•treq• .~0.4knOte..01.V.V.14., .11 , (cid:9)
`..„ • (cid:9)
`44•••••, • *,} (cid:9)
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`'1'i.: DIG t;::T.1 UN
`
`19134
`j10600 U0
`
`'11
`
`30/1/84
`Released August 1984
`
`rimmiTiu;v•—•
`
`\
`
`/I
`
`NATIONAL
`LIBRARY
`3 1 AUG 1984
`0:
`MEDI
`
`C .
`
`S. Karger
`Medical and Scientific
`Publishers
`Basel • Mtinchen Paris
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`122225MMEMV (cid:9)
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`1:•
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`•-•
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`Ex. 1065 - Page 1
`
`

`

`'21
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`Ex. 1065 - Page 2
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`This mat E i i
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`SU NEC' (cid:9)
`:7= (cid:9)
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`I Z, Laws
`
`Ex. 1065 - Page 3
`
`(cid:9)
`

`

`Vol. 30, No. 1, 1984
`
`ISSN 0012-282.•
`DIGEBW
`30(1) J-64 (1.0,4
`
`
`
`
`
`Original Papers
`Autoantibodies and Immunoglobulins in Patients with Alcoholic Cirrhosis.
`Relation to Measurements of Hepatic Function and Hemodynamics
`Gluud, C.; Tage-Jensen, U.; Rubinstein, E.; Henriksen, J.H. (Hvidovre/Copenhagen) (cid:9)
`Faecal Weight, Constituents, Colonic Motility, and Lactose Tolerance in the Irritable
`Bowel Syndrome
`Eastwood, M.A.; Walton, B.A.; Brydon, W.G.; Anderson, J.R. (Edinburgh)
`Relationship between Rectal Mucosal Prostaglandin Production and Water Electrolyte
`Transport in Ulcerative Colitis
`
`Rampton, D.S.; Sladen, G.E. (London) (cid:9)
`Investigations on the Toxicity of Bile Salt Solutions, Capmul 8210 and a Bile Salt-EDTA
`Solution for Common Bile Duct Perfusion in Dogs
`Leuschner, U.; Sieratzki, J.; Klempa, I.; BaumOrtel, H.; Lang, S.; Siede, W.; Hubner, K.; Classen, M.
`(Frankfurt a. M.)
`Timoprazole Is a Unique Cytoprotective Agent in the Rat
`Ruwart, M.J.; Nezamis, J.E.; Rush, B.D.; Lancaster, C.; Davis, J.1).; Nichols, N.M.; Ochoa, R.
`(Kalamazoo, Mich.) (cid:9)
`Residual Function of Exocrine Pancreas after Operation for Chronic Pancreatitis by
`N-Benzoyl-L-Tyrosyl-p-Aminobenzoic Acid Test (NBT-PABA Test)
`Kodama, M.; Tanaka, T. (Hiroshima)
`Pancreatic Polypeptide and Gastrin Release during Sham Feeding in Man
`Koop, H.; Arnold, R.; Creutzfeldt, W. (Gottingen)
`Aspirin-Induced Damage in the Dog I leidenhain Pouch and Cytoprotection with
`16,16-Dimethyl PGE2
`Reele, S.B.; Gumbleton, T.J.; Stryd, R.P.; 13runden, M.N.; Gilbertson, T.J. (Kalamazoo, Mich.)
`Sulfated Glycoprotein Biosynthesis in Human Gastric Mucosal Biopsies
`Kakei, M.; Ohara, S.; Ishihara, K.; Goso, K.; Okabe, 11.; Hotta, K. (Kanagawa)
`
`
`
`
`
`
`
` I •
`
`
`
`Cover illustration. The different parts of the intogngtjgkuppliffig. 1-3), Coecum (Fig. 4 + 5) and Rectum (Fig. 6 + -
`Godefridi Bidloo, Anatomia Humani CorporisktablelApAnuterdam (1685).
`Subject U-1 C, • i :Laws
`
`
`
`
`
`
`
`Ex. 1065 - Page 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`rson
