Review article: non-steroidal anti-inflammatory drug-induced gastrointestinal permeability

Review article: non-steroidal anti-in¯ammatory drug-inducedgastrointestinal permeability

N. M. DAVIES

The University of Calgary, Faculty of Medicine, Department of Pharmacology and Therapeutics, Intestinal Disease Research

Unit, Calgary, Alberta, Canada

Accepted for publication 12 November 1997

INTRODUCTION

The anti-in¯ammatory, analgesic, anti-pyretic and anti-

thrombotic properties of non-steroidal anti-in¯amma-

tory drugs (NSAIDs) make this therapeutic class of

particular utility in the management of chronic arthro-

pathies, in the treatment of pain, in the alleviation of

fever, and for the prevention of myocardial infarction

and stroke. In addition, recent evidence suggests

possible therapeutic bene®ts of NSAIDs in the preven-

tion of colorectal cancer and in the treatment of

Alzheimer's disease.1, 2

There are currently more than 35 NSAIDs available for

clinical use world-wide.3 Previous estimates of their use

include >100 million prescriptions written throughout

the world, at a cost of well over $5 billion.4 All NSAIDs,

when given in equivalent therapeutic doses, demon-

strate comparable ef®cacy.5, 6 Given this apparently

equivalent ef®cacy, the relative safety pro®le of individ-

ual NSAIDs is becoming a principal criterion for

therapeutic selection. The clinical utility of NSAIDs is

determined as a compromise between therapeutic

ef®cacy and acceptable side-effects. However, the `safe-

ty' of NSAIDs is promotionally driven, as it is a main

determinant of the success of an NSAID's marketability.

Unfortunately, there does not appear to be a consensus

as to what constitutes a `safer' NSAID. There is no

precise de®nition of `safer' in terms of symptomatic

gastrointestinal (GI) side-effects, short-term endoscopy

studies, 6-month endoscopy studies or clinically signi-

®cant GI complications. More rigorous scienti®c sub-

stantiation of claims of reduced NSAID toxicity is

required in the development of GI-safe NSAIDs.

The GI side-effects of NSAIDs were recognized more

than a century ago.7 The clinical use of NSAIDs has

SUMMARY

Non-steroidal anti-in¯ammatory drugs induce damage

throughout the entire gastrointestinal tract. Adminis-

tration of site-speci®c permeability probes is a

non-invasive technique for assessing the functional

integrity of the gastrointestinal mucosa. A systematic

search for NSAID-induced permeability studies using

MEDLINE and EMBASE, and an analysis of the

literature on NSAID-induced gastrointestinal perme-

ability, were carried out. The advantages and disad-

vantages of the various probes and study protocols are

discussed.

Identi®cation of the underlying mechanisms of regu-

latory control of the epithelial tight junction is still

needed. A greater appreciation of the pharmacokinetics

and distribution of NSAIDs, coupled with gastrointesti-

nal permeability studies, may help delineate the

pathogenesis of NSAID-induced gastrointestinal toxic-

ity. Non-invasive tests of gastric, intestinal and colonic

permeability have shown promise in both basic research

and in clinical practice. While such tests could not

replace endoscopy, they may represent clinically useful

techniques for identifying patients who would bene®t

from endoscopy, to assess the response to treatment,

and perhaps to predict the clinical course of disease.

Correspondence to: Dr N. M. Davies, University of Calgary, Faculty of

Medicine, Department of Pharmacology and Therapeutics, Intestinal DiseaseResearch Unit, Calgary, Alberta T2N 4N1, Canada.

Aliment Pharmacol Ther 1998; 12: 303±320.

Ó 1998 Blackwell Science Ltd 303

been associated with numerous side-effects, the most

important in frequency and clinical impact being GI

disturbance.8 NSAID GI pathology accounts for more

than 70 000 hospitalizations and 7000 deaths annu-

ally in the USA.9 Adverse effects in the GI tract have

contributed to the termination of clinical development

and also the withdrawal from the market of several

NSAIDs.8 Epidemiological studies indicate signi®cant

differences in the incidence of various NSAID-induced

adverse effects, including those occurring in the upper

GI tract.6, 9±11

Numerous articles have been published examining the

gastric and duodenal damage caused by NSAIDs.

However, there is often a lack of correlation between

gastric symptoms and gastroscopic evidence of ulcers,

with as many as one-third of patients being completely

asymptomatic.12 Moreover, amongst patients with

upper GI lesions and blood loss, healing of the lesions

is not always accompanied by an improvement in

anaemia, which may suggest the occurrence of NSAID-

induced af¯ictions in more distal sites of the GI tract.13

There is a growing body of evidence that more distal GI

damage may be widespread and of more serious

consequence than previously thought.

