi:10.1161/strokeaha.115.009960]
In addition, UA therapy reduced infarct growth
in women. The interaction between UA treatment
and serum UA levels on infarct growth was sig-
AUGUST 2015 N E W S 16
nificant only in women (p<0.001).
While results point to a better reduction in
infarct growth (difference between 72-hour
diffusion-weighted imaging infarct volume and
baseline nonviable tissue volume on CT perfu-
sion) with UA therapy in women, larger studies
are necessary to confirm these findings, said
the authors.
In terms of circulating biomarkers, treatment
and gender had a significant interaction with
UA levels at 6-12 hours (p=0.026), with serum
allantoin (AL) at 6-12 hours (p=0.029) and 48
hours (p=0.023), and with the AL/UA ratio at
6-12 hours (p=0.034) and 48 hours (p=0.028).
These results were obtained from a segment
of the study group who underwent multimodal
brain imaging and blood tests.
Our reanalysis of the URICO-ICTUS trial
highlighted the clinical value of UA administra-
tion in women with acute ischaemic stroke who
received thrombolysis within 4.5 hours of clini-
cal onset, the authors said.
One theory put forth to explain the beneficial
response to UA therapy in women was the sex-
dependent pathways through which cell death
occurs after ischaemic stroke. However, further
study is warranted to determine this, they con-
cluded.

Gene mutations linked to acute liver
failure in young children
SARAS RAMIYA
R esearchers using whole genome sequenc-
ing reveal mutations in a specific gene lead
to acute liver failure in young sick children.
A rare but life-threatening disease among
young children, acute liver failure often occurs
quickly and in about 50 percent of cases, the
cause is unclear. Researchers headed by Tech-
nische Universitt Mnchen (TUM), the Helm-
holtz Zentrum Munich and Heidelberg Univer-
sity Hospital in Germany, found that specific
gene mutations that affect transport processes
in cells were the cause of liver disease. [Am J
Hum Genet 2015;97:163169]
Professor Georg Hoffmann of the Heidel-
berg University Hospital noted similarities in
the progression of recurrent acute liver failure
in some of his patients and suspected a com-
mon cause. So, researchers examined children
who had recurrent acute liver failure triggered
by fever. In our study, we initially focused on
the genetic similarities in these children to de-
termine a possible cause for their disease, said
Dr. Tobias Haack, Institute of Human Genetics
(IHG), Munich.
Using exome sequencing to sequence all
subsets of a patients DNA that contain infor-
mation on creating protein in addition to ex-
amining the DNA of close family members, the
researchers found mutations in one specific
gene.
AUGUST 2015 N E W S 17
We identified mutations in the NBAS gene
in a total of 11 patients. This is the first time that
we have been able to establish a link between
this gene and liver disease. This discovery
could also be interesting for other illnesses,
said Dr. Holger Prokisch, IHG.
Further experiments revealed that the mu-
tations in the NBAS gene resulted in reduced
amounts of NBAS protein produced. NBAS
protein is involved in cell transport processes
that transport proteins in vesicles from one cell
compartment to another.
We were able to show that the faulty protein
is more susceptible to heat. This means that
when an individual has a fever, there are fewer
proteins available for coordinating the transport
processes. This, in turn, can have a negative im-
pact on metabolic processes in the liver in an
acute situation, said Prokisch.
The researchers believe the results will pro-
vide an important starting point for further re-
search, which may improve the diagnosis of

rare diseases in childhood and lead to targeted
treatment.
When a child suffers from liver failure trig-
gered by fever, we can now specifically investi-
gate the NBAS gene, said Haack.
Diagnosis already triggers a specific
therapeutic path, said Hoffmann. Over the
Guselkumab bests adalimumab
for plaque psoriasis
SMRITI RANA
N ew research has shown that anti-interleu-
kin-23 therapy using guselkumab may
have better outcomes for moderate-to-severe
plaque psoriasis than adalimumab, the com-
monly used anti-tumour necrosis factor ther-
apy.
Psoriasis is a chronic skin condition that af-
fects 125 million people worldwide, according
to the US National Psoriasis Foundation and
results in erythematous lesions with inflamma-
tion and keratinocyte proliferation, mediated
by interleukin-12 and interleukin-23 signalling
pathways. Guselkumab inhibits interleukin-23
signalling and has shown significant patient re-
sponse in phase I trials.
In the phase II X-PLORE dose-ranged trial, 293
patients (aged 18 years) underwent treatment
for40 weeks and were followed-up from weeks
40-52. Patients were randomized to regimens of
placebo (n=42), adalimumab (n=43), or one of
AUGUST 2015 N E W S 18
years, we have been able to empirically de-
velop a therapy that uses specific drugs as
well as sugar and fat infusions. These can be
immediately administered once a patient is
diagnosed. We can now use the latest find-
ings to further improve our therapeutic appr
oach.
five groups of guselkumab (5 mg, n=41; 15 mg,
n=41; 50 mg, n=42; 100 mg, n=42; 200 mg,
n=42). [N Engl J Med 2015;373:136-144]
The primary outcome was the percentage of
patients with a Physicians Global Assessment
(PGA) score of 0 (cleared psoriasis) or 1 (mini-
mal psoriasis) in each group at 16 weeks.
A significantly higher proportion of patients
achieved the primary outcome in all gusel-
kumab groups (p=0.002 for 5 mg dose group;
p<0.001 for all other dose groups) compared
to the placebo group at week 16. Compared
to adalimumab, the primary outcome propor-
tion was significantly greater in the 50 mg, 100

