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Benoxaprofen in the treatment of active ulcerative colitis
Prostaglandins
Leukotrienes
and Medicine
10: 405-409, 1983
BENOEAPROFEN IN THE TRRATMENT OF ACTIVE ULCERATIVECOLITIS C.J. Hawkey, D.S. Rampton.* Department of Medicine, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UR, UR, and * Department of Medicine, University College London School of Medicine, London WClE 655, UK. (Reprint requests to CJE). ABSTRACT We have conducted an open pilot trial to assess the therapeutic effect of the lipoxygenase inhibitor, benoxaprofen, in IO patients with After 18 days treatment with benoxaactive ulcerative proctocolitis. profen (600 mg daily) there was no significant change in bowel habit, appearance, rectal bleeding, constitutional upset , sigmoidoscopic mucosal histology, haemoglobin, ESR, serum albumin or serumorosomucoid. Benoxaprofen itself seems unlikely to prove useful in ulcerative colitis, but evaluation of the therapeutic potential of other lipolcygenase inhibitors in inflammatory bowel disease may be worthwhila. INTRGDUCTI ON Benoxaprofen was promoted as a non-steroidal anti-inflasxsatory drug with a novel ability to inhibit lipoxygenase pathways and to reduce the egress of leucocytes into sites of inflammation (l-3). Be cause of these properties we have assessed its value in the treatment of active ulcerative colitis. PATIENTSAND METHODS Ten patients (median age 35 yrs) (range 18-62); 7 male, 3 female) in whom active ulcerative proctocolitis had been diagnosed by conventional clinical, histological and radiological criteria, were assessed before and after 18 days of treatment with benoxaprofen 300 mg twice One patient had proctitis, 7 left-sided colitis, 1 subtotal daily. disease and 1 pan-colitis. The median length of history was 3 years (range 6 weeks - 11 years) and the median length of relapse was 4.5 Five patients were receiving maintenance weeks (2 days - 1 year). sulphasalazine (which was continued throughout the trial) and none was receiving cortico-steroids or any other drug.
405
and throughout the trial period, patients For 3 days before, used diary cards to record their frequency of bowel action, and, on four point scales, stool consistency, urgency, bleeding and degree they also recorded drug intake and sideof constitutional upset; rectal mucosal disease activity effects. Before and after treatment, was assessed by an observer-independent sigmoidoscopic score (4), and Blood count, ESR, a rectal biopsy taken 7-10 cm from the anal verge. orosomucoid and liver function plasma urea and electrolytes, proteins, tests were measured before and after benoxaprofen. Rectal biopsy specimens were fixed in formalin and sections were they were then coded and assessed stained using haematoxylin and eosin; Histological appearances were rated without knowledge of their origin. surf ace pus , on a three point scale for each of seven variables: goblet cell depletion, vascular epithelial cell destruction, congestion, focal aggregation of polymorphonuclear leucocytes, crypt and intensity of infiltration of the lamina propria by abscesses, lymphocytes and plasma cells (5). test
Results were compared using Wilcoxon’s for paired data.
two-tailed
signed
ranks
RESULTS
all patients were clinically At the start of the study, and showed sigmoidoscopic and histological evidence relapse, inflanrmation (Table 3).