`
`et of
`man
`erol-
`
`h a v-
`-4 8 3
`
`()hal (cid:9)
`Gas. (cid:9)
`
`Pa
`j
`
`i, J.;
`Dwei
`
`Co.
`Syn.
`8).
`the
`t.
`
`Ohs (cid:9)
`
`Digestion 30: 13-22 (1984) (cid:9)
`
`01984 S. Karger AG, Basel
`0012-2823/84/0301-0013$2.75/0
`
`Relationship between Rectal Mucosal Prostaglandin Production
`and Water and Electrolyte Transport in Ulcerative Colitis
`
`D.S. Rampton, G.E. Sladen
`Newham General Hospital, and Gastroenterology Unitfbuy's Hospital Medical School.)_ondon, UK
`
`Key Words. Prostaglandins • Ulcerative colitis • Diarrhoea • Intestinal absorption •
`Rectum
`
`Abstract.1We have used in vivo rectal dialysis to test the hypothesis that the diarrhoea of
`patients with active ulcerative colitis (UC) is due to inhibition of large intestinal salt and water
`absorption by enhanced local mucosal prostaglandin (PG) synthesis. In 28 patients with
`untreated UC, increased rectal mucosal PGE2 release varied inversely with sodium transport
`and directly with potassium transport; higher PGE2 release was also associated with lower (i.e.
`less negative) potential difference (PD). Disease activity assessed sigmoidoscopically was pos-
`itively related to PGE2 release, potassium transport and lower PD. Similar relationships were
`found in 33 patients treated with sulphasalazine and/or corticosteroids and in 9 patients stud-
`ied serially when on unaltered conventional, or no treatment. In contrast, when 10 patients
`with UC were given the PG synthesis inhibitor, flurbiprofen, a significant fall in PGE2 release
`was associated with deteriorations in mucosal PD and transport of sodium and potassium.
`Increased PG production is therefore unlikely to be a major determinant of the abnormalities
`of electrolyte transport found in UC. The correlations between mucosal PGE2 release and
`electrolyte transport were probably due to the relationship of these variables with some other
`consequence of tissue damn ze.
`
`The explanation for the abnormalities of
`colorectal salt and water transport observed
`in ulcerative colitis (UC) [l-9] is not yet
`clear. Prostaglandin (PG) synthesis is en-
`hanced in the large intestinal mucosa of pa-
`tients with active disease [6, 7, 9-12], and
`because stable PGs evoke intestinal secretion
`of water and electrolytes pharmacologically
`and experimentally [14-23], it has frequently
`been suggested that these ubiquitous fatty
`acids may be responsible for the impairment
`
`of colorectal fluid transport found in UC [9,
`17-19, 21-23].
`We have tested this hypothesis using in
`vivo rectal dialysis in patients with UC to
`assess rectal mucosal net water and electro-
`lyte transport [24] and, as a simultaneous
`index of intramucosal net PG production,
`immunoreactive PGE2 release [7]. Rectal
`mucosal potential difference was measured
`as a guide to sodium pump activity and epi-
`thelial permeability [4, 5], and disease activ-
`
`This (cid:9)
`at (cid:9)
`
`a (cid:9)
`
`az meled
`and —Ey -
`
`Ex. 1065 - Page 5
`
`(cid:9)
`(cid:9)
`