mg, and 200 mg guselkumab groups at week
40 (49 percent vs 71 percent, 77 percent, and
81 percent, respectively; p<0.05 for all dose
groups).
Patients in the placebo group crossed over
at week 16 to receive 100 mg guselkumab ev-
ery 8 weeks; their PGA scores were similar to
patients in the 100 mg guselkumab group. The
AUGUST 2015 N E W S 19
rate of adverse events, the most common be-
ing infection, was similar in all the trial groups.
Guselkumab has more robust efficacy than
does adalimumab and has a mechanism of ac-
tion that is more specifically targeted to pso-
riasis, the researchers said. Phase III trials are
underway to further establish the efficacy of
guselkumab therapy for psoriasis.
 AUGUST 2015 O BST E T R I C S & G Y N A E CO L O G Y F O C U S 20
World Breastfeeding Week, August 1-7
Breastfeeding induces antigen-
specific immune responses
LIANNE COWIE
E arly oral antigen exposure through breast
milk leads to tolerance or immune priming
depending on the nature of the antigen trans-
ferred and the accompanying maternal milk co-
factors, according to Dr. Valerie Verhasselt from
the University of Nice Sophia Antipolis in Nice,
France.
Breastfed infants are protected from infec-
tious diseases via a passive immunotherapy
mechanism in which maternal immunoglobulin
A (IgA) antibodies specific for mucosal respira-
tory and enteric pathogens are transferred to
the infant through breast milk, along with anti-
microbial factors such as lactoferrin. However,
recent data from murine models suggest that
breastfeeding can also actively shape the im-
mune response of offspring and affect long-
term susceptibility to allergic disease.
Verhasselt and colleagues showed in a se-
ries of experiments that the induction of an im-
mune response to an antigen transferred via
breast milk is strictly dependent on cofactors
present in the milk. Moreover, cofactors such
as transforming growth factor (TGF)-, vitamin
A, and IgG actually condition the type of im-
mune response induced. [Phil Trans R Soc B
370:20140139]
We demonstrated that soluble ovalbumin
transfer through breast milk induced long-
term prevention of allergy by induction of T
helper type 1 (Th1) cells. Importantly, we also
demonstrated that in contrast to the adult
where the sole administration of an antigen
is sufficient for tolerance induction, maternal
milk TGF- was required to induce tolerance
in offspring, said Verhasselt. Neonatal gut
permeability and immune system maturation,
which are important for the optimal induction
of the Th1 immune response to ovalbumin,
were also found to be dependent on maternal
milk-derived vitamin A.
However, early oral exposure to house dust
mite (Dermatophagoides pteronyssinus) an-
tigens through breast milk was shown to in-
crease allergic sensitization, demonstrating the
importance of the nature of the antigen that is
transferred.
It is possible that milk transfer of microbial
antigen could actively affect the immune re-
sponse in breastfed children and thereby their
long-term susceptibility to infectious disease,
said Verhasselt. We believe that these data
strongly encourage the development of re-
search on the possibility to immunize children
through maternal milk to confer long-term pro-
tection from infectious disease.
 AUGUST 2015 O BST E T R I C S & G Y N A E CO L O G Y F O C U S 21
World Breastfeeding Week, August 1-7
Term infants should be fed directly from
the breast within 2448 hours of life
LIANNE COWIE
H ealthy term infants who are fed directly
from the breast in the first 2448 hours af-
ter birth are more likely to continue to receive
breast milk at 6 months than those who receive
some expressed breast milk and/or infant for-
mula in the early postpartum period, according
to Professor Della Forster from La Trobe Univer-
sity in Melbourne, Australia, lead author of the
prospective Mothers and Infants Lactation Co-
hort (MILC) study.
Although the WHO recommends exclusive
breastfeeding for 6 months, there are no clear
guidelines regarding the method by which
breast milk is to be given to healthy infants.
An increasing number of women in developed
countries are expressing milk for breast milk
feeds and while this is usually performed in
conjunction with direct breastfeeding, little is
known about the consequences of the practice.
Forster and colleagues aimed to address
this research gap with the MILC study. They
collected data from 1,003 English-speaking
women recruited from three maternity hospitals
in Melbourne, Australia. All had given birth to a
healthy singleton term infant whom they intend-
ed to breastfeed. Nine hundred and twenty-four
women were followed up at 6 months post-
partum to determine whether early exclusive
breastfeeding affected breastfeeding practices
after 6 months. Data were obtained using struc-
tured face-to-face interviews at recruitment and
telephone interviews when the infant was 6
months old. [BMJ Open 2015; doi:10.1136/bm-
jopen-2014-007512]
In the first 2448 hour postpartum, 48.8 per-
cent of the infants had been exclusively breast-
fed, while 46.2 percent had received some
expressed breast milk and 20.9 percent some
infant formula. At 6 months, 76.4 percent of
those who had been exclusively breastfed were
still receiving breast milk compared with 56.9
percent of infants who had received expressed
breast milk or infant formula. Women who had
exclusively breastfed their infant in the hospital
were more likely to continue to give their child
breast milk at 6 months (adjusted odds ratio
[OR], 1.80, 95 percent confidence interval [CI],
1.272.55) as well as to only give breast milk
(adjusted OR, 1.61, 95 percent CI, 1.182.2)
than women who had also fed their infant ex-
pressed breast milk or formula.
Clinicians should be able to provide sup-
port for mothers of healthy term infants to
feed their infants directly from the breast in
the early postpartum period, the researchers
concluded.
 AUGUST 2015 O BST E T R I C S & G Y N A E CO L O G Y F O C U S 22
World Breastfeeding Week, August 1-7
High-protein human milk fortifiers
improve preterm infant growth
LIANNE COWIE
H uman milk fortifiers with high protein con-
tent can improve preterm infant growth,
says Professor Tian-Tian Liu from the First Hos-
pital of Jilin University in Changchun, China.
Although breast milk offers complete nutri-
tion for infants, the protein, sodium, and zinc
concentrations in milk decline over time. This
can be problematic for very low birth weight in-
fants who have much higher nutritional needs
than healthy term infants. Human milk fortifiers
may be used as a supplement to provide such
infants with the increased nutrients and energy
they require. However, it now appears that forti-
fiers with higher protein content may be a bet-
ter choice than fortifiers with standard protein
content.
Liu, lead author of a meta-analysis compar-
ing the growth of preterm infants fed with stan-
dard or high-protein human milk fortifiers, and
colleagues searched the PubMed, Embase,
CINAHL, and Cochrane Library databases for
randomized controlled trials and prospective
observational intervention studies published
by 31 May 2014 that included information on
preterm infants fed human milk fortifiers. A to-
tal of five studies that collectively included 352
infants with a birth weight 1750 g and a ges-
tational age 34 weeks were included in the
meta-analysis; 178 of these infants received
human milk supplemented with a fortifier with
standard protein content, while 174 received a
fortifier with higher levels of protein. [J Int Med
Res 2015;43:279-289]
Growth was significantly greater among in-
fants fed with high-protein human milk fortifiers.
The mean difference in weight between these
infants and those who received standard fortifi-
ers was 202.94 g (95 percent confidence inter-
val [CI], 119.01-286.86 g; p<0.00001) and the
mean difference in length was 1.12 cm (95 per-
cent CI, 0.59-1.64 g; p<0.0001). Gains in weight
(mean difference 1.77g, 95 percent CI, 0.81-2.73;
p=0.0003) and length (mean difference 0.21, 95%
CI, 0.12-0.29; p<0.00001) were also significantly
greater in these patients.
 AUGUST 2015 O BST E T R I C S & G Y N A E CO L O G Y F O C U S 23