The distal intestinal disturbances caused by NSAIDs

have recently received closer attention.14±16 It has been

suggested that the prevalence of lower GI side-effects

may be higher than that detected in the upper GI tract

and may be of major clinical signi®cance.17 In a 1985

epidemiological study, the expected incidence of lower

bowel perforations and bleedings was determined to be

10 and 7 per 100 000, respectively.18 Although the

increased incidence of small intestinal ulceration in

patients prescribed NSAIDs is less commonly clinically

appreciated than those in the stomach or duodenum,

the serious clinical manifestations of the ulcers (bleeding

and perforation) may be life-threatening.19 It has also

been reported that 41% of rheumatoid arthritis (RA)

patients taking NSAIDs with iron de®ciency anaemia

and undiagnosed GI blood loss had evidence of small

intestinal lesions, erosions and ulcers iatrogenically

attributed to NSAIDs upon small bowel enteroscopy.13

Blood loss from the lower GI tract may result in

signi®cant morbidity contributing to the anaemia of RA

patients taking NSAIDs. Vitamin B12 and bile acid

absorption may also be impaired, contributing to

anaemia and increasing morbidity.13, 20 Some studies

have demonstrated that up to 70% of patients taking

NSAIDs chronically develop intestinal in¯ammation

associated with blood and protein loss; on discontinu-

ation of NSAIDs this intestinal in¯ammation may persist

for up to 16 months.21±23 Further studies have shown

that long-term NSAID treatment leads to enhanced

migration of 111indium-labelled leucocytes, predomi-

nantly to the mid-small intestine, which suggests

mucosal in¯ammation of the small bowel. This, together

with evidence of increased faecal 111indium excretion,

provides further evidence that NSAIDs cause intestinal

in¯ammation in a substantial number of patients

chronically receiving these drugs.20, 24, 25 Considering

the extent of world-wide NSAID use, the clinical

manifestations in the distal GI tract (bleeding, perfora-

tion and ulceration) undoubtedly contribute to signi®-

cant morbidity in many patients.

Because NSAIDs have been linked to the development

of serious GI side-effects, numerous strategies have been

employed to reduce this mucosal damage before it

occurs. Various approaches have been taken to this

problem, including the development of prodrugs, once

daily dosing (long t1/2 NSAIDs), and enteric-coated and

modi®ed-release formulations. An alternative approach

has been the concomitant treatment with protective

substances to circumvent NSAID-induced GI side-

effects. Preventative measures evaluated to-date have

utilized a wide variety of pharmacological approaches,

including antisecretory agents (H2-receptor antagonists,

proton pump blockers, anticholinergic agents and

antacids); as well as attempts to increase mucosal

defence (sucralfate, and prostaglandin analogues).

However, none of these approaches has solved the

problem of NSAID-induced GI damage.

In recent years, there have emerged three approaches

to the development of new `GI-safe' NSAIDs. Intensive

efforts are now being made to develop selective inhib-

itors of cyclooxygenase-2 (COX2), assuming that these

agents will inhibit this isoform when it is induced at

sites of in¯ammation, but will not inhibit prostaglandin

synthesis in other tissues such as the stomach, where

cyclooxygenase-1 (COX1) is constitutively expressed.26

Another novel strategy to reduce the GI ulcerogenicity

of NSAIDs that has recently been described is the

incorporation of a nitric oxide (NO) generating moiety

into the NSAID molecule. NO may counteract the

detrimental effects of COX suppression such as main-

taining blood ¯ow, and prevent leucocyte adherence

such that mucosal damage does not occur.27 Finally,

the pre-association of NSAIDs with zwitterionic phos-

pholipids (DPPC±NSAIDs) may reduce the ability of

304 N. M. DAVIES

Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 303±320

NSAIDs to associate with phospholipids in the mucus

gel, and therefore may reduce ulcerogenicity.28

The main clinical goal still remains to solve the

problem of NSAID-induced GI toxicity, with its resultant

morbidity and mortality, while obtaining optimal ther-

apeutic effect. Although there are several alternatives to

traditional NSAIDs emerging (i.e. COX2 inhibitors, NO±

NSAIDs, DPPC±NSAIDs) that hold such promise, any

new therapeutic agent, no matter what the rationale

behind its introduction, must be assumed to induce GI

toxicity until clinically proven otherwise.