`

`14 (cid:9)
`
`Ram pton/Slaqen
`
`ity was assessed using observer-independent
`sigmoidoscopic criteria [25]. Having estab-
`lished normal ranges in control subjects
`(group A), we used these methods to evaluate
`the relationships between rectal mucosal PG
`production and fluid transport in untreated
`(group B) and conventionally treated patients
`with UC (group C); paired serial observations
`were made in a further group of colitics
`(group D). Finding negative correlations be-
`tween mucosal PGE2 release and electrolyte
`transport in these patients, we proceeded to
`investigate the effect of treatment of further
`patients with UC with the potent PG synthe-
`sis inhibitor, flurbiprofen (group E). The de-
`terioration in electrolyte transport produced
`by this drug indicated that PGs are unlikely
`to be major determinants of the abnormali-
`ties of fluid transport found in UC.
`
`Methods
`
`Control Subjects (Group A)
`18 subjects with various minor bowel symptoms
`for which thorough investigation had revealed no or-
`ganic cause served as controls. They were thought to
`have the irritable bowel syndrome, and had had no
`treatment for at least 2 weeks when studied.
`
`Patients with UC (Groups B—E)
`UC was diagnosed by conventional clinical, radio-
`logical and histological criteria. 28 patients (group 11)
`were studied on no treatment; they either had never
`had treatment or had been off all therapy for at least 2
`weeks. 33 patients (group C) were studied after con-
`ventional treatment for at least 1 week with either oral
`sulphasalazine (17 patients), topical or oral corticoste-
`roids (8) or both (8). 9 further patients with UC
`(group D) were studied twice at an interval of at least 1
`week; their treatment — oral sulphasalazine (2 pa-
`tients), topical or oral steroids (2), both (3) or none (2)
`— was the same on each occasion. 10 patients (group E)
`were studied before and again after 1 week's treatment
`with flurbiprofen, 50 mg four times daily by mouth.
`
`Each participant gave informed consent for the
`investigations, approval for which was obtained frwn
`the Guy's and University College Hospital Ethical
`Committees. Limited data from the control subjcts
`(group A) and some of the patients with UC (grotips
`B—E) has been published elsewhere [6, 7, 27, 31].
`
`Protocol
`At the beginning of the study, disease activity in
`the distal colon and rectum of the patients with UC
`was scored sigmoidoscopically [25], grade 0 indicating
`normal mucosal appearance, 1 loss of the vascular hat..
`tern, 2 contact bleeding and 3 spontaneous bleeding,
`After measurement of rectal mucosal PD [7], reuai
`dialysis was performed using a solution containing
`Na+ 120 mmol/l, K+ 30, Cl- 120, HCO3 30, pH 8.1
`[7]. After 1 h, the dialysis bag was removed and its
`volume change measured by weighing.
`
`Analyses
`Dialysate concentrations of PGE2-like material
`were measured by radioimmunoassay [7], and of Na+
`and K+ by flame photometry.
`
`Calculations and Statistics
`Standard formulae were used to calculate net flux
`rates [24]. Positive values for water and electrolyte
`transport indicate net absorption, and negative values
`net secretion. Rectal PD was negative with respect to
`the lurninal aspect of the mucosa, and in the text a
``higher' PD indicates a more negative PD.
`Results are shown as mean ± SEM. Paired Ind
`unpaired data were compared using Wilcoxon's sighed
`ranks test (two-tailed) and sum of ranks test (two-
`tailed), respectively. Linear regressions were calcu-
`lated by the method of least squares, and correlation
`coefficients and their statistical significance by Spear-
`man's rank correlation test.
`
`Results
`
`Group A — Control Subjects (n = 1)
`Table I shows the values for rectal muco-
`sal PGE2 release, water and electrolyte trans-
`port, and PD in the control subjects. In ezIch
`individual the mucosal appearance at sign-wi_
`doscopy was normal (score 0).
`
`Th.k ma - Erial a= :nried
`
`Subj:t (cid:9)
`
`=
`
`3
`
`Ex. 1065 - Page 6
`
`

