Aliment. Pharmacol. Thherap. (1990) 4, 41 7-422.
Effect of mefenamic acid on bowel transit time in healthy adult volunteers
M. U. R A S H I D & D. N. B A T E M A N Wolfson Unit of Clinical Pharmacology, University of Newcasfle upon Tyne, Claremonf
Place, Newcasfle upon Tyne UK Accepted for publication 2 April 1990
SUMMARY
The effect of mefenamic acid on bowel transit time was investigated. Seven healthy adult male subjects of age 39 f2.4 years (mean fS.E.M.) received placebo or mefenamic acid (500 mg t.d.s) orally in randomized order for five days, with a 7-day washout between studies. On the third morning after starting the drug they had a meal containing Redi-Brek and baked beans with radio-opaque markers. Small bowel transit time was measured using breath hydrogen, and whole gut transit time was measured using radio-opaque markers. The small bowel transit times were 160 min (median) with placebo and 50 min with mefenamic acid ( P < 0.05). The percentages of appearance of marker in stool within 24 h were 24.9 f11.8 (mean fS.E.M.) with placebo and 48.9 f11.7 with mefenamic acid ( P < 0.05). The times of appearance of twenty-fifth marker in stool were 41.0 f4.4 h with placebo and 26.9 f3.2 h with mefenamic acid ( P < 0.05).The total weights of faeces in 72 h were 500.9f96.2 g with placebo and 657.1 f118.8 g with mefenamic acid ( P < 0.05). Mefenamic acid in therapeutic doses (500 mg t.d.s.) accelerated bowel transit time in healthy subjects.
Correspondence to : Dr D. N. Bateman, Wolfson Unit of Clinical Pharmacology, Clarernont Place, The University, Newcastle upon Tyne NEl 7RU, UK. 417
418
M. U. RASHID & D. N.BATEMAN
INTRODUCTION Mefenamic acid, a potent NSAID, is a widely prescribed drug in Britain. This drug produces diarrhoea and colitis as adverse effects.’” In Britain as a whole the Committee on Safety of Medicines had received 1485 reports of adverse effects to mefenamic acid (July 1963-July 1989) and out of these 264 (i.e. 18%) were of diarrhoea and colitis. In most cases diarrhoea stopped promptly with the withdrawal of mefenamic acid therapy. Recurrence on rechallenge was also reported. These observations suggest that this drug causes disturbance of bowel motility, but the precise mechanisms and incidence is unknown. Excessively rapid bowel transit is commonly considered to be a cause of malabsorption and diarrhoea. The production of diarrhoea with mefenamic acid may be due to its effect on bowel transit. While this concept is intuitively appealing, there is no quantitative information which clearly documents the effect of mefenamic acid on bowel transit. The objective of the present study was to investigate the effects of mefenamic acid on small bowel transit time and whole gut transit time in healthy adult subjects. MATERIALS A N D M E T H O D S Seven healthy adult male subjects of mean age 39 years (range 31-48 years) were studied on two occasions separated by a week in a double-blind manner. The subjects had no history of gastrointestinal or renal disease and were not on any concurrent medication. The study was approved by the Joint Ethics Committee of the University of Newcastle upon Tyne and the Newcastle Health Authority. Subjects were asked to avoid alcoholic drinks and foods likely to generate hydrogen for the first two days of each study period. They took one capsule (placebo or 250 mg mefenamic acid) three times daily for these two days and for the subsequent three days of the experiment. O n the morning of the third day subjects attended after an overnight fast, but after taking drug or placebo. After obtaining three fasting end expiratory breath samples subjects had a breakfast of 16 g Redi-Brek and 225 g baked beans containing 50 segments of radio-opaque markers. These markers were prepared by cutting 4 mm segments from radioopaque polythene tubing of 3 mm external diameter (Portex Ltd, Hythe, Kent). The time of starting the meal was designated time zero. Small bowel transit time was determined by measuring end expiratory hydrogen excretion. End expiratory breath samples were collected into 20 ml plastic syringes at 10 min intervals up to 6 h.7 Hydrogen concentrations in breath samples were determined using an exhaled hydrogen monitor supplied by Gas Measuring Instruments Ltd, Renfrew, Scotland.$ Free access to food or drink was allowed from four hours after the meal. Placebo or mefenamic acid tablets were continued for the next three days. Whole gut transit times were measured using a modification of the method for