World Breastfeeding Week, August 1-7

Longer breastfeeding
duration enhances
adaptive immunity
LIANNE COWIE

B reastfeeding is known to have a protective

effect against infectious diseases in infan-
cy and this appears to be at least partly due to
enhanced adaptive immunity, says an expert.
Longer breastfeeding is associated with
increased CD8 T-cell memory, but not B-cell
memory numbers in the first 6 months of life,
and this transient skewing towards T-cell mem-
ory might contribute to the protective effect of
breastfeeding, said Dr. Michelle Jansen from
the Erasmus University Medical Center in Rot-
terdam, The Netherlands.
Jansen and colleagues undertook an immu-
nophenotypic analysis of blood samples taken
from children who were participants in The
Generation R Study, a population-based pro-
spective cohort study in The Netherlands that
follows pregnant women and their children from
infancy. Data were collected from all children
aged 6 months (n=258), 14 months (n=166),
25 months (n=112), and 6 years (n=332)
whose mothers had completed questionnaires
on breastfeeding and who had their total B-
and T-cell numbers and memory subsets ana-
lysed by six-colour flow cytometry. [PLoS ONE
2015;10:e0126019]
Each extra month of breastfeeding was asso-
ciated with a 3 percent decrease in CD27+IgM+
cells, a 2 percent decrease in CD27+IgA+ cells,
and a 2 percent decrease in CD27-IgG+ mem-
ory B-cells at age 6 months. Similar trends for
breastfeeding duration and total B-cell numbers
were observed at age 14 months, but were no
longer significant. At older ages, the effects dis-
appeared altogether. In addition, compared with
infants who had never been breastfed, levels of
CD8+ T-cells were 19 percent higher in 6-month
old infants who had been breastfed for less than
3 months and 20 percent higher in those who
were breastfed for 6 months. The number of
central memory cells (CD45RO+CCR7+) pres-
ent at 6 months was 30 percent higher in infants
who had been breastfed for 3 months com-
pared with those who had not been breastfed at
 AUGUST 2015 O BST E T R I C S & G Y N A E CO L O G Y F O C U S 24
all. As with B-cells, similar trends were observed
at 14 months but were no longer apparent at
older ages.
Three pathways link breastfeeding
to obesity prevention
SMRITI RANA
B reastfeeding has long been thought to pro-
tect against the development of obesity
but the mechanism was unclear. Now, a meta-
analysis has shown that maternal obesity, the
gut microbiome and taste preferences are key
pathways that link breastfeeding to obesity later
in life.
Though proving the association between
breastfeeding and obesity protection has been
difficult, meta-analyses from 81 studies con-
ducted in the past 20 years have shown that
longer or exclusive breastfeeding protects
against obesity in childhood breastfed infants
have a 12-24 percent less chances of develop-
ing obesity (odds ratio, 0.76-0.88) compared
to those who are not breastfed. [Curr Obes Rep
2015;4:207216]
However, these results are likely biased in
their interpretation and the fact that positive
studies are more likely to be published than
negative ones.
Observational studies may never be able
to definitively resolve the question of whether
breastfeeding is directly associated with lower
These findings suggest that breastfeeding
enhances T-cell maturation in the first 6 months
of life, concluded Jansen.
adiposity, the researchers said.
Nevertheless, certain biological pathways
could reduce the risk of obesity.
Many human milk components [such as
leptin and insulin] differ between obese and
lean mothers, potentially offering different pro-
tection against obesity development in the con-
text of maternal obesity, the researchers said.
Obese mothers also have delayed lactogen-
esis and reduced lactation performance com-
pared with non-obese mothers.
Gut microorganisms, which the infancy diet
contributes to significantly, influence how much
energy can be harvested from food and could
contribute to obesity. Non-obese mothers milk
carries higher concentrations of Bifidobacteria
strains compared to obese mothers and may
 AUGUST 2015 O BST E T R I C S & G Y N A E CO L O G Y F O C U S 25

help decrease fat accumulation and increase
glucose use in a high-fat diet.
Breastfeeding is related to a higher accep-
tance of new flavours in infancy, as the flavour
of human milk is modified by maternal diet, re-
sulting in an increased likelihood of establish-
ing healthy food habits in early life. This has a
strong influence on the development of taste
preferences leading to life-long healthy eating
habits.
These [review] results suggest that there
may be an underlying biologic basis for the
protective effect of breastfeeding on later obe-
sity identified by epidemiologic studies, the
researchers said.
The worldwide prevalence of obesity has
more than doubled since 1980 with 42 million
children under the age of 5 found obese in
2013. [World Health Organization, Obesity and
overweight, 2015] Difficulties treating obesity
have led researchers to focus on preventive
strategies, such as modifying childhood feed-
ing practices, including breastfeeding, to con-
trol obesity.

Study finds positive long-term

association between breastfeeding
and IQ
SMRITI RANA

P rolonged breastfeeding has a beneficial

long term effect on a persons intelligence
quotient (IQ) in adulthood and may be associ-
ated with higher levels of education and income
potential, a recent study has shown.
Breastfeeding plays an important role in
promoting brain development and resistance
to diseases during childhood, but the effect of
breastfeeding in later life has not been clearly breastfeeding on IQ, education and income
established until now. potential. Information about breastfeeding was
A large population-based birth cohort study recorded in early childhood, and the IQ (using
conducted in Brazil in 1982 followed 3,493 neo- Wechsler Adult Intelligence Scale), education-
nates to adulthood to determine the impact of al attainment, and income of the participants
 AUGUST 2015 O BST E T R I C S & G Y N A E CO L O G Y F O C U S 26
were assessed during 2012-2013. [Lancet Glob
Health 2015;3:199205]
Breastfeeding data indicated that one in ev-
ery five mothers (21 percent) breastfed for less
than 1 month, one in six (17 percent) did for
a year or more, and few mothers (12 percent)
continued to maintain breastfeeding as the main
form of nutrition for 4 months or more.
Participants who were breastfed for over a
year scored higher by 3.76 IQ points (95 percent
confidence interval (CI), 220533, p<0.0001),
attained 0.91 more years of education (95 per-
cent CI, 0.421.40, p=0.003), and earned 341
more Brazilian reals (95 percent CI, 93.8588.3,
p<0.0001) on average than those who were
breastfed for less than one month. The results
were adjusted for confounding variables that
might contribute to IQ increase, such as mater-
nal education and family income.
Higher IQ seemed the key to greater income
and a mediation analysis showed that 72 per-
cent of the total effect of breastfeeding on in-
come potential was a result of adult IQ.
Because earning ability is associated with
both IQ and educational attainment, breast-
feeding has been postulated to have a positive
economic effect on society as a whole, the re-
searchers said.
 AUGUST 2015 D R U G P R O F I L E 27

Vortioxetine for major depression

Major depressive disorder (MDD) is a wide-ranging disorder that is most consistently
characterized by low mood and has significant negative effects on sufferers quality of
life. Though thought to be less common in Asian than in Western countries, more data
is being collected on the prevalence of depression. Meanwhile, suicide rates between
many Asian countries, Europe, and North America are comparable. Correcting
neurotransmitter levels is the primary pharmacological method of combating MDDs.
Vortioxetine (Brintellix, Lundbeck) is the first in a new class of antidepressants that
modulate and stimulate serotonin.

NAOMI ADAM
MSc (Med), Category 1
Accredited Education Provider
(Royal Australian College
of General Practitioners)

Introduction
Depressive disorders range from milder dys-
thymia through to major depression and signifi-
cantly reduce quality of life for sufferers. Typi-
cal symptoms include anhedonia (low mood),
insomnia and diminished concentration. De-
pression is frequently comorbid with other
psychiatric disorders such as anxiety, panic at-
tacks, eating disorders and substance abuse.
Profound feelings of hopelessness in severely
depressed patients can lead to suicidal ideation
and actual suicide attempts.
While it is thought that depression may be
less common in Asia compared with Western
nations, it is difficult to state precisely the preva-
lence of depression in Asian countries due to the
lack of large epidemiological studies and vary-
ing diagnostic criteria in those that have been
completed. Estimates of current or 1-month
major depression range from 1.3 to 5.5 percent
and lifetime prevalence is between 1.1 and 19.9
percent (median 3.7 percent). Regardless of
the uncertainty in the available prevalence data,
suicide rates in the Asian region are now com-
parable to those in Europe and North America
(with the exception of China and South Korea).
[Australas Psychiatry 2004; 12 Suppl: S4-10]
Imbalances in levels of neurotransmitters
such as serotonin, noradrenaline and dopamine
are thought to cause depressive disorders, how-

