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Prescribing & medicines management
Mesalazine: is changing
to the cheapest really
cost-effective?
With over a dozen mesalazine products available for ulcerative colitis, choosing
between them can be difficult. Anja St.Clair Jones discusses some of the factors
that prescribers should consider. Choice should not be based on cost alone, she
says, but should take into account current management strategies and adherence
.pdf
d.pdf
Mesalazine is well established as the mainstay
of treatment to manage mild to moderate
ulcerative colitis (see “Ulcerative colitis:
background information” Panel, p2). Most
clinicians are familiar with its use but may feel
unsure about the different products, their
efficacy and their place in therapy. The aim of
treatment is:
•
•
•
•
•
Symptom relief
Induction and maintenance of remission
Mucosal healing
Avoiding surgery
Reducing the likelihood of cancer
A number of reviews have considered the
impact of different mesalazine products and a
recent one of modified release formulations
advocated the substitution of generic versions
as a pragmatic, cost-saving approach for the
NHS.3 This review, which excluded some
preparations owing to their different release
mechanisms, suggested that Mesren 400mg
tablets be prescribed instead of the market
leader Asacol MR for all new patients and
those who require a change to their drug
regimen. I believe, however, that this proposed
approach might only result in short-term
savings. Once current strategies in
management of ulcerative colitis and
adherence issues are taken into account it is
possible that change to the cheaper
preparation could result in decreased
maintenance of remission, more hospital
admissions and, perhaps, an increased
incidence of colorectal cancer.
Recent trials have looked at high-dose or
once-daily treatment regimens, or both. The
non-inferiority of once-daily regimens
together with mounting evidence of the
negative impact of non-adherence is changing
the way management of ulcerative colitis is
approached.
There is also a trend in practice towards
the use of higher doses. According to the
British Society of Gastroenterology, 4g/day of
mesalazine is more effective than placebo for
inducing remission in mild to moderate
ulcerative colitis, and greater clinical
improvement (but not necessarily remission)
is associated with doses greater than 3g/day.
The Ascend II trial, comparing 1,600mg tds
with 800mg of Asacol tds for six weeks,
indicated that patients with moderate
ulcerative colitis did better on the higher dose,
with a 72 per cent response compared with 59
per cent (P=0.036).4
Currently, however, for many preparations,
the British National Formulary lists the dose
for acute attacks as 2.4g/day. And for most
preparations, it says that doses for both acute
attacks and remission should be divided.
The European Crohn’s and Colitis
Organisation (ECCO) recommends a
minimum daily dose of 1g to maintain
remission but evidence is emerging that
daily doses of 2g and above may be more
effective.5
Non-adherence
Non-adherence is generally regarded as taking
less than 80 per cent of prescribed medicine.
Adherence is a particular issue in patients in
remission (in an acute attack patients are more
likely to comply with treatment). For example,
Kane et al found that overall adherence was
around 40 per cent in patients using
mesalazine for maintenance of quiescent
ulcerative colitis.6 Similar results were shown
in the Manitoba inflammatory bowel diseases
cohort study, in which about a third of
patients were found to be low adherers.7
The clinical impact of non-adherence is
considerable. It increases the chance of relapse
to 61 per cent in non-adherers compared with
11 per cent in adherers (P=0.001),8 reduces
quality of life, and increases colorectal cancer
risk to 31 per cent in non-adherers in
comparison with 3 per cent in adherers
(P=<0.001).9 A review by Hawthorne
confirms that adherence to mesalazine therapy
reduces the risk of colorectal cancer by 75 per
cent and favours a multidisciplinary team
approach to improve adherence rates.10
In 2004, the economic cost for caring for
patients with inflammatory bowel diseases
over six months in the UK ranged from £73
to £33,254, with the mean cost for ulcerative
colitis patients being£1,256. Only 14 per cent
of patients in the study needed admission to
hospital but they accounted for 49 per cent of
total secondary care cost.11
Strategies to achieve adherence In a
systematic review Kane also found varied
factors and reasons for non-adherence,
including disease duration, male gender, single
status, full-time employment and three times a
day dosing.12 Patients gave forgetfulness,
questioning the need for medication,
inconvenient regimens and having to take
many tablets as reasons for non-adherence.
