<title>1. INTRODUCTION</title> <p>It is a remarkable
epidemiological observation that whilst ulcerative colitis (UC) is related to
nonsmoking [##UREF##0##1##–##REF##2598752##4##], the opposite
applies to Crohn's disease (CD).<italic/>
Patients with CD are more often smokers compared with the general
population [##REF##6435736##5##], and smoking has an adverse effect on the course of their
disease [##REF##2323505##6##]. Several mechanisms for this could be relevant; components of
tobacco smoke, such as oxidizing chemicals, which, unlike nicotine, have
prothrombotic effects, could exacerbate microvasculature abnormalities and
ischaemia of the bowel wall [##UREF##1##7##]. It has also been suggested that CD could be
caused by an impaired host response to luminal bacteria; this, in turn, could
be exacerbated by the immunosuppressive effects of smoking on macrophages [##REF##11385576##8##, ##UREF##2##9##].
It is likely that different mechanisms are responsible for the “opposite effects” of smoking in CD and
UC, which are in many other respects similar diseases. The effects of <italic>smoking</italic> should not be considered synonymous with <italic>nicotine</italic>. Nicotine, as opposed to smoking, may have a beneficial effect in patients
with Crohn's colitis, given that there is a considerable overlap in the
treatments for the two conditions and nicotine has been shown to be of benefit
in UC. Although the specific mechanisms
underlying this effect remain unclear, nicotine has a number of actions that
could be potentially beneficial, including effects on the immune system [##UREF##3##10##]
and gut motility [##REF##10563544##11##].</p> <p>A recent Cochrane
Review [##UREF##4##12##] has confirmed benefit from transdermal nicotine in active UC: a
meta-analysis of two eligible randomized placebo-controlled trials [##REF##8114833##13##, ##REF##9054280##14##] so
far performed showed that after 4 to 6 weeks treatment, 19 of 71 patients
treated with transdermal nicotine were in remission compared to 9 of 70 given
placebo (odds ratio 2.56, 95% confidence interval 1.02–6.45). A nicotine enema has also been developed and
found to be of benefit when given as additional therapy in two uncontrolled
pilot studies in active distal UC [##REF##9354193##15##, ##REF##9305473##16##], but not in a recent randomised
controlled trial [##REF##16271342##17##]. A phase I-II
trial of delayed release oral nicotine has shown promise [##REF##16306772##18##] but a controlled
trial is awaited.</p> <p>The aim of this open pilot study was to examine the efficacy and safety of nicotine enemas in active distal Crohn's colitis.</p>
<title>2. MATERIALS AND METHODS</title> <title>2.1. Patients</title> <p>Patients with CD, based on the clinical, endoscopic, and histological features of Lennard-Jones' criteria [##UREF##5##19##], were recruited from the gastroenterology outpatient department
of a single centre; the key selection criteria were clinical and sigmoidoscopic evidence of active disease in the rectosigmoid region. Although the presence of CD in other regions
of the gastrointestinal tract was permitted, the patient's principal clinical problem had to relate to active distal colitis.<italic/>
Patients were not enrolled if they were current smokers, had other
unstable medical problems, were pregnant or lactating, had used enemas in the previous week, had changed their CD therapy with mesalazine, steroids, or antibiotics within the last 2 weeks, or had changed immunosuppressive therapy with azathioprine in the previous 3 months.<italic/>
The dosage of all concomitant medications was kept unchanged during the study period.</p> <title>2.2. Study design</title> <p>This was an open pilot study of 4 weeks' duration in which nicotine enemas were given as additional therapy—subjects
continued their conventional treatment without change during the study
period. Each 100 mL liquid enema
contained 6 mg of nicotine complexed with 400 mg of the high molecular weight polyacrylic acid carbomer, Carbopol 974P (Goodrich, UK), as already described [##REF##9759592##20##]. At the time of enrolment, a record was made
of the patient's symptoms of colitis including stool frequency, abdominal pain,
general well being, any complications of CD and urgency of defaecation; the
latter was graded as none, mild, moderate, or severe enough to cause
incontinence. Although Crohn's colitis
may be patchy, sigmoidoscopy with a biopsy of the most inflamed area was also performed by the same investigator in each case.<italic/>Patients were also asked to complete an inflammatory bowel disease quality of life questionnaire (SIBDQ) [##REF##8759664##21##] and blood
tests were taken for a full blood count, liver and renal function, and
inflammatory markers.</p> <p>During the study, patients kept a diary of their bowel symptoms and any adverse events (AEs). The
patients were assessed at the end of the 4-week trial period, or at premature withdrawal, or at any other time at the patient's request. The initial assessments were repeated by the
same physician. Sigmoidoscopy with a
biopsy, again from the most inflamed area, was repeated.</p> <title>2.3. Outcome measures</title> <p>The main outcome measures used were clinical improvement as measured by Crohn's disease activity index (CDAI) [##REF##1248701##22##], and changes in bowel frequency and urgency of defaecation. Urgency was included because it is a useful
guide to the severity of inflammation in distal colitis. At sigmoidoscopy, the severity of
inflammation of the worst affected area was graded visually according to the system described by Dick et al.