ever the mechanisms are poorly understood.
Drug treatments for depression all work by in-
creasing the levels of one or more neurotrans-
mitters. Several classes of pharmacotherapy
are available for depressive disorders. First-
generation antidepressants were introduced
in the 1950s and sparked the development of
two new classes of drugs: tricyclic antidepres-
sants (TCAs) and monoamine oxidase inhibi-
tors (MAOIs). The 1980s saw the introduction of
second-generation antidepressants, known as
selective serotonin reuptake inhibitors (SSRIs),
which quickly replaced the TCAs and MAOIs
due to their better tolerability. Subsequently, the
mixed serotonin and noradrenaline reuptake in-
hibitors (SNRIs) were introduced.
Vortioxetine
Vortioxetine is the first in a new class of anti-
depressants, with two modes of action upon the
serotonin system. It selectively blocks the 5-HT
transporter system and also binds with high af-
finity to a number of receptor subclasses within
the 5-HT family, including: 5HT1A (where it is a
full agonist); 5-HT1B (partial agonist); and 5-HT1D,
5-HT3 and 5-HT7 (antagonist for all three). [Psy-
chopharmacology 2015;232:2343-52]
The pharmacokinetics of once-daily vortiox-
etine are linear within the dose range of 2.5-60
mg, with maximum plasma levels occurring
at 7-11 hours post-dosing. Mean half-life is
66 hours and steady-state concentrations are
reached after 2 weeks. Food does not affect ab-
sorption of the drug.
Metabolism of vortioxetine is mostly oxida-
tion via the cytochrome P450 pathway. The
AUGUST 2015 D R U G P R O F I L E 28
CYP2D6 isozyme is the primary contributor, but
others are also involved (CYP3A4/5, CYP2C19,
CYP2C9, CYP2A6, CYP2C8 and CYP2B6).
Clearance of vortioxetine is not changed in the
presence of hepatic impairment (mild or mod-
erate) or renal impairment (from mild through
to end-stage renal disease). [Brintellix (vortiox-
etine) Prescribing Information]
Clinical efficacy
A recent systematic review of studies on the
safety and efficacy of vortioxetine for the acute
treatment of major depressive disorder (MDD)
with reported outcomes for response and remis-
sion rates identified 11 randomised, controlled
trials for inclusion in a meta-analysis. Of these,
eight were published in peer-reviewed journals
and three were unpublished (but had summa-
ries available in US Food and Drug Administra-
tion documents oratwww.ClinicalTrials.gov).
[Systematic Reviews 2015;4:21]
All of the trials were placebo-controlled, and
six also included an SNRI comparator (one trial
with venlafaxine and the others with duloxetine).
Outcomes were highly variable, with some stud-
ies showing no effect for vortioxetine compared
with placebo. Pooled analysis found a benefit
for vortioxetine in response and remission rates
as well as change in depression severity (mea-
sured by the Montgomery-sberg Depression
Rating Scale) compared with placebo. Interest-
ingly, a dose-related effect was not seen, with
doses as low as 5 mg apparently offering similar
efficacy to 20 mg. When compared with SNRIs,
vortioxetine appeared to have similar or slightly
lower efficacy.

An expert commentary that accompanied
the publication of two placebo-controlled trials
that showed no significant difference in out-
comes with vortioxetine offered possible ex-
planations for the inconsistencies in the clini-
cal data. It is possible that the rigor with which
some study procedures were conducted may
be partly responsible (eg, lack of centralised
rating, rapid on-boarding of sites and patients).
More likely however, is the differences in study
populations between trials. Historically, many
negative and failed trials of antidepressants
have had high response rates in the placebo
group, suggesting that these are cohorts with
reduced disease severity. In these patients it
is more difficult to demonstrate a significant
benefit for pharmacotherapy. However in the
vortioxetine trials, the opposite was observed,
with no benefit in trials with low placebo re-
sponse rates and vice versa. It seems that an
unmeasured confounding variable is respon-
sible perhaps socioeconomic status of the
patient population. [J Clin Psychiatry 2015;76:
e657]
Safety and tolerability
The most frequently reported adverse
events in clinical trials of vortioxetine were
nausea and vomiting. This was more common
on commencement of therapy, particularly in
the first days and week. Sexual dysfunction is
another side effect of many antidepressants,
although there is a high background inci-
dence in depressed patients. In some vortiox-
etine trials, the prospective use of validated
scales has shown that treatment-emergent
AUGUST 2015 D R U G P R O F I L E 29
sexual dysfunction occurs, particularly at
higher doses. Vortioxetine has not been asso-
ciated with weight gain or any clinically signif-
icant effects upon vital signs (eg, blood pres-
sure and heart rate). Like all antidepressants,
vortioxetine carries a black box warning that
patients should be monitored and observed
closely for clinical worsening, suicidality and
unusual changes in behaviour, especially in
the initial months of therapy and around the
time of dose changes.
Dosing and administration
Vortioxetine is indicated for the treatment
of major depressive disorder at a starting
dose of 10 mg once daily. As some trials
have suggested an enhanced benefit with
a 20 mg dose, the prescribing information
suggests that the vortioxetine dose be in-
creased if tolerated or decreased if not.
Vortioxetine should not be used within 14
days of an MAOI intended to treat a psy-
chiatric disorder or within 21 days of oth-
ers such as linezolid or methylene blue. As
with all antidepressants, patients should be
screened for bipolar disorder before start-
ing vortioxetine as there is a risk of activa-
tion of mania or hypomania.
Most of the registration studies of vor-
tioxetine have been short-term (6-8 weeks),
however it is accepted clinical practice to
continue antidepressant treatment for sever-
al months or more. One maintenance study
of vortioxetine showed a reduced risk of re-
lapse compared with placebo. [J Psycho-
pharmacol 2012;26:1408-16]
 AUGUST 2015 D R U G P R O F I L E 30

Although vortioxetine may be discontin- bursts of anger, dizziness, and runny nose
ued without dose tapering, some studies upon abrupt cessation. Therefore, in patients
have shown symptoms such as headache, taking higher doses of vortioxetine, a gradual
muscle tension, mood swings, sudden out- reduction may be considered.

European Academy of Allergy and Clinical Immunology (EAACI) Annual Congress,
June 6-10, Barcelona, Spain
High-fibre diet during pregnancy
may prevent allergy, asthma
LIANNE COWIE
N utrition plays a fundamental role in all as-
pects of health and development. Experi-
ments in mice have shown that a high-fibre diet
during pregnancy can prevent the development
of allergic airway disease in their offspring, which
raises the question of whether changing the ma-
ternal diet can protect against allergy and asth-
ma in humans, says Professor Susan Prescott
from the School of Pediatrics and Child Health,
The University of Western Australia. [Nat Com-
mun 2015;6:7320]
Dietary fibre influences the composition and
metabolic activity of the gut microbiome in both
animals and humans. Short-chain fatty acids such
as acetate and butyrate, which are produced by
gut bacteria as they ferment dietary fibre, are pow-
erful molecules that have many anti-inflammatory
and metabolic effects, she said. Short-chain fatty
acids can modulate body weight and glucose ho-
meostasis, and can cross the blood-brain barrier
and suppress appetite by altering hypothalamic
neuronal activation patterning.
Moreover, a recent landmark study showed
for the first time that these fatty acids can modu-
late the maturation, morphology, and function
of microglia, the innate immune cells of the cen-
tral nervous system, providing clear evidence
AUGUST 2015 CO N F E R E N C E COV E R AG E 31
that altering the diet and the gut microbiome
can have a significant effect on immune func-
tion and brain development. [Nature Neurosci
2015;18:965-977]
Human studies have also shown a correlation
between maternal dietary fibre and short-chain
fatty acids in maternal circulation. Moreover, the
offspring of women with higher levels of short-
chain fatty acids during pregnancy were less
likely to have cough and wheezing symptoms.
[Nat Commun 2015;6:7320]
A randomized controlled trial, the SYMBA
study, is currently underway in Perth to deter-
mine the effects of prebiotic supplementation on
multiple infant outcomes. Promoting early im-
mune health is a vital part of preventing not just
allergy but all inflammatory non-communicable
diseases, said Prescott. However, we have to
remember that to change the world, we have to
change the menu first.