TECHNIQUES FOR ASSESSING NSAID-INDUCED

GI DAMAGE

A major problem in the care of patients on long-term NSAID

therapy is the diagnosis of GI complications induced by

these agents. Gastroduodenal endoscopy has become the

gold standard method for assessing NSAID-induced GI

damage, because it has been generally believed that the

side-effects of NSAIDs are usually con®ned to the gastrodu-

odenal mucosa. Endoscopy for the diagnosis of upper

gastrointestinal disease is widely available, precise, sensitive

and easy to perform. However, endoscopy for diagnosis of

upper GI damage induced by NSAIDs is unsuitable as a

routine screening test as it is time-consuming, expensive

and may not be available in all centres.

The majority of patients with endoscopically-deter-

mined NSAID-induced gastric damage are asymptom-

atic.29, 30 Clinical diagnosis of NSAID-induced gastro-

duodenal abnormalities is also associated with

dif®culties such as the determination of the site of

af¯iction and dif®cult distinctions between degrees of

damage. There is little consistency in the published

literature on the type of injury being assessed. The

gastroduodenal lesions associated with NSAIDs may be

described as oedema, erythema, mucosal haemorrhage,

erosions or ulcers. The distinction between erosions and

ulcers is not clear and can vary among clinicians.31

Investigators often give numerical values to each type of

lesion and total them up to obtain a score for each

patient. The Lanza scale has been demonstrated to be

relatively effective, with few inter- and intra-observer

differences. However, this scoring system is also subjec-

tive and therefore susceptible to error and inconsisten-

cies in interpretation.32 For example, in one study, an

ulcer was de®ned as a break in the mucosa greater than

3 mm in diameter.33 This `ulcer' could easily be

described as an erosion by others. Such damage is later

described by the same investigator as `trivial lesions'

and a re-de®nition of an ulcer was suggested to be

damage greater than 5 mm or even 1 cm in diameter.34

Endoscopic detection as a surface view cannot give any

information as to whether the lesion is actually a true

ulcer that penetrates through to the muscularis muco-

sae, unless biopsies are also taken. It may be argued that

an important ulcer is one which produces symptoms

and that can be improved with treatment or on

discontinuing NSAIDs, or that leads to a serious

complication (bleeding, perforation or stricture). Detec-

tion upon endoscopy is usually only demonstrated after

a complication (obstruction, perforation or haemor-

rhage) becomes clinically apparent. It has also been

suggested that a distinction be made between `endo-

scopic' ulcers, seen during routine endoscopic surveil-

lance, and `clinically relevant' ulcers, seen during

investigation of complications, which may provide an

approximation to the problem.31

It is still essential that a means of detecting NSAID-

induced lesions exists before clinically signi®cant

sequelae and hospitalization is required. Since the early

1980s, substantial efforts have been made to develop

non-invasive methods of detecting GI abnormali-

ties.35, 36 As the intercellular junctions of GI epithelial

cells appear to be particularly susceptible to a variety of

noxious agents, they may be the ®rst organelle to suffer

when the energy production of the enterocyte is

compromised. This disruption of intercellular integrity

allows permeation of macromolecules into the GI

mucosa. The degree of GI penetration by passively

absorbed water-soluble molecules is referred to as

permeability. Tests of GI permeability are designed to

assess the functional integrity of the intestinal barrier.

This is accomplished non-invasively by measurement of

urinary recovery of a variety of orally administered

probes. Methods based upon measurement of GI per-

meability have been found to be valuable research tools

and have clinical utility in measuring gastroduodenal,

intestinal and colonic damage induced by NSAIDs in

numerous clinical studies (Table 1).