[##REF##14218553##23##]. The biopsy specimens were stained
with haematoxylin and eosin and graded by one histopathologist (GTW) according
to the Truelove and Richards system [##REF##13316140##24##] adapted for Crohn's colitis; see ##TAB##0##Table 1##.</p> <title>2.4. Ethical considerations</title> <p>This study was
approved by the Bro Taf Local Research Ethics Committee.</p>
<title>3. RESULTS</title> <p>Of the 13 patients recruited, 3 were excluded because they were also given antibiotics for a chest
infection, a middle ear infection, and recurrence of a finger infection during the study period. Demographic details of
the remaining 10 patients are in ##TAB##1##Table 2##; 7 were male and the mean age was 52
years. Seven patients were exsmokers whilst the remainder had never smoked.<italic/>The mean duration of disease relapse was 45 weeks and in 4 patients was greater than 99 weeks. Half of the
patients were on concomitant oral 5-ASAs, 2 were on prednisolone (10 mg) and 2 were on azathioprine; several patients had been intolerant of thiopurines. Only one patient had recently taken enemas,
asacol foam. The mean baseline CDAI
score was 202 (SD 80, range 73 to 348).<italic/>
In addition to their colonic involvement, one patient also had small
bowel CD. Three patients had disease
limited to the left side of the colon.</p> <title>3.1. Efficacy</title> <p>Patient 10 withdrew from the study after only 2 weeks due to failure to respond to treatment, but was kept in the intention-to-treat analysis; she had the highest CDAI score (348) at baseline; all other patients completed 4 weeks' treatment. Changes in the main outcome
measures for each patient are in ##FIG##0##Figure 1##.<italic/>
The mean CDAI score decreased from 202 to 153—the score was
reduced in 6 patients, unchanged in 3, and increased in one patient. The frequency of bowel movements each day was
reduced in 8 patients and unchanged in 2, and the urgency to defaecate was reduced in 7 patients, in one case from severe to nil, and was unchanged in the other 3. The sigmoidoscopy score improved in 7 patients and was unchanged in 3, but changes in histology showed no clear trend with a wide variation in the baseline scores.<italic/>One of the two patients taking oral steroids improved sufficiently to consider a gradual reduction of the dose
after the study.</p> <p>The mean SIBDQ score increased from 39 to 47.<italic/>Mean
levels of the inflammatory markers C-reactive protein (CRP), erythrocyte sedimentation
rate (ESR), and fibrinogen all fell from 22.0 mg/L, 19.1 mm/h, and 4.4 g/L,
respectively, to 12.3 mg/L, 12.5 mm/h, and 4.0 g/L, respectively, whilst the mean white cell count was unchanged at 8.4 × 10<sup>9</sup>/L and the mean
platelet count increased slightly from 310 to 320 × 10<sup>9</sup>/L.<italic/> Renal function and liver function tests were unaffected.</p> <p>The effect of disease location on outcome was briefly considered. The only patient with ileal disease improved
during the study, with a CDAI reduction from 150 to 74. Of the 3 patients with disease restricted to the left colon, one improved, one remained the same, and the other deteriorated;
the respective changes in CDAI score were from 144 to 67, from 348 to 345, and from 156 to 189. <italic/>In terms of the
duration of disease relapse, of the 4 patients who had been in relapse for more than 99 weeks, 3 improved, with CDAI changes from 272 to 169, from 200 to 64, and from 150 to 74, whilst one remained the same, with a CDAI change from 73 to 71.</p> <title>3.2. Safety</title> <p>Eight of the 10 patients experienced an adverse event but none were classified as serious.<italic/>In total, 12 AEs were reported (##FIG##1##Figure 2##) and 11 of these were thought to be related to nicotine, the other being a localised
skin rash that resolved spontaneously.<italic/>Two-thirds of the AEs occurred on commencement of treatment and were
temporary, lasting 2 days or less.<italic/>The
most common AE was difficulty sleeping, which included vivid dreams, reported by 4 patients. The other AEs were lightheadedness, nausea, and headache.</p>
<title>4. DISCUSSION</title> <p>These are the first observations of topical nicotine in patients with active Crohn's colitis. In the 10 patients, there was a
CDAI reduction in 6 and an increase in one; the mean score decreased from 202 to 153. Frequency of bowel movements was
reduced in 8 patients, urgency to defaecate was reduced in 7, and the
sigmoidoscopy score improved in 7; the mean SIBDQ score increased from 39 to 47. Clinical improvement was noted in
patients who also had disease in locations other than the rectosigmoid,