MEFENAMIC ACID A N D BOWEL TRANSIT TIME
419
studying gut transit times using radio-opaque markers.’ The subjects, having first passed urine, collected each bowel movement in separate polythene bags for a period of 72 h. Stool samples were then X-rayed and the markers were counted in each radiograph to obtain data for estimating whole gut transit time. The following parameters were used to estimate the whole gut transit time: appearance of markers in stool 0-24, 25-48 and 49-72 h ; time of appearance of first marker in stool (h); time of appearance of twenty-fifth marker in stool (h); weight of faeces (g)0-24, 25-48 and 49-72 h; total weight of faeces in 72 h (g); frequency of defaecation in 72 h. STATISTICAL M E T H O D S Student’s Paired t-test was used to determine the significance of differences in measurements of whole gut transit time and stool output. Wilcoxon signed rank test was used to determine the significance of differences in measurements of small bowel transit time. In each of the above tests, the level considered to be significant was P < 0.05. RESULTS Small Bowel Transit Time The effect of drug treatment on small bowel transit for each individual subject is shown in Table 1. The small bowel transit times were 160 min (median) with placebo and 50 min with mefenamic acid. Mefenamic acid resulted in a significantly shorter small bowel transit time than placebo ( P < 0.05). Table 1. Effect of placebo (P) or mefenamic acid (M) on small bowel transit time (breath hydrogen), faecal weight in the first 24 h, and time of appearance of twenty-fifth marker in stools Small bowel transit (min)
(€9
P
P
M
P
M
616 347 313 76 203 108 175
46 23 25 48 47 48 50
23 23 23 24 46 23 26
203
47
23
__
Subject
Stool weight
Twenty-fifth marker (h)
~~
M -
1 2 3 4 5 6 7
Median
160 80 > 360 130 90 210 350
50 50 > 360 80 30 50
326 255 122 53 161 66 120
160
50
122
90
420
M. U.RASHID & D. N. BATEMAN
Table 2. Effects of mefenamic acid on the transit of a solid meal through the whole gut. The significance of differences were calculated using Student's Paired f-test Indicator to estimate whole g u t transit Appearance of markers in stool 0-24 h (Yo) Time of appearance of first marker in stool (h) Time of appearance of twenty-fifth marker in stool (h) Weight of faeces 0-24 h (g) Weight of faeces 25-48 h (g) Weight of faeces 49-72 h (g) Total weight of faeces in 72 h (g) Frequency of defaecation in 72 h
Placebo (mean kS.E.M.)
Mefenamic acid (mean f S.E.M.)
P
24.9+ 11.8
4 8 . 9 k 11.7
< 0.05
29.6 f 5.0
21.9f 1.7
N.S.
41.0 k 4.4
26.9k3.2
< 0.05
157.6 f 3 7 . 8 149.1f49.4 194.1 f 4 2 . 7 500.9 f96.2 3.9h0.7
262.6 f69.8 243.7 f34.5 150.9 & 48.6 657.1 & 118.8 4.3 k 0.7
< 0.05 N.S. N.S.
< 0.05 N.S.
Whole Gut Transit Time The results of whole gut transit time parameters are shown in Table 2. The percentages of appearance of marker in stool within 24 h were 24.9k 11.8 (mean S.E.M.) with placebo and 48.9 f11.7 with mefenamic acid. A greater percentage of markers appeared in the stools in the first 24 h after mefenamic acid than placebo (P < 0.05). Times of appearance of the first and twenty-fifth marker in stool were 29.6 5.0h(+S.E.M.)and41.0f4.4hwithplacebo, a n d 2 1 . 9 f 1 . 7 h a n d 2 6 . 9 f 3 . 2 h with mefenamic acid, respectively. The time of appearance of the twenty-fifth marker in stool with mefenamic acid was significantly shorter than that with placebo (P < 0.05). Weight of faeces during the 0-24 h period and total weight of faeces (0-72 h) were greater with mefenamic acid than with placebo ( P < 0.05). Although the frequency of defaecation in 72 h tended to be more with mefenamic acid than with placebo, this did not reach the level of statistical significance.