in of active
Benoxaprofen had no significant effect on bowel habit, rectal mucosal appearance at sigmoidoscopy, constitutional well-being, or any of the haematological and biochemical variables measured Histological appearances were also unaltered in the group (Table 1). 5 patients showing an overall deterioration, 2 an as a whole, There appeared to be a improvement and 3 no change after treatment. significant increase in the amount of pus seen on the mucosal surface after treatment with benoxaprofen (p < 0.05)) but there were no changes focal in the extent of round cell infiltration of the lamina propria, aggregation of polymorphonuclear leucocytes or crypt abscess formation. Three patients complained of headaches while on treatment, and in one of these a photosensitivity reaction necessitated the drug’s withdrawal after 9 days. oids,
At the end of the trial 8 patients were treated with corticosterand all but one showed prompt clinical improvement. DISCUSSION
Several lines of evidence suggest that lipoxygenase products could play a role in the pathogenesis of ulcerative colitis. Firstly, these compounds have recently been shown to be synthesised in human colonic mucosa (6,7) . Secondly, as well as making a possible contribution to the histological appearance of active disease by stimulating leucocyte emigration from the vasculature (8), lipoxygenase products may’be partly responsible for the associated diarrhoea: a recent stu& indicates that, at leastin vitro, they influence ileal and cblonic 406
T&BLB 1 Effect of treatment with benoxaprofen. (600 mg daily) for 18 days -1 habit, constitutional upset, sigmoidoocopic appearance, mucoeal ESR, albumin and orosomucoid in 10 patients with histology, haemoglobin, ulcerative colitis. Before
Criteria Stool frequency (per day) Stool
treatolent
5(1-11)
consistency*
2.5(1-4)
After
treatment
P
4(1-9)
NS
2( l-4)
NS
Urgency*
3( l-4)
2( 1-4)
NS
Rectal
3(1-4)
2( 1-4)
NS
bleeding*
Constitutional
upset*
2( l-2)
1 (I-4)
NS
Sigmoidoscopic
score*
3(2-4)
3(1-4)
NS
2( 1-3)
2( l-3)
NS
13.3(9.6-15.0)
12.9(9.1-14.9)
NS
ESR (mm in 1st h)
19(3-47)
10(3-40)
NS
Albumin (g/l)
46(40-50)
44 (37-52)
NS
Histological Haemoglobin
Orosomucoid
score+ (g/dl)
(g/l)
1.00(0.80-l
.40)
1.10(0.55-l
.40)
NS
Results are shown as median (range). NS denotes * Scored 1-4 (with increasing abnormality). + Scored 1-3 (with increasing abnormality).
not Significant.
mucosal electrolyte transport in the direction of secretion (9). Thirdly, although colonic mucosal prostaglandin production is increased in active ulcerative colitis (10-13) potent cycle-oxygenase inhibitors are at best ineffective therapeutically (14-16). While this might in theory be due to a breakdown in colonic mucosal cytoprotection by prostaglandins (I 7)) it could also be explained by diversion of arachidonic acid down lipoxygenase pathways (18,19). Lastly, sulphasalazine, a drug of proven value in ulcerative colitis, is now known to be capable of lipoxygenase inhibition (20). It therefore seemed important to evaluate the effect of benoxaprofen in active ulcerative colitis, not only in an attempt to obtain an alternative to conventional therapy, but also to shed light on the role of lipoxygenase products in the pathogenesis of the disease. The failure of benoxaprofen in this study to modify disease activity assessed either clinically or histologically could be taken to indicate that leucotrienes do not play a major role in the development of active disease, but there are other possible explanations. Dosage may have been inadequate to achieve inhibition of colonic mucosal lipoxygenase. The duration of treatment with benoxaprofen may have been too short; however, neither of two patients given the drug for a further 3 weeks improved clinically or microscopically. Any possible benefit due to lipoxygenase inhibition may have been outweighed by the consequences of benoxaprofen’s albeit weak activity as a prostaglandin synthesis in407
hibitor (vi& sups) (2). Finally, benoxaprofen is an inhibitor of the 5-lipoxygenase pathway, whereas it appears that 12- and 15-lipoxygenase pathways are more abundantly represented in human colonic mucosa (7) . These caveats suggest that the evaluation of other lipoxygenase inhibitors in the treatment of ulcerative colitis would not be unwarrantInvestigation of the effect of lipoxygenase inhibition might also ed. be worthwhile in patients with Crohn’s disease. ACKNOWLEDGEMFNTS We are grateful to Drs. P.J. Toghill and M. Atkinson to study their patients, and to Dista Products Ltd for support.
for permission financial
REFERENCES 1.