In 2009, the National Institute for Health
and Clinical Excellence clinical guideline
CG76, “Medicines adherence: involving
patients in decisions about prescribed
medicines and supporting adherence”,
recommended simplifying drug regimens in
order to tailor therapies to the needs of
individual patients, integrating regimens into
their lives. Addressing barriers to adherence
resulting from patients’ beliefs is complex and
proposed interventions are probably of limited
benefit, but offering simpler, less intrusive
drug delivery methods are of proven value.
Patients tend to prefer once daily oral
formulations. With the trend of treatment
to higher dose regimens tablet burden
needs to be reduced to improve compliance.
Higher dose preparations, such as Asacol
800mg tablets and Pentasa 2g sachets,
have been formulated for the treatment of
active disease.
Rectal preparations ECCO guidelines
advise adding topical (rectal) mesalazine to
oral because oral mesalazine alone is less
effective in improving symptoms. However,
rectal preparations tend to be less acceptable
than oral preparations and are associated
with leakage, retention issues and bloating,
and can reduce adherence to therapy.
Therefore they tend to be used in the
treatment of active distal disease or in
combination with oral formulations for
extensive disease. A review of rectal
preparations is outside the scope of this article
but it should be noted that, as with oral
preparations, different rectal formulations
deliver mesalazine to different parts of the
distal colon, in different concentrations and
with variable acceptability to patients.
Further considerations
Because the action of mesalazine is
predominantly topical, the aim is to deliver
active drug to the site of inflammation, with
minimal systemic absorption. Only 15 per
cent of patients initially presenting with
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Learning & development
ULCERATIVE COLITIS: BACKGROUND INFORMATION
Ulcerative colitis is a life-long disease arising
from interaction between genetic and
environmental factors observed predominantly
in developed countries. The condition is
characterised by diffuse mucosal inflammation
which can be divided into distal (proctitis and
proctosigmoiditis) or more extensive disease
(left sided colitis, extensive colitis and
pancolitis). The Montreal classification is
favoured by the European Crohn’s and Colitis
Organisation (ECCO) to describe the disease
extent, as follows:
• Proctitis (E1) Limited to the rectum (ie, extent
of inflammation is distal to the rectosigmoid
junction)
• Left-sided (E2) Limited to the proportion of
the colon distal to the splenic flexure
(analogous to “distal” colitis)
• Extensive (E3) Extends proximal to the
splenic flexure (includes pancolitis)
About the disease
In the UK, about one in 1,000 people develop
ulcerative colitis, most commonly between the
ages of 10 and 40 years.
Symptoms and diagnosis Symptoms include:
• Mild to severe diarrhoea (which can be watery
and contain mucus or blood) or urgency to get
to the toilet but with nothing to pass
• Cramps in the abdomen
• Pain on passing stools
• Feeling generally unwell (especially if an attack
affects a large portion of the large intestine or
is prolonged)
Diagnosis usually involves a sigmoidoscopy
or colonoscopy to look at the appearance of the
lining of the rectum and colon. The mucosa
appears inflamed and ulcered.
Disease activity Management is dictated not
only by disease distribution but by disease
activity, which ECCO has classified into four
groups: remission, mild, moderate and severe.
However, ECCO did not agree criteria to assess
these and the Truelove and Witts classification
still seems to be a favoured approach. This
classes the disease as mild, moderate or severe
using the following factors:
• Number of bloody stools per day (<4 mild; 4–6
moderate; ≥6 severe)
• Pulse (<90bpm mild; ≤90bpm moderate;
>90bpm severe)
• Temperature (<37.5C mild; ≤37.8C moderate;
>37.8C severe)
• Haemoglobin (>11.5g/dL mild; ≥10.5g/dL
moderate; <10.5g/dLsevere)
• Erythrocyte sedimentation rate (<20mm/h
mild; ≤30mm/h moderate; >30mm/h severe) or
C-reactive protein (<5mg/L mild; ≤30mg/L
moderate; >30mg/L severe)
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mesalazine is tolerated
by 80 per cent of those
unable to tolerate
sulfsalazine. Balsalazide
and olsalazine are
Descending
Ascending colon
alternatives but are not
colon
always well tolerated
and are used in low
Caecum
Rectosigmoid
volumes in the UK.
junction
Patients taking
Sigmoid colon
aminosalicylates should
Appendix
be advised to report any
Rectum
unexplained bleeding,
bruising, sore throat or
Proximal (right) side
Distal (left) side
malaise.