DISCUSSION In the present study mefenamic acid administered orally in a standard therapeutic dose of 500 mg t.d.s. produced significantly shorter small bowel transit time than with placebo. Interpretation of the results is affected due to subject no. 3 who failed to produce a significant increase of exhaled hydrogen above the baseline within 6 h in both treatments. A small fraction of the population, less than 5%, excrete little or no hydrogen in the basal situation and do not excrete increased hydrogen following lactulose (non-absorbable disaccharide) ingestion." The cause may be inadequate bacterial overgrowth to produce available hydrogen. Thus, subject no. 3 may be within this non-hydrogen producing population.
MEFENAMIC ACID A N D BOWEL TRANSIT TIME
421
Among the parameters of estimating whole gut transit, mefenamic acid produced significant differences from placebo in time of appearance of the twentyfifth marker in stool, percentage of markers appearing in faeces within the first and last 24 h of collection, weight of stool collected during the first 24 h and total weight of stool collected during 72 h. These findings indicate that mefenamic acid may shorten the whole gut transit time of solid meals in man and produce greater faecal mass acutely. It is of note that many cases of diarrhoea reported to the Committee on Safety of Medicines occur early in treatment. These data suggest that mefenamic acid accelerates whole gut transit and increases stool output which may be one of the causes of diarrhoea production by mefenamic acid, as it is widely assumed that diarrhoea is associated with rapid colonic transit. Both small bowel and whole gut transit being rapid in patients with irritable bowel syndrome and diarrhoea." The mechanism by which mefenamic acid produces rapid bowel transit is not clear. Gastric emptying may affect small bowel transit time. Cisapride, a gastrointestinal prokinetic drug significantly decreased small bowel transit time of a solid meal without significant effect on gastric emptying." BatemanI3 showed that cisapride significantly increased gastric emptying of liquid. Mefenamic acid could affect gastric emptying but no studies have been done to explore this. An increase in small bowel transit might explain a more rapid whole gut transit. Indeed the percentage change in small bowel transit correlated significantly with the change in time of appearance of the twenty-fifth marker (Y = 0.79) but not with change in stool weight. Mefenarnic acid has been reported as causing both small bowel inflammation and a colitis mimicking Crohn's d i s e a ~ e . ~I4, ~ Small ,~, bowel inflammation and colitis may be a cause of rapid bowel transit, but colitis is unlikely to be the cause of findings in the present study however, and frank diarrhoea did not occur in these subjects. Prostaglandins are present in most mammalian cells and tissues and have a cy topro tective action on the gastrointestinal trac t.I5 Non-s teroidal anti-inflammatory drugs (NSAIDs), including mefenamic acid, cause inhibition of gastrointestinal prostaglandin synthesis.16 Gullikson and colleague^'^ have shown in vitvo that NSAIDs, including in particular mefenamic acid, inhibit fluid transport across the small bowel mucosa, in a manner similar to that of some prostaglandins. A similar effect in vivo could account for the observations found in this study. The fact that stool weights appear to have returned to normal by the third study day, the fifth on mefenamic acid, suggests the development of tolerance to this effect. In conclusion, mefenamic acid in therapeutic doses accelerates bowel transit in healthy subjects. The precise mechanism involved requires further investigation, and this finding may explain in part the frequency of diarrhoea as an adverse effect to this drug.