including the one patient with small bowel disease.<italic/>Three of the 4 patients with chronically active disease for more than 99 weeks improved. There were no serious AEs and no premature withdrawals due to
intolerance.</p> <p>A relatively small open pilot study of this nature can only provide preliminary data on efficacy and safety. Hence, although our
observations suggested improvement in most of the patients, and certainly no overall deterioration, the findings will need to be corroborated by larger randomised controlled studies. Formal
tests of significance were not performed because, in this relatively small study, they may have been misleading.<italic/>
Initially, it was planned to recruit 20 patients to the study, but
recruitment was slow for two main reasons; 10 patients with active Crohn's colitis, who were identified as suitable for entry to the study, were current smokers and therefore excluded. In
addition, because the study preparation was an enema, those patients whose principal symptoms were related to left-sided active colitis were
targeted. However, identifying such a
homogenous group proved hard, as a number of patients screened had to be
excluded because they had symptoms that related primarily to other sites of disease involvement. This may have
reduced potential sources of error from our study, but it will probably make it difficult to recruit sufficient numbers to achieve a larger study of homogeneous patients, as defined by the Vienna
classification [##REF##10701144##25##]. For this small
pilot study, full Vienna classification of patients was not performed and subgroup analyses were avoided.</p> <p>It is noteworthy that methods used to assess the response of Crohn's colitis to treatment have some limitations. The patchy nature of
Crohn's colitis means sigmoidoscopy and histology findings should be
interpreted with caution. The separate
recording and analysis of stool frequency and urgency of defaecation was an attempt to assess some of the more troublesome symptoms of distal colitis, although a contribution from more proximal disease cannot be excluded. This was used in addition to the global
assessment provided by the CDAI, the more conventional composite scoring system of disease activity that contains systemic features less relevant to this study. Two of the 10 patients had a CDAI
score less than 150 at study entry, which might imply disease remission;
however, all patients had rectosigmoid inflammation on sigmoidoscopy and had
symptoms of active distal disease.</p> <p>The negative
association between smoking and CD raises questions about whether topical
nicotine is an appropriate treatment for patients with Crohn's colitis. However, this was justified on the basis that
the treatments for UC and CD are very similar, and transdermal nicotine has
been found to provide benefit in UC. It
is possible that the detrimental effect of smoking on CD is mediated through
mechanisms independent of nicotine; these could, for example, include
exacerbation of underlying ischaemia of the bowel wall at the microvascular
level [##UREF##1##7##] due to prothrombotic oxidizing chemicals present in tobacco
smoke. It has also been suggested that
CD could be caused by an impaired host response to luminal bacteria; this, in
turn, could be exacerbated by the immunosuppressive effects of smoking on macrophages [##REF##11385576##8##, ##UREF##2##9##]. These effects could
mask any benefit from nicotine in Crohn's colitis. It is also possible that the response to
nicotine differs between ileal and colonic diseases. Rectal enema treatment of the transmural
inflammation of Crohn's colitis is not well described in the literature,
however it is used in clinical practice.</p> <p>Possible
mechanisms for a therapeutic effect of topical nicotine in distal colitis
include alterations in colonic motility.<italic/>
Nicotine has been shown to reduce tone and muscular activity in the
sigmoid colon [##REF##10563544##11##], an effect mediated primarily through nitric oxide that is
released by nicotine [##REF##11069313##26##]. Another
potential mechanism is via a reduction in mucosal tumour necrosis factor
(TNF<italic>α</italic>), a key cytokine in the generation of inflammation in CD [##REF##2117510##27##]. Nicotine has been found to reduce the secretion of TNF<italic>α</italic> from macrophages, by activation of <italic>α</italic>7 nicotinic acetylcholine receptors [##REF##12508119##28##].</p> <p>Our pilot study has shown that, in the 10 patients with active Crohn's colitis, 6 mg nicotine
enemas were associated with clinical improvement in the majority of patients,
they were safe and well tolerated, and did not appear to worsen the