`

`Prostaglandins and Electrolyte Transport in Ulcerative Colitis (cid:9)
`
`15
`
`Table I. Rectal mucosal PGE2 release, net water and electrolyte transport, PD and sigmoidoscopic score in
`control subjects (group A), untreated patients with UC (group B) and conventionally treated patients with UC
`(group C)
`
`Variable
`
`Control subjects
`
`Untreated UC
`
`(group A)
`
`(group B)
`
`Conventionally
`treated UC
`(group C)
`
`PGE2 release, pg • cm-2 • h-1
`Water transporta, nl • cm-2 • min- i
`Sodium transporta, nmol • cm -2 • min-
`Potassium transporta, nmol • cm-2 • min- I
`PDb, mV
`Sigmoidoscopic score'
`
`39±7 (13)
`+294±37 (11)
`+99±7 (11)
`—37±6 (11)
`—52±1 (18)
`0 (cid:9) (11)
`
`635± 127 (28)**
`+ 156± 10 (28)**
`+64 ±5 (28)**
`—14 ± 5 (28)**
`—35 ±2 (28)**
`1.7 ±0.2 (28)**
`
`572± 110 (33)**
`+196 ± 14 (33)*
`+71 ±7 (33)*
`—15 ±5 (33)*
`—36 ±3 (33)**
`1.6 ± 0.2 (33)**
`
`Results are shown as mean ± SEM (n).
`*p < 0.05 from control subjects (group A); ** p < 0.01 from control subjects (group A).
`a (cid:9) Net absorption is denoted by + sign and net secretion by — sign.
`b (cid:9)
`PD is negative with respect to the luminal surface of the mucosa.
`Scored 0-3 with increasing abnormality (see Methods).
`
`Group B — Patients with Untreated UC
`(n= 28)
`Untreated UC was associated with a sig-
`nificant increase in rectal mucosal PGE2 re-
`lease and significant impairments of water,
`sodium and potassium transport, and of PD
`(table I). Sigmoidoscopic appearance was ab-
`normal in all but 1 patient (table I).
`In patients with untreated UC there was a
`significant negative linear correlation between
`rectal mucosal PGE2 release and sodium
`transport; PGE2 release was also directly re-
`lated to potassium transport and lower (less
`negative) PD (fig. 1, table II). The relationship
`between PGE2 release and water transport was
`not statistically significant (fig. 1, table II).
`Sodium transport was directly related to
`water transport and inversely to potassium
`transport. A higher (i.e. more negative) PD
`varied directly with sodium transport and in-
`versely with potassium transport (table II).
`
`Disease activity assessed sigmoidoscopi-
`cally [25] varied directly with mucosal PGE2
`release, potassium transport and lower PD,
`but the relationships between sigmoidoscopic
`score and transport of water and of sodium
`did not reach statistical significance (fig. 2,
`table II).
`To see whether the correlations between
`mucosal PGE2 release and electrolyte trans-
`port shown in figure 1 were due to the rela-
`tionships between these variables and disease
`activity assessed sigmoidoscopically (fig. 2),
`the patients in group B were subdivided ac-
`cording to sigmoidoscopic score; the correla-
`tions between PGE2 release and transport
`function were then re-calculated for the 12
`patients with sigmoidoscopic scores of 1, for
`the 10 patients with scores of 2, and for the 5
`patients with scores of 3, respectively (data
`points distinguished in figure 1). Of these, the
`only one to reach statistical significance was
`
`st:'e (cid:9)
`Sub.:.E:: (cid:9)
`
`Tcm-pn eed
`and — .B.: :e
`::•i+:Laws
`
`Ex. 1065 - Page 7
`
`

`

`16 (cid:9)
`
`Rampton/ShuRn
`
`Table H. Correlations between rectal mucosal PGE2 release, net water and electrolyte transport, PP and
`sigmoidoscopic score in untreated patients with UC (group B) and in conventionally treated patients with UC
`(group C)
`
`Variable
`
`Group
`
`m
`
`c
`
`Spearman's r
`
`x
`
`y
`
`PGE2 release
`
`water
`
`PGE2 release
`
`sodium
`
`PGE2 release
`
`potassium
`
`PGE2 release
`
`PD
`
`Sig. score
`
`PGE2 release
`
`Sig. score
`
`water
`
`Sig. score
`
`sodium
`
`Sig. score
`
`potassium
`
`Sig. score
`
`PD
`
`Sodium
`
`water
`
`Sodium
`
`potassium
`
`Sodium
`
`PD
`
`PD
`
`potassium
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`B
`C
`
`-0.024
`-0.029
`
`-0.017
`-0.032
`
`0.025
`0.016
`
`0.013
`0.019
`
`596
`518
`
`-13.6
`-26.1
`
`- 11.6
`-17.8
`
`18.1
`14.4
`
`8.2
`14.0
`
`0.88
`0.96
`
`-0.72
`-0.50
`
`-0.34
`-0.30
`
`1.62
`1.10
`
`171
`213
`
`75
`89
`
`-30
`
`-43
`-47
`
`-365
`-275
`
`178
`239
`
`83
`100
`
`-45
`-39
`
`-49
`-58
`
`100
`128
`
`32
`20
`
`-13
`-14
`
`42
`24
`
`-0.31
`-0.28
`
`-0.38
`-0.37
`
`0.57
`0.53
`
`0.73
`0,73
`
`0.72
`0.91
`
`-0.15
`-0.26
`
`-0.32
`-0.38
`
`0.48
`0.51
`
`0.50
`0.72
`
`0.42
`0.55
`
`-0.57
`-0.71
`
`-0.64
`-0.56
`
`0.62
`0.71
`
`Ns
`Ns
`
`0.05
`0.0
`)
`10,01
`10.01
`10.01
`10.01
`10.01
`10.01
`Ns
`Ns
`
`Ns
`<0.05
`
`<0.0
`1
`<0.0
`1
`
`<0.0
`1
`<0.0
`
`<0.0,
`<0.0)
`1
`<0,0
`<0.01
`1
`<0,0
`< 0.01
`1
`< 0.0
`<0.01
`1
`
`Units are as in table I. NS denotes not significant.
`
`r
`
`This -E.: E`lal
`a: (cid:9)
`
`:a
`
`14,NE2Z l651.1d41110246
`
`Ex. 1065 - Page 8
`
`