Sebastian Kaulitzki | Dreamstime.com
Mesalazine is the
first-line therapy for
induction and maintenance of remission in mild
It should be noted that a review in 2007 of
to moderate disease. It is safe in long-term use.
activity indices (and clinical trial endpoints)
The drug has a topical action on epithelial cells
concluded that “an optimal scoring instrument
and is, therefore, more active in ulcerative colitis
for ulcerative colitis is still to be developed and
(a mucosal disease) than in Crohn’s disease (a
will require validation before extensive use in
transmural disease). Oral mesalazine is
clinical trials can be promoted”.1
completely absorbed in the small intestine but
Ulcerative colitis is a relapsing condition,
poorly absorbed in the colon.
with acute attacks and periods of remission.
To obtain a high concentration of the drug at
More than 50 per cent of patients with a flare up
the site of inflammation it is essential to
have a relapse within a year. The relapse rate for
minimise systemic exposure and insure topical
patients in remission and not taking any
delivery to the affected tissue.2 As for choice of
medicine is 38–76 per cent.
mesalazine, this cannot be made on grounds of
efficacy alone — route of delivery, disease
Treatment options
pattern, dose frequency, patient acceptability,
Treatment goals are to control symptoms and
cost and availability are also relevant factors
maintain remission. Drugs used include
(see main article).
aminosalicylates, immunosuppressants,
steroids and laxatives (proctitis sufferers resist
the urge of a bowel movement because it is
Prognosis and lifestyle
painful and constipation results) but, with so
In most cases ulcerative colitis starts in the
many types of ulcerative colitis described
rectum (proctitis). In some patients the disease
(eg, mild, active, quiescent, left-sided) choice
spreads up to affect some, or all, of the colon.
can be confused. Rectal preparations are
People who have had ulcerative colitis for a
usually used during attacks and for proctitis
number of years are at a higher risk of
(acute and remission). More detailed
developing colorectal cancer, especially those
recommendations for different types of
who have frequent flare-ups affecting the whole
ulcerative colitis from ECCO are available at
of the large intestine.
www.ecco-ibd.eu. In general, however, for mild
People with ulcerative colitis do not usually
to moderate disease, mesalazine is prescribed
need any special diet but a high-fibre diet may
initially. If two episodes of steroids are needed
help those with proctitis to avoid constipation.
within a year, therapy will be stepped up to
Iron tablets will be needed in those who develop
thiopurines, before an anti-tumour necrosis
anaemia (due to blood lost in stools).
factor drug.
Patients taking steroids, especially those
Steroids are only used to induce remission.
needing more than two courses per year,
In the UK, a recommended steroid regimen is
should take calcium and vitamin D.
prednisolone 40mg daily for one week, 30mg
daily for one week, then 20mg daily for two
Resources
weeks followed by a review and further step
• British Society of Gastroenterology guidelines
down, depending on response, until the
for the management of inflammatory bowel
prednisolone is stopped. A severe attack can be
disease in adults are available at
life-threatening and must be referred to a
www.bsg.org.uk/pdf_word_docs/ibd.pdf.
hospital for intravenous steroid therapy.
• Standards for NHS services for inflammatory
About a quarter of people with ulcerative
bowel disease are available at
colitis will need surgery.
/www.ibdstandards.org.uk.
Hepatic flexure
Tranverse colon
First-line therapy The original treatment was
sulfasalazine but side effects, including
exfoliating dermatitis, are common. Choice of
aminosalicylate is influenced by tolerability and
Splenic flexure
Signposting
• Information and support for people with
ulcerative colitis is available from Crohn’s and
Colitis UK (www.nacc.org.uk).
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Prescribing & medicines management
PANEL 1: FORMULATION AND RELEASE CHARACTERISTICS OF ORAL MESALAZINE MR *
Drug
Formulation
Optimal drug release pH
Site of drug release
Asacol MR
pH dependent delayed release (>7)
Ipocol
Mesren MR
Mezavant XL
400mg: Enteric coated with Eudragit S; 800mg: Enteric
coated with layer of Eudragit S followed by Eudragit S+L
Enteric coated with Eudragit S
Enteric coated with Eudragit S
Film coated with methacrylate copolymers type A, type B
Pentasa
Ethylcellulose coated microgranules
Terminal ileum and large bowel (colon
and rectum)
Terminal ileum and colon
Terminal ileum and colon
Colon
Colon
Duodenum to rectum
Salofalk
Tablets: Enteric coated with Eudragit L;
Granules: Eudragit L plus matrix granule structure
>7
>7
Gastroresistant coating with
lipophylic and hydrophilic matrix(7)
Diffusion through semi-permeable
membrane (enteral pH)
pH dependent delayed release (>6) Terminal ileum and colon
(granules have extra delayed release)
*Adapted from UK Medicines Information Q&A 67.2. What are the differences between different brands of mesalazine tablets?