422
M. U. RASHID & D. N. BATEMAN
REFERENCES Ravi S, Keat A C, Keat E C B. Colitis caused by non-steroidal anti-inflammatory drugs. Postgrad Med J 1986; 62: 773-6. Hall R I, Petty A H, Cobden I. et al. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1182. Philips M S, Fehilly B, Stewart S, et al. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1626. Edward A L, Heagerty A M, Bing R F. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1626-7. Rampton D S, Tapping P J. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1627. Williams R, Glazer G. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1627.
Perman J A, Barr R G, Watkins J B. Sucrose malabsorption in children: Noninvasive diagnosis by internal breath hydrogen determination. J Pediatr 1978; 93 : 17-22. Bartlett K, Dobson J V, Eastham E. A new method for the detection of hydrogen in breath and its application to acquired and inborn sugar malabsorption. Clin Chim Acta 1980; 108: 189-94.
Hinton J M, Lennard-Jones J E, Young A C. A new method for studying gut transit times using radioopaque markers. Gut 1969; 10: 842-7.
10 Bond J H, Levitt M D. Investigation of small
bowel transit time in man utilizing pulmonary hydrogen (H,) measurements. J Lab Clin Med 1975; 85(4): 546-55. 11 Cann P A, Read N W, Brown C, Hobson N, Holdsworth C D. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut 1983 ; 24 : 405-11. 12 Edwards C A, Holden S, Brown C, Read N
W. Effect of cisapride on the gastrointestinal transit of a solid meal in normal human subjects. Gut 1987; 28: 13-6. 13 Bateman D N. The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam. Eur J Clin Pharmacol 1987; 30: 205-8. 14 Hawkey C J, Rampton D S. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease or treat1985 ; 89: ment. Gastroenterology 1162-88. 15 Robert A. Cytoprotection by prostaglandins. Gastroenterology 1979; 77: 761-7. 16 Vane J R. Inhibition of prostaglandin syn-
thesis as a mechanism of action for aspirinlike drugs. Nature 1971; 231: 232. 1 7 Gullikson G W, Sender M, Bass P. Laxativenonsteroidal antilike effects of inflammatory drugs on intestinal fluid movement and membrane integrity. J Pharmacol Exp Ther 1982; 220: 236-42.
Effect of mefenamic acid on bowel transit time in healthy adult volunteers
M. U. R A S H I D & D. N. B A T E M A N Wolfson Unit of Clinical Pharmacology, University of Newcasfle upon Tyne, Claremonf
Place, Newcasfle upon Tyne UK Accepted for publication 2 April 1990
SUMMARY
The effect of mefenamic acid on bowel transit time was investigated. Seven healthy adult male subjects of age 39 f2.4 years (mean fS.E.M.) received placebo or mefenamic acid (500 mg t.d.s) orally in randomized order for five days, with a 7-day washout between studies. On the third morning after starting the drug they had a meal containing Redi-Brek and baked beans with radio-opaque markers. Small bowel transit time was measured using breath hydrogen, and whole gut transit time was measured using radio-opaque markers. The small bowel transit times were 160 min (median) with placebo and 50 min with mefenamic acid ( P < 0.05). The percentages of appearance of marker in stool within 24 h were 24.9 f11.8 (mean fS.E.M.) with placebo and 48.9 f11.7 with mefenamic acid ( P < 0.05). The times of appearance of twenty-fifth marker in stool were 41.0 f4.4 h with placebo and 26.9 f3.2 h with mefenamic acid ( P < 0.05).The total weights of faeces in 72 h were 500.9f96.2 g with placebo and 657.1 f118.8 g with mefenamic acid ( P < 0.05). Mefenamic acid in therapeutic doses (500 mg t.d.s.) accelerated bowel transit time in healthy subjects.