`

`Prostaglandins and Electrolyte Transport in Ulcerative Colitis
`
`17
`
`r = -0 36, p<0 05
`
`O
`
`o U
`
`300 -
`
`7c 200 -
`E
`
`•
`
`COQ
`
`t (cid:9)
`
`100
`
`P1/, •
`
`150
`t1
`E 100 •
`
`E u 50
`2..
`
`q
`
`.0
`
`0
`
`50
`
`0
`
`-100
`
`7
`C
`E (cid:9)
`ro
`▪ ;
`,„
`
`E N u -50
`• L, (cid:9)
`1-5
`(13 (cid:9)
`
`0.
`
`r.0.57, p<0,01
`
`1,000 (cid:9)
`0 (cid:9)
`PGE 2 release, pg • cm-2 • h-1
`
`2,000
`
`2,000 -
`
`r =0.72, p< 0 01
`
`50
`
`0
`
`•
`rr. 0.40, p<0.01
`11T
`
`-50
`
`g.- (cid:9)
`fl! E (cid:9)
`
`• E
`'01 (cid:9)
`ro
`
`r =0.73, p<0.01
`
`-60 - q
`1,000 (cid:9)
`0 (cid:9)
`PGE2 release, pg • cm-2. h-1
`
`2,000
`
`150 -
`
`r=-0,32, NS
`
`E 100
`
`•
`
`•
`
`•E
`
`E (cid:9)
`2
`
`50-
`
`r• cz„
`
`0
`
`0
`
`-20-
`
`-40 -
`
`O
`
`(cid:9)1
`
`q
`
`a
`r=0.50, p<0.01
`0 (cid:9)
`2 (cid:9)
`1 (cid:9)
`3
`Sigmoidoscopic score
`
`g -100
`
`3
`0 (cid:9)
`2 (cid:9)
`1 (cid:9)
`Sigmoidoscopic score
`
`a_ (cid:9)
`
`-60 -
`
`Fig. 1. Relationships between rectal mucosal PGE2 release and net water, sodium and potassium transport,
`and PD in patients with untreated UC (group B). + transport is net absorption and - transport net secretion. PD
`is negative with respect to the luminal surface of the mucosa. NS denotes not significant. • denotes patient with
`sigmoidoscopic score 0, ri patients with score 1, • patients with score 2, and o patients with score 3, where
`sigmoidoscopic score indicates increasing mucosal abnormality (see Methods).
`Fig. 2. Relationships between disease activity assessed sigmoidoscopically and rectal mucosal PGE2 release,
`net sodium and potassium transport, and PD in patients with untreated UC (group B). Symbols as in figure 1.
`
`ThiS (cid:9)
`
`az
`
`Ex. 1065 - Page 9
`
`q
`(cid:9)
`