Meacock SCR, Kitchen EA. Effects of the non-steroidal anti-inflammatory drug benoxaprofen on leucocyte migration. Journal of Pharmacology 31:366, 1979.
2.
Dawson W, Boot JR, Harvey J, Walker JR. The pharmacology of benoxaprofen with particular reference to effects on lipoxygenase product formation. European Journal of Rheumatology and Inflammation 5:61, 1982.
3.
Lee VY, Hughes JM, Seale JP, Temple DM. Effect of benoxaprofen on release of slow-reacting substances from human lung tissue in Clinical Science 63:219, 1982. vitro.
4.
Baron JH, Connell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearances in proctocolitis. British Medical Journal 1:89, 1964.
5.
Morson BC, Dawson IMP. Blackwell Scientific
6.
Bennett A, Hensby CN, Sanger GJ, Stamford IF. Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers. British Journal of Pharmacology 74:435, 1981.
7.
Hawkey CJ, Boughton Smith NK, Whittle BJR. Synthesis of lipoxygenase and cycle-oxygenase products by human colonic mucosa. Gut 23:A897, 1982.
8.
Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJH. Leucotriene B4: a potent chemokinetic and aggregating substance released from polymorphonuclear leucocytes. Nature 286: 264, 1980.
9.
Musch M, Miller RJ, Field M, Siegel M. Lipoxygenase metabolites of arachidonic acid: potential mediators of electrolyte secretion. Gastroenterology 82:1257, 1982.
p.551 in Gastrointestinal Pathology. Publications, Oxford, 1979.
408
2nd ed.
IO.
Sharon P, Ligumsky M, Rachmilewitz D, Zor U. Role of prostaglandins enhanced production during active in ulcerative colitis: disease and inhibition by sulfasalazine. Gastroenterology 78~638, 1978.
Il.
of prostaglandin Harris DW, Smith PR, Swan CRJ. Determination synthetase in rectal biopsy material and its significance in Gut 19:875, 1978. colonic disease.
12.
on prostaglandin Hawkey CJ, Truelove SC. Effect of prednisolone synthesis by rectal mucosa in ulcerative colitis: investigation by laminar flow bioassay and radioimmunoassay. Gut 22:190, 1981.
13.
Rampton DS, Sladen GE, Youlten LJF. Rectal mucosal prostaglandin E2 release and its relation to disease activity, electrical potential difference and treatment in ulcerative colitis. Gut 21:591, 1980.
14.
Gilat T, Ratan J, Rosen P, Peled Y. Prostaglandins Gastroenterology 76:1083, 1979. colitis.
15.
Campieri M, Lanfranchi GA, Bazzochi G, Brignola Boccia S, Labo G. Prostaglandins, indomethacin 78:193, 1980. colitis . Gastroenterology
16.
synthesis inhibitors in Rampton DS, Sladen GE. Prostaglandin ulcerative colitis: f lurbiprofen compared with conventional Prostaglandins 21:417, 1981. treatment.
17.
Robert A. Cytoprotection 761, 1979.
18.
Engineer DM, Niederhauser U, Piper PJ, Sirois P. Release of of prostaglandin synthesis mediators of anaphylaxis : inhibition and the modification of release of slow reacting substances of anaphylaxis and histamine. British Journal of Pharmacology 62: 61, 1978.
by prostaglandins.
and ulcerative
C, Benatti A, and ulcerative
Gastroenterology
77:
19. Siegel MI, McConnell RT, Cuatrecasas P. Aspirin-like drugs interfere with arachidonate metabolism by inhibition of the l2hydroperoxy-5,8,IO-,l4-eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway. Proceedings of the National Academy of Sciences 76~3744, 1979. 20. Stenson WF, Lobos E . Sulfasalazine inhibits the synthesis of chemotactic lipids by neutrophils. Journal of Clinical Investigation 69:494, 1982.