PANEL 2: RECENT MESALAZINE TRIALS OF MAINTENANCE OF
REMISSION IN MILD TO MODERATE ULCERATIVE COLITIS
Sandborne et al 200916 Once a day dosing of Asacol 400mg tablets was compared with twice a
day dosing to achieve doses between 1.6g and 2.4g/day for 12 months (n=1,023). Using the simple
clinical colitis activity index (SCCAI), maintenance of remission was 85 per cent in both groups. In
other words, non-inferiority was found. The study was not powered to prove superiority and 70 per
cent of patients were already taking 2.4g/d at the start of the trial.
Dignass et al 200917 A dose of 1g twice a day of pentasa granules was compared with 2g daily in
362 patients for 12 months. The ulcerative colitis disease activity index (UCDAI) was used for
assessment. At one year, it was found that maintenance of remission in the twice-a-day group was
59 per cent compared with 71 per cent in the once-daily group (P=0.024). However, the trial
population was small.
Kruise et al 2008 18 Three regimens of Salofalk granules were compared: 3.0g daily, 1.5g daily and
0.5g three times a day, for 12 months (n=647). At one year, maintenance of remission was 75 per
cent, 61 per cent and 69 per cent, respectively, suggesting that 3g daily is the more efficacious
dosage. However, this research is accessible in abstract form only so in depth analysis of data is
not possible. Assessment indices used were clinical activity index (CAI) and endoscopy index (EI).
Kamm et al 20084 A regimen of Mezavant tablets 2.4g daily was compared with 1.2g twice a day
for 12 months (n=459). Maintenance of remission in the once-daily regimen was 64 per cent
compared with 68 per cent in the twice-daily regimen (P=0.351). The UCDAI was used for
assessment.
ulcerative colitis have disease extending
beyond the splenic flexure (ie, extensive, E3).
Most have distal disease. However, use of
formulations, such as pH dependent release
preparations (eg, Asacol, Ipacol, Mesren,
Salofalk tablets), that release the drug as a
bolus in the proximal colon, and azo-bonded
preparations (eg, olsalazine, and sulfasalazine)
may mean insufficient concentrations are
achieved in the distal part of the colon.
Formulations such as MMX Multi
Matrix (eg, Mezavant) and pH
independent delayed release system (eg,
Pentasa and Salofalk granules), which
release the drug all the way through the colon
might address such problems and, therefore,
be better for most patients, but this needs
further investigation, taking into account
limitations of techniques assessing
intra-luminal concentrations.
A review of methods of assessing active
drug release, intra-luminal concentration and
colonic distribution concluded that although
assessing drug release was important, due to
the limitations of the individual techniques,
randomised clinical trials remain the best
guide for dosing and treatment regimen
decisions.13
Panel 1 gives a summary of formulations
of modified release oral mesalazine products
and their characteristics. Both Mesren and
Ipocol are generics of Asacol and studies
indicate that the in vitro dissolution profile of
Mesren MR seems to be nearly identical to
that of Asacol MR 400mg while the Ipocol
dissolution profile seems to be slightly
different.3,13,14 However, a study comparing
Ipocol with Asacol MR 400mg in 88 patients
with mild to moderate relapse of ulcerative
colitis found both preparations to be equally
effective.1 Mesren has not been clinically
compared with other preparations (it is not a
requirement for licensing because the product
has the same bioequivalence as Asacol MR).
It is also worth noting that Asacol
formulations in different countries are not
equivalent due to different manufacturing
processes and coating so, for example, US
trial data might not be valid for comparison
with UK data.
Recent evidence
Despite individual trial results, systematic
reviews fail to find conclusive dose-dependent
responses to mesalazine therapies, partly due
to study designs and partly due to the fact that
attainment of remission is affected by disease
severity, duration and interpatient variability.
This might reflect the inability of current
formulations to deliver consistently
therapeutic drug levels to affected tissue —
gut function, distribution of gut content and
effect of the drug on gut flora is still poorly
understood and these factors may all affect
efficacy.