condition. Larger randomised controlled
trials are needed to confirm these observations and longer-term outcome data
would also be of interest.</p>
<p>Recommended by Julian Walters</p> <p>
<italic>Background</italic>. Smoking has a detrimental effect in Crohn's disease (CD), but this may be due to factors in smoking other than nicotine. Given that transdermal nicotine benefits ulcerative colitis (UC), and there is a considerable overlap in the treatment of UC and CD, the possible beneficial effect of nicotine has been examined in patients with Crohn's colitis. <italic>Aims</italic>. To assess the efficacy and safety of nicotine enemas in active Crohn's colitis. <italic>Patients</italic>. Thirteen patients with active rectosigmoid CD; 3 patients were excluded because they received antibiotics.
<italic>Methods</italic>. Subjects were given 6 mg nicotine enemas, each day for 4 weeks, in an open pilot study. At the beginning and end of the trial, a Crohn's disease activity index (CDAI) score was calculated, sigmoidoscopy was performed, and haematological inflammatory markers measured. 
<italic>Results</italic>. Mean CDAI decreased from 202 to 153—the score was reduced in 6 patients, unchanged in 3, and increased in one. Frequency of bowel movements decreased in 8 patients and the sigmoidoscopy grade was reduced in 7. Mean C-reactive protein decreased from 22.0 to 12.3 mg/L. There were no withdrawals due to adverse events. 
<italic>Conclusions</italic>. In this relatively small study of patients with active Crohn's colitis, 6 mg nicotine enemas appeared to be of clinical benefit in most patients. They were well tolerated and safe.</p>
<title>ACKNOWLEDGMENTS</title> <p>J. R. Ingram was supported by the Gastrointestinal Foundation Trust. SLA Pharma gave financial support to the project. The authors are indebted to Dr. J. T. Green (of Cardiff and Vale Hospitals Trust) who referred patients, and to Professor G. T. Williams (GTW) who performed all histological assessments.</p>
<fig id="fig1" position="float"><label>Figure 1</label><caption><p>
<italic>Outcome measures.</italic> Response of 10 patients
with active Crohn's colitis given 6 mg nicotine enemas daily for 4 weeks. Where 2 or 3 patients had the same baseline
and end values, this is indicated above the connecting line, which is drawn more boldly. CDAI is Crohn's disease
activity index. Frequency is the number
of stools/24 hours. Urgency of
defaecation is graded: 0 = none, 1 = mild, 2 = moderate, and 3 = severe enough to cause incontinence. Sigmoidoscopic
score is graded 0, normal to 4, fulminant disease. Histological scores are based on acute
inflammatory activity: grade 0, no polymorphs to grade 4, florid acute
inflammation with polymorphs and ulceration.<italic/>
Histology data is given for only 8 patients because the end-of-study
biopsies of 2, both with baseline scores of 2, were insufficient for
analysis.<italic/>QOL is a score of quality of
life as measured by the short inflammatory bowel disease questionnaire [##REF##8759664##21##].<italic/>Paired data were available for CRP in 7 patients and for ESR in 8 patients.</p></caption></fig> <fig id="fig2" position="float"><label>Figure 2</label><caption><p>
<italic>
Adverse events during study.</italic> Adverse events 
experienced during nicotine enema treatment with the number of patients
affected in each case.<italic/>“Sleep prob” refers to disturbed sleep or vivid dreams.<italic/>The “rash” was a 2 cm diameter erythematous maculopapular lesion on the forearm of a patient which resolved spontaneously.</p></caption></fig>
<table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>
<italic>Histological grade of inflammation.</italic> The histological grade of inflammation present in biopsies taken
from the most inflamed area of the rectosigmoid region at sigmoidoscopy,
adapted by GTW for Crohn's
colitis from the system described by Truelove and Richards [##REF##13316140##24##] for ulcerative
colitis.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Grade of inflammation</th><th align="left" rowspan="1" colspan="1">Description</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1">No polymorphs</td></tr><tr><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">Small number of
polymorphs in the lamina propria with minimal cryptitis</td></tr><tr><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">Focal cryptitis
with crypt rupture or affecting groups of two or more adjacent crypts</td></tr><tr><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">Florid diffuse
polymorph infiltrate with crypt abscesses</td></tr><tr><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">Florid acute