409
Leukotrienes
and Medicine
10: 405-409, 1983
BENOEAPROFEN IN THE TRRATMENT OF ACTIVE ULCERATIVECOLITIS C.J. Hawkey, D.S. Rampton.* Department of Medicine, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UR, UR, and * Department of Medicine, University College London School of Medicine, London WClE 655, UK. (Reprint requests to CJE). ABSTRACT We have conducted an open pilot trial to assess the therapeutic effect of the lipoxygenase inhibitor, benoxaprofen, in IO patients with After 18 days treatment with benoxaactive ulcerative proctocolitis. profen (600 mg daily) there was no significant change in bowel habit, appearance, rectal bleeding, constitutional upset , sigmoidoscopic mucosal histology, haemoglobin, ESR, serum albumin or serumorosomucoid. Benoxaprofen itself seems unlikely to prove useful in ulcerative colitis, but evaluation of the therapeutic potential of other lipolcygenase inhibitors in inflammatory bowel disease may be worthwhila. INTRGDUCTI ON Benoxaprofen was promoted as a non-steroidal anti-inflasxsatory drug with a novel ability to inhibit lipoxygenase pathways and to reduce the egress of leucocytes into sites of inflammation (l-3). Be cause of these properties we have assessed its value in the treatment of active ulcerative colitis. PATIENTSAND METHODS Ten patients (median age 35 yrs) (range 18-62); 7 male, 3 female) in whom active ulcerative proctocolitis had been diagnosed by conventional clinical, histological and radiological criteria, were assessed before and after 18 days of treatment with benoxaprofen 300 mg twice One patient had proctitis, 7 left-sided colitis, 1 subtotal daily. disease and 1 pan-colitis. The median length of history was 3 years (range 6 weeks - 11 years) and the median length of relapse was 4.5 Five patients were receiving maintenance weeks (2 days - 1 year). sulphasalazine (which was continued throughout the trial) and none was receiving cortico-steroids or any other drug.
405
and throughout the trial period, patients For 3 days before, used diary cards to record their frequency of bowel action, and, on four point scales, stool consistency, urgency, bleeding and degree they also recorded drug intake and sideof constitutional upset; rectal mucosal disease activity effects. Before and after treatment, was assessed by an observer-independent sigmoidoscopic score (4), and Blood count, ESR, a rectal biopsy taken 7-10 cm from the anal verge. orosomucoid and liver function plasma urea and electrolytes, proteins, tests were measured before and after benoxaprofen. Rectal biopsy specimens were fixed in formalin and sections were they were then coded and assessed stained using haematoxylin and eosin; Histological appearances were rated without knowledge of their origin. surf ace pus , on a three point scale for each of seven variables: goblet cell depletion, vascular epithelial cell destruction, congestion, focal aggregation of polymorphonuclear leucocytes, crypt and intensity of infiltration of the lamina propria by abscesses, lymphocytes and plasma cells (5). test
Results were compared using Wilcoxon’s for paired data.
two-tailed
signed
ranks
RESULTS
all patients were clinically At the start of the study, and showed sigmoidoscopic and histological evidence relapse, inflanrmation (Table 3).