`

`18 (cid:9)
`
`Rampton/Sladen
`
`Table III. Rectal mucosal PGE2 release, net water and electrolyte transport, PD and sigmoidoscopic score in
`conventionally treated patients with UC (group C; table I) subdivided according to whether they were on corti—
`costeroids, sulphasalazine or both
`
`Variable
`
`Corticosteroids Sulphasalazinc Corticosteroids
`and sulphasalazine
`(n = 8)
`
`(n = 17) (cid:9)
`
`(n = 8) (cid:9)
`
`PGE2 release, pg • cm-2 • h- I
`Water transporta, n1 • cm-2 • min-1
`Sodium transporta, nmol • cm-2 • min- I
`Potassium transporta, nmol • cm-2 • min- I
`PDb, mV
`Sigmoidoscopic score
`
`686± 185**
`+169 ± 36*
`+58±19
`+1 ±8**
`—26 ± 6**
`1.9 ± 0.3**
`
`277 ± 96*
`+210+20
`+78±6
`—20±5*
`—45±2**
`1.2+0.2**
`
`1,087+292**
`+ 193 ± 22
`+70± 18*
`—20 ±13
`_ 24±6**
`2.2±0.1**
`
`Results are shown as mean ± SEM. Symbols and footnotes as explained in legend to table I.
`
`Table IV. Paired studies (A and B) of rectal mucosal PGE2 release, net water and electrolyte transport,
`and sigmoidoscopic score in 9 patients with UC taking unaltered conventional or no treatment (group E)
`
`Variable
`
`PGE2 release, pg • cm-2 • h-1
`Water transporta, nl • cm-2 • min- I
`Sodium transporta, nmol • cm-2 • min-1
`Potassium transporta, nmol • cm-2 • min- t
`PDb, mV
`Sigmoidoscopic score
`
`Study A
`
`Study B
`
`1,114±228
`+ 180±21
`+51±9
`+8±5
`—22±4
`2.3 ± 0.2
`
`551±81
`+214±29
`+82± 14
`—6 ± 8
`—29 ±4
`2.1 ±0.2
`
`<0.01
`NS
`<0.05
`<0.05
`= 0.05
`NS
`
`Results are shown as mean ± SEM. Symbols and footnotes as explained in legend to table I.
`
`Table V. Effect of treatment with oral flurbiprofen on rectal mucosal PGE2 release, net water and electrolytt2.
`transport, PD and sigmoidoscopic score in 10 patients with UC (group D)
`
`Variable (cid:9)
`
`PGE2 release, pg • cm-2 • 1r
`Water transporta, nl • cm-2 • min-
`Sodium transporta, nmol • cm-2 • min-1
`Potassium transport, nmol • cm-2 • min-1
`PDb, mV
`Sigmoidoscopic score
`
`Before (cid:9)
`
`996 ± 225 (cid:9)
`+170±15 (cid:9)
`+81±9 (cid:9)
`—14 ±8 (cid:9)
`—31±4 (cid:9)
`1.8+0.2 (cid:9)
`
`During (cid:9)
`flurbiprofen
`
`671 ± 170 (cid:9)
`+168 ± 21 (cid:9)
`+55±11 (cid:9)
`+2±7 (cid:9)
`—22±4 (cid:9)
`2.2±0.3 (cid:9)
`
`p
`
`= 0.05
`NS
`= 0.01
`<0.05
`<0.01
`NS
`
`Results are shown as mean ± SEM. Symbols and footnotes as explained in legend to table I.
`
`;•
`
`2t E -= I a (cid:9)
`
`iAEct
`
`Ex. 1065 - Page 10
`
`