A Cochrane review in 2009 concluded that
the differences in efficacy are likely to be
marginal and further trials should look at
enhancing patient adherence with medication
rather than comparing the efficacy of various
mesalazine agents.15
Recent studies on maintenance of
remission in quiescent disease are outlined in
Panel 2. Remission rates between studies
cannot be compared due to difficulties in
interpretation and differences of study design.
Furthermore, unlike Crohn’s disease, the lack
Anja St.Clair Jones will be available to answer
questions online on the topic of this article
until 6 September 2010
Ask the
expert
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of standard indices for ulcerative colitis (see
“Ulcerative colitis” Panel) precludes the
collection of consistent treatment efficacy
data. It should be noted that most of the
assessment indices used in these recent
studies are unvalidated (with the exception of
clinical activity index, which was validated in
one study) or not formally validated
(ulcerated colitis activity index). Moreover,
because assessment indices are inconsistent, as
was the selection of patient groups and
subgroups, comparisons across these studies
are difficult.
Recent research is mainly concerned with
increased dose range and formulations that
reduce the pill burden on patients. Adherence
is increasingly included as secondary
endpoints in the maintenance of quiescent
ulcerative colitis studies underlining the
increasing importance of this factor on
maintenance of remission.
The need to develop standard assessment
indices for ulcerative colitis is paramount to
evaluate the efficacy of different formulations
because only trial data can accurately
determine the effect of formulation on
response. Intraluminal concentration
assessment methods remain limited in their
usefulness.
Costs
Panel 3 compares pill burden, dosage and cost
of recommended regimens. Asacol 800mg
tablets are large and may not be acceptable to
all patients. Pentasa may be a preferable
option for maintenance of remission in view
of cost and adherence issues as discussed —
one 2g sachet once daily compares favourably
to Mesren and Asacol MR, in terms of
reduced unit load burden. Salofalk has limited
data but those reported so far seem to favour
higher doses of 3g.
Currently, it is a patient-centred approach
to management that will result in long-term
cost-effectiveness.
Conclusion
Adherence to mesalazine treatment in is
complex and multifactorial, and differs with
time.18 Studies of several formulations of
once daily dosing in induction and in
maintenance therapy have shown that oncedaily dosing is efficacious and safe, that
formulations are probably not of significant
importance to the effect of mesalazine but that
high strength and once-daily dosing may
improve adherence.
Research has shown that divergence
of adherence at month three (when
maintenance treatment begins)16,19 affects
the maintenance of remission so it is
imperative to reduce pill burden. It is
questionable if generic low-dose tablets offer a
patient-centred reliable alternative — like
Asacol MR, they are not licensed to be used
once a day.
It remains to be investigated if a change to
once-daily dosing and low tablet loads reduces
hospital admissions and long-term incidence
of colorectal cancer. Anecdotal reports exist
but this must be a priority area of research in
the future.
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PANEL 3: DOSE AND COST COMPARISON OF ORAL MESALAZINE
Asacol MR
Active disease (higher dose)
Unit load/day Dose
Cost*
6x800mg tabs ii tds (4.8g/d) £224
Mezavant XL
4x1.2g tabs
Mesren MR
12x400mg tabs iv tds‡ (4.8g/d) £140
Pentasa granules
2x2g sachets
Salofalk granules
2x1.5g sachets ii od (3g/d)
iv od (4.8g/d) £233
i bd (4g/d)
Maintenance of remission
Unit load/day
Dose
Cost†
3x800mg tabs
i tds (2.4g/d) £730
2x1.2g tabs
ii od (2.4g/d) £759
6x400mg tabs
ii tds (2.4g/d) £475
£135
1x2g sachets
i od (2g/d)
£92
2x1g sachets
ii od (2g/d)‡ £428
£438
* Eight weeks BNF 59 March 2010; †12 months BNF 59 March 2010; ‡ unlicensed
DECLARATION OF INTEREST The
author has provided training support work to
Ferring in the past.
References
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Mikhailova TL et al. Once daily 3g
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Gastroenterology 2008:134:A489. Abstract.
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Predictors of persistence with 5aminosalicylic acid therapy ulcerative colitis.
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This article has not been peer-reviewed.
The author
Anja St.Clair Jones, MRPharmS, is lead
pharmacist, surgery and digestive diseases,
at Brighton and Sussex University Hospitals
NHS Trust