in of active
Benoxaprofen had no significant effect on bowel habit, rectal mucosal appearance at sigmoidoscopy, constitutional well-being, or any of the haematological and biochemical variables measured Histological appearances were also unaltered in the group (Table 1). 5 patients showing an overall deterioration, 2 an as a whole, There appeared to be a improvement and 3 no change after treatment. significant increase in the amount of pus seen on the mucosal surface after treatment with benoxaprofen (p < 0.05)) but there were no changes focal in the extent of round cell infiltration of the lamina propria, aggregation of polymorphonuclear leucocytes or crypt abscess formation. Three patients complained of headaches while on treatment, and in one of these a photosensitivity reaction necessitated the drug’s withdrawal after 9 days. oids,
At the end of the trial 8 patients were treated with corticosterand all but one showed prompt clinical improvement. DISCUSSION
Several lines of evidence suggest that lipoxygenase products could play a role in the pathogenesis of ulcerative colitis. Firstly, these compounds have recently been shown to be synthesised in human colonic mucosa (6,7) . Secondly, as well as making a possible contribution to the histological appearance of active disease by stimulating leucocyte emigration from the vasculature (8), lipoxygenase products may’be partly responsible for the associated diarrhoea: a recent stu& indicates that, at leastin vitro, they influence ileal and cblonic 406
T&BLB 1 Effect of treatment with benoxaprofen. (600 mg daily) for 18 days -1 habit, constitutional upset, sigmoidoocopic appearance, mucoeal ESR, albumin and orosomucoid in 10 patients with histology, haemoglobin, ulcerative colitis. Before
Criteria Stool frequency (per day) Stool
treatolent
5(1-11)
consistency*
2.5(1-4)
After
treatment
P
4(1-9)
NS
2( l-4)
NS
Urgency*
3( l-4)
2( 1-4)
NS
Rectal
3(1-4)
2( 1-4)
NS
bleeding*
Constitutional
upset*
2( l-2)
1 (I-4)
NS
Sigmoidoscopic
score*
3(2-4)
3(1-4)
NS
2( 1-3)
2( l-3)
NS
13.3(9.6-15.0)
12.9(9.1-14.9)
NS
ESR (mm in 1st h)
19(3-47)
10(3-40)
NS
Albumin (g/l)
46(40-50)
44 (37-52)
NS
Histological Haemoglobin
Orosomucoid
score+ (g/dl)
(g/l)
1.00(0.80-l
.40)
1.10(0.55-l
.40)
NS
Results are shown as median (range). NS denotes * Scored 1-4 (with increasing abnormality). + Scored 1-3 (with increasing abnormality).
not Significant.
mucosal electrolyte transport in the direction of secretion (9). Thirdly, although colonic mucosal prostaglandin production is increased in active ulcerative colitis (10-13) potent cycle-oxygenase inhibitors are at best ineffective therapeutically (14-16). While this might in theory be due to a breakdown in colonic mucosal cytoprotection by prostaglandins (I 7)) it could also be explained by diversion of arachidonic acid down lipoxygenase pathways (18,19). Lastly, sulphasalazine, a drug of proven value in ulcerative colitis, is now known to be capable of lipoxygenase inhibition (20). It therefore seemed important to evaluate the effect of benoxaprofen in active ulcerative colitis, not only in an attempt to obtain an alternative to conventional therapy, but also to shed light on the role of lipoxygenase products in the pathogenesis of the disease. The failure of benoxaprofen in this study to modify disease activity assessed either clinically or histologically could be taken to indicate that leucotrienes do not play a major role in the development of active disease, but there are other possible explanations. Dosage may have been inadequate to achieve inhibition of colonic mucosal lipoxygenase. The duration of treatment with benoxaprofen may have been too short; however, neither of two patients given the drug for a further 3 weeks improved clinically or microscopically. Any possible benefit due to lipoxygenase inhibition may have been outweighed by the consequences of benoxaprofen’s albeit weak activity as a prostaglandin synthesis in407
hibitor (vi& sups) (2). Finally, benoxaprofen is an inhibitor of the 5-lipoxygenase pathway, whereas it appears that 12- and 15-lipoxygenase pathways are more abundantly represented in human colonic mucosa (7) . These caveats suggest that the evaluation of other lipoxygenase inhibitors in the treatment of ulcerative colitis would not be unwarrantInvestigation of the effect of lipoxygenase inhibition might also ed. be worthwhile in patients with Crohn’s disease. ACKNOWLEDGEMFNTS We are grateful to Drs. P.J. Toghill and M. Atkinson to study their patients, and to Dista Products Ltd for support.
for permission financial
REFERENCES 1.