inflammation with ulceration</td></tr></tbody></table></table-wrap> <table-wrap id="tab2" position="float"><label>Table 2</label><caption><p>
<italic>Baseline characteristics of 10 patients with Crohn's colitis.</italic> Extent of disease: 1 = proctitis, 2 = sigmoid colon, 3 = descending
colon, 4 = transverse colon, 5 = ascending colon, 6 = pancolitis, 7 = ileal, 8
= perianal. “Recent enemas” refers to
any steroid or 5 aminosalicylate (5-ASA) enemas taken from 1 to 3 weeks before
entry into the study. All concomitant
medication doses given are the daily amounts, the only oral steroid taken was
prednisolone, aza = azathioprine. CDAI =
Crohn's disease activity index.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1"> No.</th><th align="left" rowspan="1" colspan="1"> Age (years)</th><th align="center" rowspan="1" colspan="1"> Sex</th><th align="center" rowspan="1" colspan="1"> Exsmoker</th><th align="left" rowspan="1" colspan="1"> Disease extent</th><th align="left" rowspan="1" colspan="1"> Duration relapse (weeks)</th><th align="left" rowspan="1" colspan="1"> Recent enemas</th><th align="left" rowspan="1" colspan="1"> 5-ASA (g)</th><th align="left" rowspan="1" colspan="1"> Oral steroids (mg)</th><th align="left" rowspan="1" colspan="1"> Aza (mg)</th><th align="left" rowspan="1" colspan="1"> Baseline CDAI score</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">41</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">1,2,3,4</td><td align="left" rowspan="1" colspan="1">&gt;99</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">73</td></tr><tr><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">27</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">+</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">156</td></tr><tr><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">52</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">+</td><td align="left" rowspan="1" colspan="1">6,7</td><td align="left" rowspan="1" colspan="1">&gt;99</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">150</td></tr><tr><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">59</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">+</td><td align="left" rowspan="1" colspan="1">2,5</td><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">3.2</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">150</td><td align="left" rowspan="1" colspan="1">246</td></tr><tr><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">73</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">+</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">&gt;99</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">2.4</td><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">200</td></tr><tr><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">38</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">6,8</td><td align="left" rowspan="1" colspan="1">9</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">167</td></tr><tr><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">59</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">+</td><td align="left" rowspan="1" colspan="1">2,3,4</td><td align="left" rowspan="1" colspan="1">&gt;99</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">1.2</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">272</td></tr><tr><td align="left" rowspan="1" colspan="1">8</td><td align="left" rowspan="1" colspan="1">79</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">+</td><td align="left" rowspan="1" colspan="1">3,4</td><td align="left" rowspan="1" colspan="1">30</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">259</td></tr><tr><td align="left" rowspan="1" colspan="1">9</td><td align="left" rowspan="1" colspan="1">27</td><td align="center" rowspan="1" colspan="1">M</td><td align="center" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">3.0</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">144</td></tr><tr><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">62</td><td align="center" rowspan="1" colspan="1">F</td><td align="center" rowspan="1" colspan="1">+</td><td align="left" rowspan="1" colspan="1">2,3</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">foam</td><td align="left" rowspan="1" colspan="1">2.4</td><td align="left" rowspan="1" colspan="1">−</td><td align="left" rowspan="1" colspan="1">50</td><td align="left" rowspan="1" colspan="1">348</td></tr></tbody></table></table-wrap>
<graphic xlink:href="GRP2008-237185.001"/> <graphic xlink:href="GRP2008-237185.002"/>
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Gastroenterol Res Pract. 2008 Mar 27; 2008:237185