_
`
`March 1981
`.rMagch-“1981 v
`Vol. 21 No. 3
`(“V011, 21 Nog3gl’
`
`_
`
`Ex. 1064 - Page 1
`
`Ex. 1064 - Page 1
`
`

`

`C--
`
`PROSTAGLANDINS
`
`OCT f 1 JORS
`
`Peter W. Ramwell, Edi
`or
`Georgetown University Medica
`Ce et°471
`Washington, D.C. 20007
`
`Prostaglandin Metabolism
`Erik Anggard
`Department of Pharmacology
`Karolinska Institutet
`S-104 01 Stockholm 60, Sweden
`
`Endocrinology
`Harold R. Behrman
`Department of Ob/Gyn
`Yale University School of Medicine
`New Haver, Connecticut 06510
`
`Smooth Muscle Pharmacology
`Alan Bennett
`Department of Surgery
`King's College Hospital
`Medical School
`London SE5 8RX, England
`
`Obstetrics and Gynecology
`Marc Bygdeman
`Department of Ob/Gyn
`Karolinska Institutet
`S-104 01 Stockholm 60, Sweden
`
`Nervous System
`Flavio Coceani
`Laboratory of Neurophysiology
`The Hospital for Sick Children
`555 University Avenue
`Toronto, 101, Canada
`
`Oncology and Immunology
`Bernard Jaffe
`State of New York
`Downstate Medical Center
`Department of Surgery
`450 Clarkson Avenue
`Brooklyn, New York 11203
`
`Cardiovascular
`Gabor Kaley
`Department of Physiology
`New York Medical College
`Valhalla, New York 10595
`
`Biochemical Pharmacology
`Phillip Needleman
`Department of Pharmacology
`Washington University School of Medicine
`St. Louis, Missouri 63110
`
`Renal
`
`Division of Clinical Pharmacology
`University of Colorado Medical Center
`4200 East Ninth Avenue
`Denver, Colorado 80262
`
`Chemistry
`John E. Pike
`The Upjohn Company
`Kalamazoo, Michigan 49001
`
`General Pharmacology
`Brendan Whittle (cid:9)
`-
`The Wellcome Research Laboratories
`Langley Court, Beckenham, Kent
`BR3 3BS, England
`
`Medicine and Clinical Therapeutics
`'Donald E. Wilson
`SUNY - Downstate Medical Center
`Department of Medicine
`450 Clarkson Avenue
`Brooklyn, New York 11203
`
`Consulting Editors:
`
`Frederick A. Kuehl, Jr. .
`Merck Institute for
`Therapeutic Research
`Rahway, New Jersey 07065
`
`Salvador Mpncada
`The Wellcome Research Laboratories
`Langley Court, Beckenham, Kent
`BR3 3BS, England
`
`Leon Wolfe
`Montreal Neurological Institute
`McGill University
`3801 University Street
`Montreal H3A 2B4, Canada
`
`Regional Editors:
`
`Richard Gryglewski
`N. Copernicus Medical Academy
`Department of Pharmacology
`31-531 Cracow, Grzegorzecka 16
`Poland
`
`Rodolpho Paoletti
`Institute of Pharmacology 6 Pharmacognosy
`University of Milan
`Via A del Sarto, 21
`Milan 20129, Italy
`
`Shozo Yamamoto
`Department of Biochemistry
`Tokushima University School of Medicine
`Kuramoto-chn, Tokushima, Japan
`
`For inquiries concerning reprints
`or subscriptions, please contact:
`Geron-X Publishers, Inc.
`Box 1108
`Los Altos, California 94022
`Tel: (415) 493-0871
`
`Acknowledgement for Cover Design: Prostaglandin conformation redrawn from Fig. 1,
`I. Rabinowitz, P.W. Ramwell and P. Davison, Conformation of Prostaglandins,
`Nature New Biology 233: 88, 1971.
`
`Ex. 1064 - Page 2
`
`