Meacock SCR, Kitchen EA. Effects of the non-steroidal anti-inflammatory drug benoxaprofen on leucocyte migration. Journal of Pharmacology 31:366, 1979.
2.
Dawson W, Boot JR, Harvey J, Walker JR. The pharmacology of benoxaprofen with particular reference to effects on lipoxygenase product formation. European Journal of Rheumatology and Inflammation 5:61, 1982.
3.
Lee VY, Hughes JM, Seale JP, Temple DM. Effect of benoxaprofen on release of slow-reacting substances from human lung tissue in Clinical Science 63:219, 1982. vitro.
4.
Baron JH, Connell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearances in proctocolitis. British Medical Journal 1:89, 1964.
5.
Morson BC, Dawson IMP. Blackwell Scientific
6.
Bennett A, Hensby CN, Sanger GJ, Stamford IF. Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers. British Journal of Pharmacology 74:435, 1981.
7.
Hawkey CJ, Boughton Smith NK, Whittle BJR. Synthesis of lipoxygenase and cycle-oxygenase products by human colonic mucosa. Gut 23:A897, 1982.
8.
Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJH. Leucotriene B4: a potent chemokinetic and aggregating substance released from polymorphonuclear leucocytes. Nature 286: 264, 1980.
9.
Musch M, Miller RJ, Field M, Siegel M. Lipoxygenase metabolites of arachidonic acid: potential mediators of electrolyte secretion. Gastroenterology 82:1257, 1982.
p.551 in Gastrointestinal Pathology. Publications, Oxford, 1979.
408
2nd ed.
IO.
Sharon P, Ligumsky M, Rachmilewitz D, Zor U. Role of prostaglandins enhanced production during active in ulcerative colitis: disease and inhibition by sulfasalazine. Gastroenterology 78~638, 1978.
Il.
of prostaglandin Harris DW, Smith PR, Swan CRJ. Determination synthetase in rectal biopsy material and its significance in Gut 19:875, 1978. colonic disease.
12.
on prostaglandin Hawkey CJ, Truelove SC. Effect of prednisolone synthesis by rectal mucosa in ulcerative colitis: investigation by laminar flow bioassay and radioimmunoassay. Gut 22:190, 1981.
13.
Rampton DS, Sladen GE, Youlten LJF. Rectal mucosal prostaglandin E2 release and its relation to disease activity, electrical potential difference and treatment in ulcerative colitis. Gut 21:591, 1980.
14.
Gilat T, Ratan J, Rosen P, Peled Y. Prostaglandins Gastroenterology 76:1083, 1979. colitis.
15.
Campieri M, Lanfranchi GA, Bazzochi G, Brignola Boccia S, Labo G. Prostaglandins, indomethacin 78:193, 1980. colitis . Gastroenterology
16.
synthesis inhibitors in Rampton DS, Sladen GE. Prostaglandin ulcerative colitis: f lurbiprofen compared with conventional Prostaglandins 21:417, 1981. treatment.
17.
Robert A. Cytoprotection 761, 1979.
18.
Engineer DM, Niederhauser U, Piper PJ, Sirois P. Release of of prostaglandin synthesis mediators of anaphylaxis : inhibition and the modification of release of slow reacting substances of anaphylaxis and histamine. British Journal of Pharmacology 62: 61, 1978.
by prostaglandins.
and ulcerative
C, Benatti A, and ulcerative
Gastroenterology
77:
19. Siegel MI, McConnell RT, Cuatrecasas P. Aspirin-like drugs interfere with arachidonate metabolism by inhibition of the l2hydroperoxy-5,8,IO-,l4-eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway. Proceedings of the National Academy of Sciences 76~3744, 1979. 20. Stenson WF, Lobos E . Sulfasalazine inhibits the synthesis of chemotactic lipids by neutrophils. Journal of Clinical Investigation 69:494, 1982.
409