European Academy of Allergy and Clinical Immunology (EAACI) Annual Congress,
June 6-10, Barcelona, Spain
MP29-02 offers new hope
for allergic rhinitis patients
LIANNE COWIE
M P29-02, an intranasal formulation combin-
ing azelastine hydrochloride and flutica-
sone propionate, is twice as effective as intranasal
steroids at relieving nasal and ocular symptoms
in patients with allergic rhinitis, says an expert.
Dr. Glenis Scadding from the Royal Nation-
al Throat Nose and Ear Hospital, London, UK
reviewed the close links between rhinitis and
asthma, highlighting the potential benefits of
MP29-02. She noted that the novel therapy will
be welcomed by many clinicians and patients
because there is a clear efficacy ceiling as-
sociated with standard therapies. [Int Arch Al-
lergy Immunol 2013;161:369-377]
Approximately 20-60 percent of patients with
allergic rhinitis have clinical asthma and >80
percent of those with allergic asthma have symp-
toms of concomitant rhinitis. Moreover, the over-
all prevalence of asthma is more than six-fold
higher in subjects with rhinitis compared with
those without, and rhinitis, even in the absence
of atopy, is a powerful predictor of adult onset
asthma. [Pediatrics 1994; 94:895-901; J Allergy
Clin Immunol 1999; 104:301-304; J Allergy Clin
Immunol 2004;113:86-93]
Significant rhinitis negatively impacts asthma
control to the same degree as smoking, so gain-
AUGUST 2015 CO N F E R E N C E COV E R AG E 32
ing control of comorbid allergic rhinitis in asthma
patients is essential. However, the standard ther-
apy, oral antihistamines, is not effective for asth-
ma control and although intranasal steroids can
improve some asthma-specific outcomes in pa-
tients with comorbid allergic rhinitis and asthma,
they do not provide sufficient symptom relief for
many patients with moderate or severe disease,
commented Scadding. [Prim Care Resp J 2009;
18:300-305; Prim Care Resp J 2010;19:266-273;
Allergy 2013;68:569-579]
MP29-02 may be a promising solution as
not only has it been shown to be superior to
standard therapies at relieving both ocular and
nasal symptoms of allergic rhinitis, but relief is
generally apparent from Day 1 and is sustained
over the entire course of treatment. In one study,
56 percent of patients with moderate-to-severe
allergic rhinitis who received MP29-02 reported
that their symptoms were well controlled by Day
3. [Int Arch Allergy Immunol 2013;161:369-377,
Allergy Asthma Proc 2015;36:40-47]

European Academy of Allergy and Clinical Immunology (EAACI) Annual Congress,
June 6-10, Barcelona, Spain
Pimecrolimus safe and effective
first-line option for atopic dermatitis
LIANNE COWIE
P imecrolimus should be considered as a
first-line therapy for infants, sensitive skin
areas, and long-term management of atopic
dermatitis, according to Thomas Werfel, Profes-
sor of Dermatology and Allergology, Hannover
Medical School, Germany.
Werfel noted that atopic dermatitis affects
up to 25 percent of children and 2-3 percent
of adults and frequently starts in early infancy.
Moreover, up to 13 percent of children have
severe disease, which has a major impact
on their quality of life. [Acta Derm Venereol
2005;85:244-247; Int J Clin Pract 2006;60:984-
992; N Engl J Med 2008;358:1483-1494; Am J
Clin Dermatol 2011;12:15-24; J Am Acad Der-
matol 2014;70:338-351]
European guidelines recommend topi-
cal corticosteroids as a first-line therapy for
atopic dermatitis in non-sensitive skin areas,
but more than 80 percent of parents of af-
fected children are concerned about possible
side effects, which impacts compliance. [J
Disch Dermatol Ges 2009;7(Suppl 1):S1-46;
Br J Dermatol 2011;165;808-814; Exp Dermatol
2012;21:184-188; J Eur Acad Dermatol Vene-
reol 2012;26:1045-1060]
Pimecrolimus is a suitable alternative to
AUGUST 2015 CO N F E R E N C E COV E R AG E 33
corticosteroids as it has a direct effect on itch-
ing and can help restore the disturbed skin
barrier, said Werfel. Moreover, it is indicated
as a first-line therapy for sensitive skin areas
such as the face, neck, and skin folds and
there is no scientific evidence of an increased
risk of malignancy or any need to limit its use
in infants.
He highlighted the outcomes from the land-
mark PETITE study, which compared the effi-
cacy of pimecrolimus and topical corticosteroids
among 2,418 infants with atopic dermatitis. Al-
though both treatments had a rapid onset of ac-
tion (week 3) and similar efficacy after 5 years
(eg, atopic eczema was cleared/almost cleared
in more than 85 percent of patients and facial
atopic eczema in more than 95 percent of pa-
tients in both groups by the end of the study),
pimecrolimus also had a notable steroid-spar-
ing effect. A total of 36 percent of pimecrolimus
users did not require topical corticosteroids.
Among those who did, these were only used for
a median of 7 days compared with a median of
178 days among patients who received topical
corticosteroid monotherapy. Pimecrolimus also
had a good safety profile as there were no reports
of impairment of the growing immune system or
of an increased risk of lymphoma. [Pediatrics
2015;135:597-606]