`

`PROSTAGLANDINS
`
`Peter W. Ramwell, Edi
`Georgetown University Medica
`Washington, D.C. 20007
`
`Prostaglandin Metabolism
`Erik Anggard
`Department of Pharmacology
`Karolinska Institutet
`S-104 01 Stockholm 60, Sweden
`
`Endocrinolqgy
`Harold R. Barman
`Department of Ob/Gyn
`Yale University School of Medicine
`New Haven, Connecticut 06510
`
`Smooth Muscle Pharmacology
`Alan Bennett
`Department of Surgery
`King's College Hospital
`Medical School
`London SE5 8RX, England
`
`Obstetrics and Gynecology
`Marc Bygdeman
`Department of Ob/Gyn
`Karolinska Institutet
`S-104 01 Stockholm 60, Sweden
`
`Nervous System
`Tlavio Coceani
`Laboratory of Neurophysiology
`The Hospital for Sick Children
`555 University Avenue
`Toronto, 101, Canada
`
`Oncology and Immunology
`Bernar. Jaffe
`State of New York
`Downstate Medical Center
`Department of Surgery
`450 Clarkson Avenue
`Brooklyn, New York 11203
`
`Cardiovascular
`Gabor Kaley
`Department of Physiology
`New York Medical College
`Valhalla, New fork 10595
`
`Biochemical Pharmacology
`Phillip Needleman
`Department of Pharmacology
`Washington University School of Medicine
`St. Louis, Missouri 63110
`
`Renal
`ATWF—Nies
`Division of Clinical Pharmacology
`University of Colorado Medical Center
`4200 East Ninth Avenue
`Denver, Colorado 80262
`Chemistry
`of hn E. Pike
`The Upjohn Company
`Kalamazoo, Michigan 49001
`
`General Pharmacology
`Brendan Whittle
`The Wellcome Research Laboratories
`Langley Court, Beckenham, Kent
`BR3 3BS, England
`
`Medicine and Clinical Therapeutics
`Ronald E. Wilson
`SUNY - Downstate Medical Center
`Department of Medicine
`450 Clarkson Avenue
`Brooklyn, New York 11203
`
`Consulting Editors:
`
`Frederick A. Kuehl, Jr.
`Merck Institute for
`Therapeutic Research
`Rahway, New Jersey 07065
`
`Salvador Mpncada
`The Wellcome Research Laboratories
`Langley Court, Beckenham, Kent
`BR3 3BS, England
`
`Leon Wolfe
`Montreal Neurological Institute
`McGill University
`3801 University Street
`Montreal H3A 284, Canada
`
`Regional Editors:
`
`Richard Gryglewski
`N. Copernicus Medical Academy
`Department of Pharmacology
`31-531 Cracow, Grzegorzecka 16
`Poland
`
`Rodolpho Paoletti
`Institute of Pharmacology & Pharmacognosy
`University of Milan
`Via A del Sarto, 21
`Milan 20129, Italy
`
`Shozo Yamamoto
`Department of Biochemistry
`Tokushima University School of Medicine
`Kuramoto-chn, Tokushima, Japan
`
`For inquiries concerning reprints
`or subscriptions, please contact:
`Geron-X Publishers, Inc.
`Box 1108
`Los Altos, California 94022
`Tel: (415) 493-0871
`
`Acknowledgement for Cover Design: Prostaglandin conformation redrawn from Fig. 1,
`I. Rabinowitz, P.W. Ramwell and P. Davison, Conformation of Prostaglandins,
`Nature New Biology 233: 88, 1971.
`
`Ex. 1064 - Page 3
`
`