Correspondence to : Dr D. N. Bateman, Wolfson Unit of Clinical Pharmacology, Clarernont Place, The University, Newcastle upon Tyne NEl 7RU, UK. 417
418
M. U. RASHID & D. N.BATEMAN
INTRODUCTION Mefenamic acid, a potent NSAID, is a widely prescribed drug in Britain. This drug produces diarrhoea and colitis as adverse effects.’” In Britain as a whole the Committee on Safety of Medicines had received 1485 reports of adverse effects to mefenamic acid (July 1963-July 1989) and out of these 264 (i.e. 18%) were of diarrhoea and colitis. In most cases diarrhoea stopped promptly with the withdrawal of mefenamic acid therapy. Recurrence on rechallenge was also reported. These observations suggest that this drug causes disturbance of bowel motility, but the precise mechanisms and incidence is unknown. Excessively rapid bowel transit is commonly considered to be a cause of malabsorption and diarrhoea. The production of diarrhoea with mefenamic acid may be due to its effect on bowel transit. While this concept is intuitively appealing, there is no quantitative information which clearly documents the effect of mefenamic acid on bowel transit. The objective of the present study was to investigate the effects of mefenamic acid on small bowel transit time and whole gut transit time in healthy adult subjects. MATERIALS A N D M E T H O D S Seven healthy adult male subjects of mean age 39 years (range 31-48 years) were studied on two occasions separated by a week in a double-blind manner. The subjects had no history of gastrointestinal or renal disease and were not on any concurrent medication. The study was approved by the Joint Ethics Committee of the University of Newcastle upon Tyne and the Newcastle Health Authority. Subjects were asked to avoid alcoholic drinks and foods likely to generate hydrogen for the first two days of each study period. They took one capsule (placebo or 250 mg mefenamic acid) three times daily for these two days and for the subsequent three days of the experiment. O n the morning of the third day subjects attended after an overnight fast, but after taking drug or placebo. After obtaining three fasting end expiratory breath samples subjects had a breakfast of 16 g Redi-Brek and 225 g baked beans containing 50 segments of radio-opaque markers. These markers were prepared by cutting 4 mm segments from radioopaque polythene tubing of 3 mm external diameter (Portex Ltd, Hythe, Kent). The time of starting the meal was designated time zero. Small bowel transit time was determined by measuring end expiratory hydrogen excretion. End expiratory breath samples were collected into 20 ml plastic syringes at 10 min intervals up to 6 h.7 Hydrogen concentrations in breath samples were determined using an exhaled hydrogen monitor supplied by Gas Measuring Instruments Ltd, Renfrew, Scotland.$ Free access to food or drink was allowed from four hours after the meal. Placebo or mefenamic acid tablets were continued for the next three days. Whole gut transit times were measured using a modification of the method for
MEFENAMIC ACID A N D BOWEL TRANSIT TIME
419
studying gut transit times using radio-opaque markers.’ The subjects, having first passed urine, collected each bowel movement in separate polythene bags for a period of 72 h. Stool samples were then X-rayed and the markers were counted in each radiograph to obtain data for estimating whole gut transit time. The following parameters were used to estimate the whole gut transit time: appearance of markers in stool 0-24, 25-48 and 49-72 h ; time of appearance of first marker in stool (h); time of appearance of twenty-fifth marker in stool (h); weight of faeces (g)0-24, 25-48 and 49-72 h; total weight of faeces in 72 h (g); frequency of defaecation in 72 h. STATISTICAL M E T H O D S Student’s Paired t-test was used to determine the significance of differences in measurements of whole gut transit time and stool output. Wilcoxon signed rank test was used to determine the significance of differences in measurements of small bowel transit time. In each of the above tests, the level considered to be significant was P < 0.05. RESULTS Small Bowel Transit Time The effect of drug treatment on small bowel transit for each individual subject is shown in Table 1. The small bowel transit times were 160 min (median) with placebo and 50 min with mefenamic acid. Mefenamic acid resulted in a significantly shorter small bowel transit time than placebo ( P < 0.05). Table 1. Effect of placebo (P) or mefenamic acid (M) on small bowel transit time (breath hydrogen), faecal weight in the first 24 h, and time of appearance of twenty-fifth marker in stools Small bowel transit (min)
(€9
P
P
M
P
M
616 347 313 76 203 108 175
46 23 25 48 47 48 50
23 23 23 24 46 23 26
203
47
23
__
Subject
Stool weight
Twenty-fifth marker (h)
~~
M -
1 2 3 4 5 6 7
Median
160 80 > 360 130 90 210 350
50 50 > 360 80 30 50
326 255 122 53 161 66 120
160
50
122
90
420
M. U.RASHID & D. N. BATEMAN
Table 2. Effects of mefenamic acid on the transit of a solid meal through the whole gut. The significance of differences were calculated using Student's Paired f-test Indicator to estimate whole g u t transit Appearance of markers in stool 0-24 h (Yo) Time of appearance of first marker in stool (h) Time of appearance of twenty-fifth marker in stool (h) Weight of faeces 0-24 h (g) Weight of faeces 25-48 h (g) Weight of faeces 49-72 h (g) Total weight of faeces in 72 h (g) Frequency of defaecation in 72 h
Placebo (mean kS.E.M.)