`

`Prostaglandins and Electrolyte Transport in Ulcerative Colitis (cid:9)
`
`19
`
`that between PGE, release and PD (r = 0.71;
`p < 0.05) in the 10 patients with a sigmoi-
`doscopic score of 2.
`
`Group C— Patients with Conventionally
`Treated UC (n = 33)
`The results obtained in colitics on treat-
`ment with sulphasalazine and/or corticoste-
`roids were similar to those recorded in un-
`treated patients (group B) and again con-
`trasted with control values (group A) (ta-
`ble I). Similar relationships between rectal
`mucosal PGE2 release and water and electro-
`lyte transport, and between sigmoidoscopic
`score and these variables, were found as in
`untreated patients with UC (table II).
`Table III shows the values for rectal mu-
`cosal PGE2 release, transport function and
`sigmoidoscopic score in the subgroups of
`group C on corticosteroids, sulphasalazine
`and both forms of conventional treatment. In
`respect of most variables each of these small
`subgroups was significantly different from
`the control subjects (group A) and similar to
`the untreated colitics (group B).
`Because the majority of patients on sul-
`phasalazine alone were in remission at the
`time of their study, this subgroup tended to
`have less abnormal rectal mucosa than the
`two other group C subgroups; the difference
`reached statistical significance in relation to
`PD (p < 0.05) in comparison with patients
`on steroids alone, and to PGE, release (p <
`0.01), PD (p < 0.01) and sigmoidoscopic
`score (p < 0.05) in comparison with the sub-
`group taking both forms of conventional
`therapy (table III). The patients on sulphasal-
`azine alone also had significantly lower mean
`PGE2 release (p < 0.05), higher water ab-
`sorption (p < 0.05), and higher PD (p <
`0.01) than the untreated colitics (group B)
`(table I, III).
`
`Group D — Patients with UC Studied
`Twice While on Unaltered Conventional,
`or No Treatment (n = 9)
`Paired observations in 9 patients with UC
`showed a mean rectal mucosal PGE2 release
`of 1,114 ± 228 pg • cm-2 • h-' on one occa-
`sion, and of 551 ± 81 pg • cm-2 • h-1 on the
`other (table IV). This fall in PGE, release was
`associated with significant improvements in
`mucosal sodium absorption, potassium
`transport and PD; the small changes in sig-
`moidoscopic appearance and water abosorp-
`tion did not reach statistical significance (ta-
`ble IV).
`
`Group E — Patients with UC Studied
`before and during Treatment with
`Flurbiprofen (n = 10)
`After I week's treatment with flurbipro-
`fen, mean rectal mucosal PGE2 release fell by
`33% (p = 0.05) (table V). Despite producing a
`fall in PGE2 release similar to that which had
`been observed in the group D patients (ta-
`ble IV), however, flurbiprofen caused signifi-
`cant deteriorations in mucosal sodium ab-
`sorption, potassium transport and PD; sig-
`moidoscopic score and water transport did
`not significantly alter (table V).
`
`Discussion
`
`In the small intestine, stable PGs evoke
`secretion of water and electrolytes both in
`vivo and in vitro [9, 14, 18, 19, 22, 23], but
`their effects in the large bowel arc less well
`established. Thus, although in the rabbit and
`rat the large intestine also responds adversely
`to high concentrations of stable PGs [15-17,
`20, 21], in vivo experiments in man failed to
`show a significant effect of PGF,,, or PGE, on
`colonic fluid transport [26]. The main aim of
`
`This- lte. 171
`
`-= (cid:9)
`
`nied
`
`Ex. 1065 - Page 11
`
`

`

`20
`
`Ram plon/Sladen
`_
`
`the present study was to test the hypothesis
`that increased mucosal PG synthesis might
`be responsible for the abnormalities of large
`intestinal fluid transport observed in UC and
`confirmed here [1-9, 17-19, 21-23].
`The significant, albeit in some cases weak
`correlations between mucosal PGE2 release
`and electrolyte transport and PD in untreated
`patients (group B) and in patients given con-
`ventional therapy (group C) confirm and ex-
`tend earlier and more limited studies [6, 7]
`and were compatible with this theory; so
`were our present and previous findings of an
`association between reduction in PGE2 re-
`lease and improvement in transport function
`in colitics studied serially while on unaltered
`treatment (group D) and when started on sul-
`phasalazine and corticosteroids [27].
`In all these studies, PGE2 release and elec-
`trolyte transport could have been related
`either directly, as postulated above, or
`through some other consequence of tissue
`damage, assessed here sigmoidoscopically.
`To evaluate these possibilities, we re-calcu-
`lated the correlations between PGE2 release
`and transport function in untreated (group B)
`patients subdivided according to sigmoidos-
`copic score. Within each subgroup, disease
`activity was similar, and the correlations be-
`tween PGE2 release and water and electrolyte
`transport should have been maintained if
`these variables were indeed directly related.
`However, none of the correlations now
`reached statistical significance, suggesting
`that the relationships between PGE2 release
`and electrolyte transport in group B as a
`whole were indirect rather than causal. It is
`difficult to interpret the significant correla-
`tion between mucosal PGE2 release and PD
`in the 10 patients with a sigmoidoscopic
`score of 2, because PD reflects not only so-
`dium pump activity, but also epithelial per-
`
`meability, which is itself probably related to
`mucosal damage [4, 5].
`As a more searching test of the role of PGs