`

`March 1981
`
`PROSTAGLANDINS
`
`Volume 21, Number 3
`The Effect of Prostaglandins A2 , E1 , E2 , 15 Methyl E2 , 16, 16 Dimethyl E2
`and Fza on Erythropoiesis
`J.A. Arce, B.A. Naughton, G.A. Kolks, P. Liu,
`A.S. Gordon and S.J. Piliero (cid:9)
`
`
`
`.... (cid:9)
`367
`
`0' (cid:9)
`
`Prostacyclin Does Not Affect Insulin Secretion in Humans
`C. Patrono, F. Pugliese, G. Ciabattoni, S.DiBlasi, A. Pierucci,
`G.A. Cinotti, A. Maseri and S. Chierchia (cid:9)
`
` .. 379
`
`Mechanism of Protection Against Arachidonate Induced Sudden Death by
`Glucocorticoid
`H. Araki, R.C. Peck, A.M. Lefer and J.B. Smith
`
`The Effect of Imidazole and Imidazole-Analogues on Bone Resorption
`In Vitro: A Suggested Role for Thromboxane A2
`J.N.M. Heersche and D.H. Jez
`
`The Inactivation of Prostaglandin E2 is Decreased by Dipyridamole and
`Sulfinpyrazone in Isolated Rat Lungs
`P. Uotila and J. Mannist6
`
`Prostaglandin Synthesis Inhibitors in Ulcerative Colitis: Flurbiprofen
`Compared With Conventional Treatment
`
`
`D.S. Rampton and G.D. Sladen
`
`Distribution of Prostaglandin E2-Sensitive Adenylate Cyclase Along the
`Rat Nephron
`
`S.Torikai and K. Kurokawa
`
`387
`
` 401
`
` 413
`
` 417
`
` 427
`
`Prostaglandin Formation in Bacteria: A Reevaluation
`E. Gulbis, N. Galand, J.E. Dumont and E. Schell-Frederick . . . . 439
`
`Carbocyclic Thromboxane A2: Aggrevation of Myocardial Ischemia by a
`New Synthetic Thromboxane A2 Analog
`E.F. Smith III, A.M. Lefer, D.Aharony, J.B. Smith,
`R.L. Magolda, D. Claremon and K. C. Nicolaou (cid:9)
`
`Bronchodilator Activity of a PGE2 Analog in Animals and in Man
`J.E. Birnbaum, N.C. Birkhead and A.L. Oronsky (cid:9)
`F. Dessy, J.P. Rihoux and L. VanHumbeeck
`
` 443
`
` . 457
`
`Thromboxane A2 is the Major Arachidonic Acid Metabolite of Human
`Cortical Hydronephrotic Tissue
`A.R. Morrison, F. Thornton, A. Blumberg and E.D. Vaughan
`
`... . 471
`
`The Ability of Vascular Tissue to Produce Prostacyclin Decreases with Age
`
`R.S. Kent, B.B. Kitchell, D.G. Shand and A.R. Whorton
`
`483
`
`Respiratory Movements Alter the Generation of Prostacyclin and Thromboxane A2
`in Isolated Rat Lungs: The Influence of Arachidonic Acid-Pathway Inhibitors
`491
`on the Ratio Between Pulmonary Prostacyclin and Thromboxane A2
`..... . ...........
`R. Korbut, J. Boyd and T. Eling
`
`1 & E2
`505
`Effect of Gestational Age on Pulmonary Metabolism of Prostaglandin E
`........
`R.I. Clyman, F. Mauray, M.A. Heymann and C. Roman
`
`Ex. 1064 - Page 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`©1981, Geron-X, Inc.
`
`PROSTAGLANDINS is published monthly by Geron-X, Inc.,
`Box 1108, Los Altos, California 94022, USA
`14151493-0871
`
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`Ex. 1064 - Page 5
`
`