Mefenamic acid (mean f S.E.M.)
P
24.9+ 11.8
4 8 . 9 k 11.7
< 0.05
29.6 f 5.0
21.9f 1.7
N.S.
41.0 k 4.4
26.9k3.2
< 0.05
157.6 f 3 7 . 8 149.1f49.4 194.1 f 4 2 . 7 500.9 f96.2 3.9h0.7
262.6 f69.8 243.7 f34.5 150.9 & 48.6 657.1 & 118.8 4.3 k 0.7
< 0.05 N.S. N.S.
< 0.05 N.S.
Whole Gut Transit Time The results of whole gut transit time parameters are shown in Table 2. The percentages of appearance of marker in stool within 24 h were 24.9k 11.8 (mean S.E.M.) with placebo and 48.9 f11.7 with mefenamic acid. A greater percentage of markers appeared in the stools in the first 24 h after mefenamic acid than placebo (P < 0.05). Times of appearance of the first and twenty-fifth marker in stool were 29.6 5.0h(+S.E.M.)and41.0f4.4hwithplacebo, a n d 2 1 . 9 f 1 . 7 h a n d 2 6 . 9 f 3 . 2 h with mefenamic acid, respectively. The time of appearance of the twenty-fifth marker in stool with mefenamic acid was significantly shorter than that with placebo (P < 0.05). Weight of faeces during the 0-24 h period and total weight of faeces (0-72 h) were greater with mefenamic acid than with placebo ( P < 0.05). Although the frequency of defaecation in 72 h tended to be more with mefenamic acid than with placebo, this did not reach the level of statistical significance.
DISCUSSION In the present study mefenamic acid administered orally in a standard therapeutic dose of 500 mg t.d.s. produced significantly shorter small bowel transit time than with placebo. Interpretation of the results is affected due to subject no. 3 who failed to produce a significant increase of exhaled hydrogen above the baseline within 6 h in both treatments. A small fraction of the population, less than 5%, excrete little or no hydrogen in the basal situation and do not excrete increased hydrogen following lactulose (non-absorbable disaccharide) ingestion." The cause may be inadequate bacterial overgrowth to produce available hydrogen. Thus, subject no. 3 may be within this non-hydrogen producing population.