11th Asia Pacific Congress of Hypertension, June 4-7, Bali, Indonesia
See-sawing BP should be target
of CVD treatment
ELVIRA MANZANO
R eduction of mean blood pressure (BP)
alone does not completely reduce car-
diovascular (CV) events, particularly stroke. In-
stead, see-sawing BP readings could be a key
danger sign that should be targeted for treat-
ment, says an expert.
Current guidance for GPs does not reflect
this, said Dr. Azani Mohamed Daud, consul-
tant cardiologist, Gleneagles Intan Medical
Centre in Kuala Lumpur, Malaysia. A large
number of patients were told their BP is ac-
ceptable with use of BP-lowering medications,
but BP variability within hours or days can be
dangerous.
BP variability the sudden, transient fluctu-
ations in BP has been regarded as a random
and unreliable basis for BP estimation in the
past. However, a plethora of evidence sug-
gests that short-term (ie, minute-to-minute,
hour-to-hour, or day-to-night) and long-term
(days, weeks, months, or years) fluctuations
in BP independently contribute to target or-
gan damage (TOD), CV events, and mortality
not only in hypertensive patients, but also in
those with diabetes and chronic kidney dis-
ease.
BP fluctuations have some physiopatho-
logical and prognostic importance, said Daud.
AUGUST 2015 CO N F E R E N C E COV E R AG E 34
In patients with mild-to-moderate hyperten-
sion, 24-hour BP variability is associated with
TOD rate and severity. For nearly any level of
24-hour mean BP, patients with low 24-hour
BP variability had a lower prevalence and se-
verity of TOD than those with high 24-hour BP
variability.
Increased awake systolic BP variability over
a 24-hour period also correlates with subclini-
cal TOD, he added. In patients with previous
transient ischaemic attack and in those with
treated hypertension, visit-to-visit variability
in systolic BP and maximum systolic BP were
strong predictors of stroke, independent of
mean systolic BP. [Lancet 2010; 13;375:895-
905].
Clearly, there is an increased risk of
stroke, TOD, and mortality with increased
BP variability, said Daud. Calcium-channel
blockers are associated with better outcomes
in ameliorating BP variability. But as clini-
cians, we need a faster way of determining
BP variability because monitoring and mea-
surement of BP variability is cumbersome in
clinical practice. We cant afford to ignore BP
variability at our patients peril.
Daud said a randomized controlled trial
enrolling patients with BP variability and
intervening with different anti-hypertensive
patients is also warranted.
 15
20 SINGAPOR E MARCH 2015
AR
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NEWS & INSIGHTS
RE M
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NE mac ast A
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International Digestive Disease Forum (IDDF) 2015, Chinese University of Hong
Kong, June 6-7 Christina Lau reports
Liver transplants for HCV infection
to become obsolete in 10-20 years
I n 10 to 20 years, liver transplantation will no
longer be performed for patients with hep-
atitis C as the infection is now curable with
direct-acting antiviral (DAA) therapies, says
an expert.
Hepatitis C virus [HCV] has been the hot-
test topic in gastroenterology. With the new
DAAs, cure rates of up to 100 percent can be
achieved, in some cases without interferons,
said Professor Michael Manns of the Hannover
Medical School in Hannover, Germany.
A number of DAA regimens are currently
available for the treatment of different HCV
genotypes. As pharmaceutical companies
continue to fight for an edge in the HCV mar-
ket, the grazoprevir/elbasvir combination,
asunaprevir/daclatasvir/beclabuvircombinatio
n,andsofosbuvir/GS-5816 combination are ex-
pected to become available in 2016, while sa-
matasvir, sovaprevir and other promising agents
are in development.
Chronic hepatitis C has become a curable
disease. Although the cure rate remains low
in many parts of the world, we will be able to
eliminate HCV in the next 25 years, suggested
Manns. Im sure in 10 to 20 years, there will
be no more liver transplantations due to HCV
infection.
Companies and researchers are on the
AUGUST 2015 CO N F E R E N C E COV E R AG E 35
way to leave hepatitis C and go into hepatitis
B, he continued. At present, we can stop the
progression of hepatitis B virus [HBV] infection,
but a cure is not available. We need to work
on strategies that interact with the covalently
closed circular DNA [cccDNA] to achieve a
finite duration of treatment and cure the dis-
ease.
HBV therapies in early phases of develop-
ment include viral core inhibitors, cccDNA in-
hibitors, entry inhibitors and immune therapies,
he added.
A common challenge in eliminating HCV
and HBV is the cost of new therapies, which
may be unaffordable for some patients.
As l iv e r tr ansp l antation remains in de-
mand for various conditions, researchers are
looking into alternatives to address chal-
lenges such as organ shortage and in-
creasing donor age. One such alternative is
hepatocyte transplantation.

The liver has a high regenerative poten-
tial. Hepatocyte transplantation can therefore
be developed for conditions such as acute
liver failure, inborn errors of metabolism, and
genetic liver diseases where we only need to re-
place one gene, explained Manns.
GI endoscopy needs faster innovations
I nnovations in gastrointestinal (GI) endosco-
py have been slow in the last few decades
not because of a lack of talents, but because
regulatory processes, conservative mindsets
and economic issues have discouraged the
commercialization of new technology.
The endoscope we are using now is 50
years old. Innovations in GI endoscopy have
come down in the last 30 years. As a result, we
havent been progressing as actively as other
fields, said Dr. Nageshwar Reddy of the Asian
Institute of Gastroenterology in Hyderabad, In-
dia.
For example, it has taken us 50 years to be
able to identify a 0.5 cm lesion in the stomach
endoscopically, he continued. The technolo-
gies for innovation are there, but inventors have
been unable to commercialize their innovative
devices due to strict regulatory procedures,
conservative mindsets, and the lack of funds.
As a result, many devices that could have
revolutionized clinical practice did not make
their way beyond the lab.
While innovations need to be balanced
against safety and ethical considerations, a dif-
AUGUST 2015 CO N F E R E N C E COV E R AG E 36
In Europe, for example, hepatocyte trans-
plantation has received orphan drug status for
inborn errors of urea cycle defects. The study is
almost completed, and the treatment will soon
be approved for this genetic liver defect, he
said.
ficulty faced by GI endoscopists is the low level
of funding supporting their research. In the
US, for example, endoscopic research was the
most under-funded area in medicine, accord-
ing to National Institutes of Health data, said
Reddy. [Gastrointest Endosc 2003;58:831-835]
Regulatory processes are very difficult to
change, but a shift from industry to university
and an interdisciplinary approach can encour-
age innovation, said Reddy. What happens
in endoscopy now is that the industry comes
up with an instrument and asks researchers to
find an indication. Engineers can sometimes

provide easy solutions to what GI endosco-
pists are trying to implement.
A form of innovation is to take things that al-
ready exist and put them together in a new way,
he added. An example is the duodenal muco-
IBD registry reveals rapid rise
in Crohns disease in HK
N ew data from a territory-wide inflammatory
bowel disease (IBD) registry in Hong Kong
reveals a rapid rise in the incidence of Crohns
disease, with a high proportion of patients hav-
ing complex and severe conditions at diagno-
sis.
Crohns disease has been increasing at a
more rapid rate than ulcerative colitis in re-
cent years. While ulcerative colitis remains
the dominant form of IBD in Hong Kong, its
incidence appears to be levelling off, said
Dr. Siew-Chien Ng of the Institute of Digestive
Disease, Chinese University of Hong Kong.
These findings are from the Hong Kong
IBD Registry, a large database that cov-
ers 2,575 patients with IBD (median age, 49
years) treated at 15 public hospitals across
Hong Kong. [Digestive Disease Week 2015,
abstract 1012]
Data from the registry shows an approxi-
mately four-fold increase in the age-adjusted
incidence of IBD over the last 20 years. In
2011-2014, the age-adjusted incidence of IBD
was more than 3 per 100,000 population.
AUGUST 2015 CO N F E R E N C E COV E R AG E 37
sal resurfacing [DMR] procedure currently being
developed for the treatment of type 2 diabetes.
A large, multicentre study is ongoing in Europe.
Early results suggest that DMR is very effective in
controlling type 2 diabetes.
We now have approximately one case of
Crohns disease for every case of ulcerative
colitis, compared with one case of Crohns
disease for six cases of ulcerative colitis in the
past, reported Ng. This trend mirrors what
was observed in the West about 50 years
ago.
Complicated Crohns disease is just as
common in Asia as it is in the West, she con-
tinued. At diagnosis, 25.1 percent of patients
in Hong Kong had stricturing disease, while
24.5 percent had perianal disease.
The median age of Crohns disease onset
was 30 years, while that of ulcerative colitis
onset was 41 years.
However, the proportion of elderly-onset
ulcerative colitis has jumped from 3 percent
before 1990 to 21 percent after 2010, pointed

out Ng. This group of patients may need spe-
cial attention and earlier surveillance, because
our data shows significantly increased risks of
infections, disease-related mortality, dysplasia
and colorectal cancer in patients diagnosed
with ulcerative colitis at the age of 60 or above
compared with those diagnosed at a younger
age.
As for treatment, 5-aminosalicylic acid (5-
ASA) remains the predoWW minant agent in
Crohns disease (88.9 percent) despite con-
AUGUST 2015 CO N F E R E N C E COV E R AG E 38
troversies over its use. Anti-tumour necrosis
factor (anti-TNF) therapies have been used in
15.3 percent of patients with Crohns disease
and 1.6 percent of those with ulcerative coli-
tis, respectively.
I anticipate the use of anti-TNF therapies
to increase over time, as infliximab and adali-
mumab are now listed as Special Drugs in the
Hospital Authority Drug Formulary so that pa-
tients with Crohns disease entitled to these
treatments are able to get them, said Ng.
 AUGUST 2015 I N D U S T RY U P DAT E 39