`

`PROSTAGLANDINS
`
`PROSTAGLANDIN SYNTHESIS INHIBITORS IN ULCERATIVE COLITIS:
`
`FLURBIPROFEN COMPARED WITH CONVENTIONAL TREATMENT.
`D.S. Rampton1
` and G.E. Sladen
`
`Gastroenterology Unit, Guy's Hospital Medical School, London SE1 9RT,
`
`Abstract
`
`U.K.
`
`It has been suggested that prostaglandins (PGs) play a
`pathogenetic role in ulcerative colitis (UC) and that treatment
`with inhibitors of PG synthesis might be of therapeutic benefit.
`We therefore performed a one-week open trial to compare the effects
`of oral flurbiprofen with those of conventional therapy with cortico-
`steroids and sulphasalazine, in two groups of patients with active
`Mean rectal mucosal release of PGE2, measured by in Vivo
`UC. (cid:9)
`rectal dialysis, fell by 44% (P< 0.05) after one week's convention-
`al treatment, and the effect of flurbiprofen was not significantly
`However, the patients given flurbiprofen fared sig-
`different. (cid:9)
`nificantly worse than those given conventional therapy in respect
`of rectal mucosal appearance at sigmoidoscopy (P=0.01), rectal
`electrical potential difference (P< 0.01), rectal mucosal sodium
`Furthermore,
`absorption (P=0.01) and rectal bleeding (P< 0.05). (cid:9)
`flurbiprofen-treated patients showed significant deteriorations in
`rectal potential difference (P< 0.05) and sodium absorption
`These results do not support the hypothesis that in-
`(P< 0.05). (cid:9)
`creased mucosal PG production is of major pathogenetic importance
`in active UC, and suggest that flurbiprofen is unlikely to prove
`a useful alternative to conventional therapy.
`
`Introduction
`
`Rectal mucosal production of prostaglandins (PGs) isAmcreased
`in patients with active ulcerative colitis (UC), and is restored
`towards normal by successful treatment with corticosteroids and
`These observations, together with the
`sulphasalazine (SASP)(1-3). (cid:9)
`apparent involvement of PGs in the inflammatory process (4) and in
`various other diarrhoeal states (5), have led to the suggestion
`that increased mucosal production of PGs may play a pathogenetic
`role in active UC, and that the therapeutic effect of steroids and
`SASP mdght be related to their ability to inhibit PG synthesis in
`This in turn has raised the possibility that
`Vitro (1,2,6-9). (cid:9)
`other potent inhibitors of PG synthesis might be of therapeutic
`
`1
`Present address and address for correspondence: Medical Unit,
`Faculty of Clinical Sciences, University College London, Rayne
`Institute, University Street, London WC1E 6JJ, U.K.
`
`MARCH 1981 VOL. 21 NO. 3
`
`417
`
`Ex. 1064 - Page 6
`
`

`

`rt
`
`PROSTAGLANDINS
`
`benefit in UC, an effect which would be of particular value in
`patients intolerant of, or unresponsive to conventional therapy.
`
`However, limited trials with sodium salicylate (10) and indo-
`methacin (11,12) enemas have been disappointing. (cid:9)
`Indeed, the
`deterioration noted in some patients (12) is consistent with the
`hypothesis, as yet supported by little direct evidence, that PGs
`may
`have a cytoprotective action in the large bowel, as they appear to
`have in the stomach and small intestine (13), and that a relative
`deficiency of PGs may have a deleterious effect upon patients with
`UC (14). (cid:9)
`Unfortunately, in none of the studies reported to date
`was an attempt made to assess mucosal PG production.
`
`We have therefore performed a short-term study comparing the
`effects of the potent PG synthesis inhibitor, flurbiprofen (15),
`given orally, with those of conventional treatment with steroids and
`SASP in two groups of patients with active UC. Disease activity was
`assessed clinically and sigmoidoscopically; objective assessments of
`rectal mucosal functional integrity were also provided by measurement
`of rectal electrical potential difference (PD)(16,17), and, using
`in vivo rectal dialysis, of mucosal sodium transport (16,17). An
`index of intramucosal PG synthesis was obtained by measurement of
`mucosal release, into the rectal dialysate, of immunoreactive PGE2
`(3), the most abundant stable PG in human large bowel (18).
`
`Methods
`
`Patients and treatment: Fourteen patients in whom UC had been diag-
`nosed by standard clinical, radiological and histological criteria
`were studied immediately before and after one week of treatment with
`either flurbiprofen, 50 mg orally four times daily (7 patients) or
`conventional therapy (prednisolone enemata 20-40 mg daily, 3 patients;
`prednisolone enemata 20 mg and oral SASP 3 g daily, 3 patients; and
`oral SASP 4 g daily, 1 patient). Of the flurbiprofen-treated group,
`3 were in relapse despite treatment with hydrocortisone enemata
`100 mg daily, with oral SASP 2 g daily and with prednisolone enemata
`40 mg and oral SASP 3 g daily, respectively; in each case, this
`treatment was continued unchanged throughout the week's trial with
`The other eleven patients were in untreated relapse
`flurbiprofen. (cid:9)
`The composition of each group of patients
`at the start of the study. (cid:9)
`was similar in respect of age, sex and weight, and of extent of
`disease at the start of the study.
`
`All patients gave informed consent to the trial, approval for
`which was obtained from the Guy's Hospital Ethical Cowmittee.
`
`Protocol: Throughout the trial period, bowel habit and rectal
`Before and after treatment, disease
`bleeding were recorded daily. (cid:9)
`activity in the distal colon and rectum was scored according to
`observer-independent sigmoidoscopic criteria (19), grade 0 indicating
`
`L
`
`418
`
`)
`MARCH 1981 VOL. 21 NO.3 ,
`
`Ex. 1064 - Page 7
`
`(cid:9)
`