MEFENAMIC ACID A N D BOWEL TRANSIT TIME
421
Among the parameters of estimating whole gut transit, mefenamic acid produced significant differences from placebo in time of appearance of the twentyfifth marker in stool, percentage of markers appearing in faeces within the first and last 24 h of collection, weight of stool collected during the first 24 h and total weight of stool collected during 72 h. These findings indicate that mefenamic acid may shorten the whole gut transit time of solid meals in man and produce greater faecal mass acutely. It is of note that many cases of diarrhoea reported to the Committee on Safety of Medicines occur early in treatment. These data suggest that mefenamic acid accelerates whole gut transit and increases stool output which may be one of the causes of diarrhoea production by mefenamic acid, as it is widely assumed that diarrhoea is associated with rapid colonic transit. Both small bowel and whole gut transit being rapid in patients with irritable bowel syndrome and diarrhoea." The mechanism by which mefenamic acid produces rapid bowel transit is not clear. Gastric emptying may affect small bowel transit time. Cisapride, a gastrointestinal prokinetic drug significantly decreased small bowel transit time of a solid meal without significant effect on gastric emptying." BatemanI3 showed that cisapride significantly increased gastric emptying of liquid. Mefenamic acid could affect gastric emptying but no studies have been done to explore this. An increase in small bowel transit might explain a more rapid whole gut transit. Indeed the percentage change in small bowel transit correlated significantly with the change in time of appearance of the twenty-fifth marker (Y = 0.79) but not with change in stool weight. Mefenarnic acid has been reported as causing both small bowel inflammation and a colitis mimicking Crohn's d i s e a ~ e . ~I4, ~ Small ,~, bowel inflammation and colitis may be a cause of rapid bowel transit, but colitis is unlikely to be the cause of findings in the present study however, and frank diarrhoea did not occur in these subjects. Prostaglandins are present in most mammalian cells and tissues and have a cy topro tective action on the gastrointestinal trac t.I5 Non-s teroidal anti-inflammatory drugs (NSAIDs), including mefenamic acid, cause inhibition of gastrointestinal prostaglandin synthesis.16 Gullikson and colleague^'^ have shown in vitvo that NSAIDs, including in particular mefenamic acid, inhibit fluid transport across the small bowel mucosa, in a manner similar to that of some prostaglandins. A similar effect in vivo could account for the observations found in this study. The fact that stool weights appear to have returned to normal by the third study day, the fifth on mefenamic acid, suggests the development of tolerance to this effect. In conclusion, mefenamic acid in therapeutic doses accelerates bowel transit in healthy subjects. The precise mechanism involved requires further investigation, and this finding may explain in part the frequency of diarrhoea as an adverse effect to this drug.
422
M. U. RASHID & D. N. BATEMAN
REFERENCES Ravi S, Keat A C, Keat E C B. Colitis caused by non-steroidal anti-inflammatory drugs. Postgrad Med J 1986; 62: 773-6. Hall R I, Petty A H, Cobden I. et al. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1182. Philips M S, Fehilly B, Stewart S, et al. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1626. Edward A L, Heagerty A M, Bing R F. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1626-7. Rampton D S, Tapping P J. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1627. Williams R, Glazer G. Enteritis and colitis associated with mefenamic acid. Br Med J 1983; 287: 1627.
Perman J A, Barr R G, Watkins J B. Sucrose malabsorption in children: Noninvasive diagnosis by internal breath hydrogen determination. J Pediatr 1978; 93 : 17-22. Bartlett K, Dobson J V, Eastham E. A new method for the detection of hydrogen in breath and its application to acquired and inborn sugar malabsorption. Clin Chim Acta 1980; 108: 189-94.
Hinton J M, Lennard-Jones J E, Young A C. A new method for studying gut transit times using radioopaque markers. Gut 1969; 10: 842-7.
10 Bond J H, Levitt M D. Investigation of small
bowel transit time in man utilizing pulmonary hydrogen (H,) measurements. J Lab Clin Med 1975; 85(4): 546-55. 11 Cann P A, Read N W, Brown C, Hobson N, Holdsworth C D. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut 1983 ; 24 : 405-11. 12 Edwards C A, Holden S, Brown C, Read N
W. Effect of cisapride on the gastrointestinal transit of a solid meal in normal human subjects. Gut 1987; 28: 13-6. 13 Bateman D N. The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam. Eur J Clin Pharmacol 1987; 30: 205-8. 14 Hawkey C J, Rampton D S. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease or treat1985 ; 89: ment. Gastroenterology 1162-88. 15 Robert A. Cytoprotection by prostaglandins. Gastroenterology 1979; 77: 761-7. 16 Vane J R. Inhibition of prostaglandin syn-
thesis as a mechanism of action for aspirinlike drugs. Nature 1971; 231: 232. 1 7 Gullikson G W, Sender M, Bass P. Laxativenonsteroidal antilike effects of inflammatory drugs on intestinal fluid movement and membrane integrity. J Pharmacol Exp Ther 1982; 220: 236-42.