Dexlansoprazole: A PPI formulation

in the treatment of GERD
Dual Delayed Release (DDR) technology enhances the efficacy of proton-pump
inhibitor (PPI) drug formulations and improves outcomes for acid related diseases.
At the recent International Digestive Disease Forum (IDDF) 2015 in Hong Kong, two
speakers highlighted innovations in PPI formulations as well as treatment regimens for
gastroesophageal reflux disease (GERD) that included dexlansoprazole (Dexilant,
Takeda), a PPI that uses DDR technology.

Prof. Ming-Shiang Wu

Prof. Ronnie Fass

Acid-related diseases and PPI
The discovery of Helicobacter pylori infec-
tion has revolutionized the concept of acid-relat-
ed diseases, said Professor Ming-Shiang Wu,
chairman at School of Medicine, National Tai-
wan University. Peptic ulcer, gastroesophageal
reflux disease (GERD), dyspepsia and other
hypersecretory diseases are common types of
acid-related diseases, and H. pylori is acknowl-
edged to be a major factor in these conditions,
he said.
GERD is now the most common and impor-
tant acid-related disease in Asia, Wu said. PPI
therapy provides the most effective healing and
symptom relief in GERD patients.
The clinical indications of PPIs include the
healing and maintenance of erosive esophagitis
[EE], symptom control in patients with GERD,
the healing and prevention of duodenal and
gastric ulcer, and the management of H. pylori
infection in combination with antibiotics.
Commonly prescribed PPIs including lan-
soprazole and esomeprazole treat GERD ef-
fectively but they need to be taken with food
and last only a few hours. However, acid reflux
can occur at any time, especially after meals,

so long-lasting and effective therapies with a
strong safety profile are necessary. [Clin Exp
Gastroenterol 2009;2:117-128]
Dexlansoprazole: An innovation in PPIs
[Dexlansoprazole] is the first and only PPI
with a dual delayed release formulation, ex-
plained Professor Ronnie Fass, director of the Di-
vision of Gastroenterology and Hepatology, Me-
troHealth Medical Center, Cleveland, Ohio, US.
Dexlansoprazole, the R-enantiomer of lanso-
prazole, has two types of granules, each with
a coating that dissolves at a different pH level.
Twenty-five percent of the granules per dose
dissolve at pH 5.5 and begins releasing the
drug within an hour of administration. The rest
of the granules, comprising 75 percent of total
dose, dissolve at pH 6.75, providing a second
release of the drug about 4 to 5 hours after ad-
ministration.
The Dual Delayed Release (DDR) for-
mulation results in a prolonged duration (ap-
proximately 12 hours) of plasma concentration
of dexlansoprazole, increasing the duration
of acid suppression and symptom control. By
contrast, the effective plasma concentration of
lansoprazole lasts for a much shorter period of
time (approximately 4-5 hours). [Clin Exp Gas-
troenterol 2009;2:117-128]
Dexlansoprazole achieves a 24-hour intra-
gastric pH >4 for a longer duration than other
PPIs such as lansoprazole and esomeprazole.
This was demonstrated in a 5-day dose admin-
istration of dexlansoprazole 60 mg versus lan-
soprazole 30 mg in healthy subjects where dex-
lansoprazole produced higher mean 24-hour
AUGUST 2015 I N D U S T RY U P DAT E 40
intragastric pH compared to lansoprazole (pH
4.55 vs pH 4.13, respectively; p<0.001). Simi-
lar results have been observed when comparing
dexlansoprazole 60 mg with esomeprazole 40
mg (pH 4.3 vs pH 3.7, respectively; p<0.001).
[Clin Exp Gastroenterol 2009;2:117-128; Clin
Exp Gastroenterol 2011;4:213-220]
Dexlansoprazole in the treatment of GERD
Two multicenter, double blind, random-
ized,
active-controlled 8-week trials, which
enrolled more than 4,000 endoscopically con-
firmed EE patients compared the efficacy of
dexlansoprazole 60 mg vs lansoprazole 30 mg.
The trials compared 4-week and 8-week EE
healing rates in these subjects. [Aliment Phar-
macol Ther 2009;29:731-741]
At week 8, noninferiority was demonstrated
in both studies and superiority was demonstrat-
ed in [the second] study, Fass said.
Adults (n=445) who completed the EE heal-
ing in the first study were enrolled in another
multicenter, double blind, randomized, place-
bo-controlled 6-month trial to study the main-
tenance of healed EE with dexlansoprazole.
Patients were randomized to dexlansoprazole
30 mg or placebo. The primary endpoint was
the percentage of patients who maintained EE
healing for over 6 months as determined by en-
doscopy, while the secondary end point was
the percentage of 24-hour periods that were
heartburn free.
[Dexlansoprazole 30 mg] provided 96
percent heartburn-free 24-hour periods in a
6-month study, as compared to only 29 per-
cent in those that received placebo, Fass said.
 AUGUST 2015 I N D U S T RY U P DAT E 41

(Figure 1) Ninety-nine percent of those who re-
ceived dexlansoprazole 30 mg reported night-
time heartburn relief compared to seventy-two
percent of those who received placebo. Both re-
sults were statistically significant. [Aliment Phar-
macol Ther 2009;29:742-754]
The efficacy of dexlansoprazole was demon-
strated through another multicenter, double-blind,
randomized, placebo-controlled 4-week trial, with
a rigorous endpoint of full 24-hour heartburn relief.
Patients were asked to record symptoms twice
daily during daytime and nighttime.
If [the patients] noted any heartburn in the
24-hour period, then the entire day was not con-
sidered heartburn free, Fass said.
Adult patients (n=947) with heartburn symp-
toms for over 6 months and endoscopically
proven non-erosive disease were randomized
to receive dexlansoprazole 30 mg or placebo.
Patients who received dexlansoprazole showed
a higher median percentage of heartburn free
periods during the 4-week trial (55 percent for
dexlansoprazole vs 19 percent for placebo),
and these results were statistically significant.
Dexlansoprazole also demonstrated significant-
ly less nighttime disturbances vs placebo. [Ali-
ment Pharmacol Ther 2009;29:1261-1272]
In a different study of patients receiving
a twice daily dose of any PPI, 88 percent re-
mained well controlled after stepping down to
once-daily dexlansoprazole 30 mg, regardless
of the PPI they were receiving previously. [Clin
Gastroenterol Hepatol 2012;10:247-253]
Safety and indications
Unlike other PPIs such as lansoprazole,
omeprazole and esomeprazole, dexlansopra-
zole can be taken with or without food. (Figure
2) No dose adjustment of clopidogrel is nec-
essary when administered with an approved
dose of dexlansoprazole. [J Am Coll Cardiol
2012;59:1304-1311]
There were no major differences in the rate of
incidence of adverse events between dexlanso-
prazole dosage and lansoprazole in controlled
studies. [Clin Exp Gastroenterol 2009;2:117128]
Conclusion
Fass concluded that dexlansoprazole may be
considered for appropriate patients with GERD,
including patients with a new diagnosis of re-
flux, non-erosive reflux, all grades of EE, and
those in need of maintenance of EE healing,
heartburn symptom relief and dosing flexibility.
Dexlansoprazole is also appropriate for patients
that require clopidogrel co-administration.