`

`PROSTAGLANDINS
`
`a normal appearance, 1 loss of the normal vascular pattern, 2
`contact bleeding and 3 spontaneous bleeding. (cid:9)
`Then, after measure-
`ment of rectal potential difference (3,16),
`dialysis (3,16)
`was performed using a solution containing Na 120, K4 30,
`Na+
`Cl 120/ HC05 30 mmo1/1, pH 8.1. (cid:9)
`After one hour, the dialysis bag
`was removed, and its volume change measured by weighing.
`
`Analytical methods: The concentration of PGE2-like material in the
`dialysate was measured in duplicate by radioimmunoassay (20), using
`an antiserum with a cross-reactivity of < 3.7% with other tested PG
`derivatives. (cid:9)
`The detection limit was 2 pg/tube, the intra-assay
`coefficient of variation of nine replicate estimations was 2.9%,
`and the recovery of PGE2 added to dialysate was 93.4 + 5.4% (mean +
`SD, n=6). (cid:9)
`Assay of serial dilutions of dialysate gave a curve
`parallel to that of the standards.
`
`+
`Dialysate Na
`concentrations were measured by flame photometry.
`Net flux rates of Na and PGE
`were calculated using a standard
`2
`formula (16).
`
`Statistical methods: Results were compared using Wilcoxon's signed
`ranks and sum of ranks tests (two-tailed) for paired and unpaired
`data, respectively.
`
`Results
`
`Stool frequency and the presence of rectal bleeding indicated
`that before starting treatment each patient had moderately active
`Relapse was confirmed by sigmoidoscopic examin-
`disease (Table 1). (cid:9)
`ation and by comparison of rectal mucosal PD, net sodium absorption
`and PGE
`release with control figures obtained previously (3,21).
`2
`These variables were similar in the two groups of patients before
`treatment was started (Tables 1 & 2).
`
`Treatment with steroids and SASP was associated with a 44% fall
`release (P< 0.05), and this was accompanied by
`in mean mucosal PGE
`2
`a tendency to improvement in sigmoidoscopic appearance, in rectal
`mucosal PD (P< 0.05) and sodium absorption (P< 0.05), in stool
`frequency and in rectal bleeding (Table).
`
`Although the effect of flurbiprofen on mean mucosal PGE2 release
`was not significantly different from that of conventional treatment
`(Table 2), there was no evidence of a reduction in disease activity
`in the subjects taking the PG synthesis inhibit:5r (Table 1). Within
`this group, the four patients in whom PGE2 release fell substantially
`(Table 2) fared no better clinically or functionally than the two
`In the group as a whole, not only was there a
`in whom it rose. (cid:9)
`failure to improve after flurbiprofen, but significant deteriorations
`in rectal mucosal PD (P< 0.05) and sodium absorption (P< 0.05)
`hi addition, significant differences between
`occurred (Table 1). (cid:9)
`
`MARCH 1981 VOL. 21 NO. 3
`
`419
`
`Ex. 1064 - Page 8
`
`