Figure 1. Median percentage of 24-hour heartburn-free periods for Figure 2. Effect of different feeding regimens on change in intragastric pH
maintaining EO healing with dexlansoprazole
5
100 Dexlansoprazole
Change in mean pH
from day 1 to day 3

*96 4 dosed at time 0

Median heartburn-free

Dexlansoprazole 30 mg
Fasting
24 hr periods (%)

80
3
30 min after
Placebo
60 2 high-fat breakfast
5 min before
*p<0.0025 vs placebo 1
40 high-fat breakfast
0 30 min before
20
29 Breakfast Lunch Dinner Snack high-fat breakfast
-1
-1 0 4 9 14 19 24
0
n=132 n=141 Time after dosing (hr)
EO= erosive oesophagitis
Adapted from Aliment Pharmacol Ther 2009;29:824-833
Adapted from Aliment Pharmacol Ther 2009;29:742-754

Softening of smoking population means smokeless tobacco,
e-cigarettes may not be necessary
It has long been assumed that as smoking
prevalence declines, individuals who remain
are more likely to be unwilling or unable to quit
(a process known as hardening). However, a
recent study in the US has found that as smok-
ing prevalence declines, remaining smokers are
actually smoking less and are more likely to quit,
challenging the need for new products such as
smokeless tobacco and e-cigarettes.
The researchers analyzed data on quit at-
tempts, quit ratios, the number of cigarettes
smoked, and smoking prevalence over time
extracted from the US Tobacco Use Supple-
ment
(1992/32010/11) and Eurobarometer
surveys (200620092012) of 31 European
countries.
Each 1 percent drop in smoking preva-
lence was associated with a 0.55 0.07 per-
cent increase in quit attempts (p<0.001) and
quit ratios (1.13 0.06, p<0.001) and a drop
in consumption of 0.32 0.02 cigarettes/day
AUGUST 2015 R E S E A R C H R E V I E W S 42
(p<0.01) in the US. In Europe, quit attempts
remained stable (p=0.53) but consump-
tion dropped by 0.22 0.05 cigarettes/day
(p<0.001). The associations remained stable
over time with significantly lower consump-
tion in the US as time passed (-0.15 0.06
cigarettes/day/year, p<0.05).
The researchers concluded that current
tobacco control policies are sufficient for
softening the smoking population and there
is no need to promote new recreational nic-
otine products, which is important due to
their potential adverse health effects.
Kulik MC and Glantz SA. The smoking population in the
USA and EU is softening not hardening. Tob Control 2015;
doi:10.1136/tobaccocontrol-2015-052329.

AUGUST 20th World Congress of the
American Psychological
Association Annual Convention
2015
6/8/2015 to 9/8/2015
Location: Toronto, Ontario, Canada
Info: American Psychological
Association
Tel: (1) 800 374 2721;
(1) 202 336 5500
Website: http://www.apa.org/
convention/index.aspx
NHF 67th Annual Meeting
13/8/2015 to 15/8/2015
Location: Dallas, Texas, US
Info: National Hemophilia Foundation
Tel: (1) 212 328 3700
Fax: (1) 212 328 3777
Website: http://www.hemophilia.
org/Events-Educational-Programs/
Annual-Meeting
10th Singapore International
Congress of O&G 2015
20/8/2015 to 22/8/2015
Location: Singapore
Info: Obstetrical & Gynaecological
Society of Singapore
Tel: (65) 6290 7400
Fax: (65) 6290 7401
Email: secretariat.sicog@mims.com
Website: http://www.sicog2015.com/
25th Meeting of the International
Society for Neurochemistry: 25th
ISN Meeting, 13th APSN and 35th
ANS Meeting
23/8/2015 to 27/8/2015
Location: Cairns, Australia
Info: International Society for
Neurochemistry
Tel: (41) 22 906 9151
Fax: (41) 22 732 2607
Website: http://www.neurochemistry.
org/biennial-meeting/isn-2015-
biennial-meeting.html
International Federation for the
Surgery of Obesity and Metabolic
Disorders
26/8/2015 to 29/8/2015
Location: Vienna, Austria
Info: IFSO Secretariat
Tel: (43) (1) 588 00 534;
(43) (1) 588 00 514
Fax: (43) (1) 588 00 520
Email: ifso2015@interconvention.at
Website: http://www.ifso2015.com/
index.php?id=1399
28th European College of
Neuropsychopharmacology
Congress 2015
29/8/2015 to 1/9/2015
Location: Amsterdam, the
Netherlands
Info: European College of
Neuropsychopharmacology
Tel: (31) 88 75 69 555
Fax: (31) 88 75 59 900
Email: secretariat@ecnp.eu
Website: http://www.ecnp-congress.
eu/
European Society of Cardiology
Congress 2015
29/8/2015 to 2/9/2015
Location: London, UK
Info: European Society of Cardiology
Tel: (33) 4 92 94 7600
Fax: (33) 4 92 94 7601
Website: http://www.escardio.org/
Congresses-&-Events/Upcoming-
congresses/ESC-Congress/ESC-
Congress-2015
UPCOMING 9/9/2015 to 12/9/2015
9th Congress of the European Pain
Federation (EFIC 2015)
2/9/2015 to 5/9/2015
Location: Vienna, Austria
Info: Kenes International
AUGUST 2015 C A L E N DA R 43
Annual Meeting of the Society of
Laparoendoscopic Surgeons and
Endo Expo 2015
2/9/2015 to 5/9/2015
Location: Sheraton New York Times
Square Hotel, New York, USA
Info: Society of Laparoendoscopic
Surgeons (SLS)
Tel: (1) 305 665 9959
Email: info@sls.org
Website: http://sls.org/mis2015/
17th Asia Pacific League of
Associations for Rheumatology
Congress (APLAR) 2015
6/9/2015 to 9/9/2015
Location: Chennai, India
Info: APLAR Congress Secretariat
Tel: (65) 6292 4710
Fax: (65) 6292 4721
E:mail: : aplar2015@kenes.com
Website: http://aplar2015.com/
congress-information/organising-
committe-1/
16th World Conference on Lung
Cancer
6/9/2015 to 9/9/2015
Location: Denver, Colorado, USA
Info: International Association for the
Study of Lung Cancer
Tel: (1) 855 464 2752
Email: Pia.Hirsch@IASLC.org
Website: https://www.iaslc.org/
events/16th-world-conference-lung-
cancer
45th Annual Meeting of
the European Society for
Dermatological Research
Location: Rotterdam, the Netherlands
Info: European Society for
Dermatological Research (ESDR)
Tel: (41) 22 321 48 90
Email: office@esdr.org
Website: http://www.esdr2015.org/
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Your problem makes my

hours fee insignificant!

As a matter of fact, you Im going to the store,

did catch me at a bad time! do we need anything?

We couldnt get you a mental

It has nothing to do with
My support group health professional, but doctor
whether Im stupid or not,
therapy told me to go to hell! Pythias here can give you
I just hate science!
a physical, free of charge
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