`

`SNIUNIVI9VISONd
`
`O
`
`TABLE 1 Stool frequency, rectal bleeding, sigmoidoscopic score, rectal mucosal potential
`
`difference and net sodium absorption before and after 1 week of treatment with
`
`conventional therapy (steroids and sulphasalazine) or flurbiprofen in active
`
`ulcerative colitis.
`
`Stool frequency
`(per day)
`
`Rectal bleeding
`(No. of patients)
`
`Conventional treatment (n=7)
`
`Flurbiprofen (n=7)
`
`Before (cid:9)
`
`4(1-7)
`
`After
`
`2(1-4)
`
`Before (cid:9)
`
`After (cid:9)
`
`5(0.5-10)
`
`4(0.5-15) (cid:9)
`
`Pb
`
`NS
`
`7
`
`2
`
`3
`
`6 (cid:9)
`
`< 0.05
`
`Sigmoidoscopic score
`
`3(2-3)
`
`1(1-3)
`
`2(2-3)
`
`3(Z-3) (cid:9)
`
`= 0.01
`
`Potential differences
`(mV)
`
`d
`Sodium absorption
`(nmol/cm2/min)
`
`-32(-7--45)
`
`-45(-10--50)a
`
`-34(-11--45)
`
`-18(-1--40)a (cid:9)
`
`< 0.01
`
`+59(+9-+119) +62(+29-+150)a
`
`+72(+25-+115)
`
`+49(-24-+62)a (cid:9)
`
`= 0.01
`
`Results are shown as median (range)
`
`a
`b
`
`d
`
`P < 0.05 f:•om pretreatment values (Wilcoxon signed ranks test, two-tailed).
`P value for difference between the changes produced by each form of treatment (Wilcoxon sum of
`ranks test, two-tailed). NS denotes not significant.
`Potential difference is negative with respect to the luminal surface of the mucosa.
`+ denotes net absorption, - denotes net secretion.
`
`Ex. 1064 - Page 9
`
`

`

`magimumffau
`
`PROSTAGLANDINS
`
`TABLE '2
`
`Redtal mucosal PGE
`2 release before and after 1 week
`
`of treatment with conventional therapy (steroids and
`
`sulphasalazine) or flurbiprofen in active ulcerative
`
`colitis.
`
`Conventional treatment
`
`Flurbiprofen
`
`Before (cid:9)
`
`After
`
`Before (cid:9)
`
`After
`
`1885
`1496
`1484
`1384
`870
`258
`129
`
`162
`675
`1290
`1202
`802
`16
`47
`
`
`
`ian (cid:9) 1384 Me
`
`675a
`
`2120
`1975
`1502
`1215
`978
`943
`530
`
`1215
`
`1218
`908
`1580
`480
`839
`1108
`131
`
`908
`
`SEM 1072+254
`Mean
`
`599+203
`
`1323+218
`
`895+181
`
`Results for individual patients are shown.
`a
`P< 0.05 from pretreatment value (Wilcoxon signed ranks test,
`two-tailed).
`
`the responses to flurbiprofen and conventional therapy were found in
`respect of sigmoidoscopic score (P=0.01), rectal PD (P< 0.01),
`rectal sodium absorption (P=0.01), and rectal bleeding (P< 0.05)
`(Table 1).
`
`After seven days' treatment with flurbiprofen the four previously
`untreated patients responded well to conventional therapy, while the
`three patients taking steroid enemata and oral SASP before and during
`the trial showed a good clinical response to conventional modifi-
`cations of their treatment; all seven achieved remission in 4(2-12)
`Similarly, the patients in whom conventional treatment was
`weeks. (cid:9)
`introduced during the trial all subsequently went into remission
`in 4(2-12) weeks.
`
`Discussion
`
`This study was performed to investigate the feasibility of
`embarking upon a randomised controlled double-blind therapeutic
`
`
`
`MARCH 1981 VOL. 21 NO. 3 (cid:9)
`
`421
`
`Ex. 1064 - Page 10
`
`

`

`PROSTAGLANDINS
`
`trial of the potent PG synthesis inhibitor, flurbiprofen, in active
`UC. (cid:9)
`Because of concern that some colitics might deteriorate on
`drugs of this type (12,22), we employed a short-term open design in
`which patients' responses were evaluated with methods resistant to
`observer bias (16,17,19). In an attempt to assess the effect of
`treatment on mucosal PG synthesis, we also measured rectal mucosal
`release of PGE,, recognising that dialysate concentrations of a
`single stable PG could provide only a limited index of intra-
`mucosal arachidonic acid metabolism.
`
`Using these techniques, we found that flurbiprofen compared
`unfavourably with steroids and SASP in respect of clinical and
`mucosal functional response. (cid:9)
`The changes in mean PGE
`2 release after
`each treatment regime were, however, similar (Table 2). Although
`the 33% decrease in mean PGE2 release after flurbiprofen did not in
`fact achieve statistical significance, indirect support for the
`notion that flurbiprofen exerted an inhibitory effect on mucosal
`PG synthesis was provided by the failure of mean PGE2 release to
`rise in these patients with deteriorating rectal appearance and
`function, a finding we would have predicted from previous studies
`(3,21).
`
`The apparent therapeutic inefficacy of flurbiprofen seems
`unlikely to be explained by a detrimental effect of the drug
`independent of, and outweighing any possible benefit arising from
`inhibition of colonic mucosal PG synthesis, because two structurally
`different inhibitors of PG synthesis, salicylate (10) and indonletha-
`cin (11,12) appear to produce equally discouraging results in UC.
`Indeed, taken together, these results do not support the hypotheses
`that enhanced mucosal PG production plays a major pathogenetic role
`in active UC, and that steroids and SASP exert their beneficial
`effect primarily through inhibition of PG synthesis.
`
`Although patients given flurbiprofen showed significant reduc-
`tions in rectal mucosal PD and sodium absorption, we have studied
`too few subjects, perhaps over too short a time period, to
`establish beyond doubt that flurbiprofen causes patients with active
`Nevertheless, suspecting that
`colitis to deteriorate clinically. (cid:9)
`our results point in that direction, we are reluctant to treat
`-
`further patients with active disease with this drug alone. Confirm
`ation that patients with UC do in fact deteriorate in response to such
`treatment would lend support to the proposal that PGs are cyto-
`It would also raise the possibility
`protective in the colon (13). (cid:9)
`unlike corticosteroids, which appear to reduce PG synthesis
`that, (cid:9)
`by limiting availability of substrate (e.g. arachidonic acid)(9),
`these cyclo-oxygenase inhibitors might exert a deleterious effect by
`diversion of arachidonic acid metabolism along the lipoxygenase path-
`way to hydroperoxide and hydroxyacid derivatives with unknown and
`perhaps damaging properties (23).
`
`422
`
`MARCH 1981 VOL. 21 NO.3
`
`Ex. 1064 - Page 11
`
`

`

`PROSTAGLANDINS
`
`It has been suggested that increased mucosal PG production
`might contribute to the diarrhoea of UC by inhibiting colonic mucosal
`water and electrolyte transport (24, 25). (cid:9)
`Our earlier demon-
`strations of negative correlations between, on the one hand,
`mucosal PGE
`2 release and, on the other, rectal PD (3) and
`absorption of sodium and water (21), were compatible with this
`hypothesis. (cid:9)
`However, in the present study we found contrasting
`changes in mucosal function in association with similar alterations
`in mean PGE
`2 release in the conventionally and flurbiprofen-treated
`groups of patients. (cid:9)
`These observations suggest that increased
`mucosal PGE
`2 production is unlikely to be an important direct deter-
`minant of mucosal water and electrolyte transport in UC; and the
`correlations between these variables (3,21) were probably due to
`their dependence upon a third factor, such as tissue damage,
`rather than to a causal relationship between them.
`
`In conclusion, the results of this study suggest that flurbi-
`profen is unlikely to prove a useful alternative to conventional
`treatment, and, taken in conjunction with reports of the effects
`of other inhibitors of PG synthesis (10-12), make uncertain the
`rationale for formal trials of the therapeutic efficacy of this
`group of drugs in patients with active ulcerative colitis.
`
`Acknowledgements
`
`We thank the Wellcome Trust for financial support and
`Sister P. Johns and the Staff of the Metabolic Ward for their' help.
`
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`
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`
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`Ex. 1064 - Page 12
`
`

`

`PROSTAGLANDINS
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`MARCH 1981 VOL. 21 N0.3
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`Ex. 1064 - Page 13
`
`(cid:9)
`

`

`PROSTAGLANDINS
`
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`
`Editor: Donald E. Wilson
`Received: 7-28-80
`Accepted: 1-7-81
`
`MARCH 1981 VOL. 21 NO. 3
`
`425
`
`17TNaMgttf.n7
`
`Ex. 1064 - Page 14
`
`(cid:9)
`

`

`(x
`
`‘ SIX/#443, +' 1‘
`
`1."
`
`Ex. 1064 - Page 15
`
`