The value of gastroscopy is that it can identify patients

who are at risk of serious complications and therefore any

non-invasive screening tests must also be able to provide

this information in order to have clinical utility. It is still

important that a means of detecting NSAID-induced

lesions exists before clinically signi®cant sequelae

and hospitalization are required. Gastrointestinal

permeability tests could be used to sequentially follow

REVIEW: NSAID-INDUCED GI PERMEABILITY 305


Table 1. NSAID-induced 51Cr-EDTA intestinal permeability studies

% 51Cr-EDTA

Reference No. Agea Dose (mg) excretion

Bjarnason et al. 6 NR A: Controls 1.94 � 0.51

(1984) 2 B: RA controls 2.07 � 0.48

1 C: OA controls 2.02 � 0.42

1 D: Ibuprofen 400 mg*3 4.47 � 2.27*

1 E: Naproxen 250*2 2.83 � 1.15*

1 250*3 5.175 � 1.01*

2 500 mg nocte 2.02

1 1000 mg 7.21*

1 750 mg 10.92*

1 E: Indomethacin 25*3 3.57*

1 50*2 4.86*

1 75*2 10.4*

1 75 mg nocte 3.59*

1 75 mg 5.45*

1 100 mg supp 5.4 � 1.03*

1 100 mg 10.02*

1 150 mg 8.02*

1 175 mg 4.00*

1 75 mg + salicylate 3 g 5.60*

Bjarnason et al. 14 26±39 A: Control 1.9 � 0.5

(1986) B: Aspirin (1.2 g + 1.2) 2.3 � 0.3

C: Ibuprofen (400 mg + 400 mg) 2.9 � 1.2*

D: Indomethacin (75 + 50 mg) 4.7 � 1.3*

E: Indomethacin (100 mg) supp 4.5 � 0.9*

7 A: Control 2.2 � 0.6

B: Indomethacin (75 mg + 50 mg) 4.6 � 1.5*

C: PGE2 (5 mg) 1.5 � 0.7

D: B + C 6.6 � 4.4*

E: Ranitidine 150 mg

()24, )12, )1, +12 h) + D

5.6 � 3.2*

Jenkins et al. 6 37.2 A: Baseline 1.54 � 0.49

(1988) (5M;1F) (31±56) B: Naproxen 375 mg t.d.s.*7 3.25 � 1.07*

C: Misoprostol 200 lg q.d.s. before + during 2.06 � 0.56

D: B + Misoprostol 200 lg q.d.s. 3.06 � 1.39*

Aabakken et al. 18 median A: Baseline 2.63

(1989) (18M) 25.5 (21±44) B: Naproxen plain tablets 4.42*

C: Baseline 2.86

D: Naproxen enteric-coated tablets 4.14*

E: Baseline 2.06

F: Naproxen coated granules in a capsule 4.18*

Aabakken et al. 17M median A: Baseline 2.6

(1989) (19±32) B: Naproxen 500 mg b.d. 3.4*

C: Naproxen 500 mg b.d. + cimetidine 400 mg

b.d. tablets

3.85*

D: Naproxen 500 mg b.d. + cimetidine 400 mg

b.d. suspension

3.9*

Aabakken et al. 16M median 21 A: Baseline 2.5

(1989) (19±32) B: Naproxen 500 mg b.d. 3.7*

C: Naproxen 500 mg b.d. + sucralfate

2 g b.d.

4.2*

306 N. M. DAVIES


Table 1 (Contd.)

% 51Cr-EDTA


Bjarnason et al. 20 (23±39) A: Baseline 0.76 � 0.07

(1990) (20M) B: Misoprostol 200 lg )16, )12, )8.5, )4,

)1.5 and 5 h

0.66 � 0.08

C: Indomethacin 75 mg )8 h; 50 mg

at )1 h

1.96 � 0.31*

D: Misoprostol and indomethacin combined 1.16 � 0.17#

Aabakken 80 median A: Baseline 2.44

& Osnes (1990) (80M) 25 B: Naproxen (500 + 250 mg) b.d.*7 3.15*

42 (18±44) C: Baseline 2.26

38 D: Naproxen (500 + 500 mg) b.d.*7 3.39*

27 A: Baseline 2.67

Within B: Naproxen (500 + 250 mg) b.d.*7 3.75*

subject C: Baseline 2.64

data D: Naproxen (500 + 500 mg) b.d.*7 4.17*

Aabakken et al. 18 26 A: Naproxen 500 mg + placebo *7 3.1*

(1990) (18M) (23±32) B: Naproxen 500 mg + 20 mg

famotidine *7

3.0*

C: Naproxen 500 mg + 40 mg

famotidine *7

3.1*

Bjarnason et al. 16 32 � 10 A: Baseline 0.51 � 0.16

(1991) (10M:6F) (20±53) B: Carbopol (200 mg q.d.s.*4) 0.61 � 0.20

C: Indo (75 + 75) )12, )1 1.57 � 0.48*

D: Indomethacin + carbopol 1.42 � 0.60*

Bjarnason et al. 12 29 � 2 A: Baseline 0.63 � 0.09

(1991) (6M:6F) B: Indomethacin (50 mg*3)*7 days 1.20 � 0.14*

C: Nabumetone 1g *7 days 0.70 � 0.10*

Davies & 25 med 23 A: Baseline 1.2 � 0.4

Rampton (1991) 16 (20±47) B: Indomethacin 2 mg/kg t.d.s.*7 2.4 � 0.7#

C: Baseline 1.4 � 0.7

9 D: Sulindac 200 mg q.d.*9 1.8 � 0.4*

Jenkins et al. 20 (22±28) 28

(1991) 6 (33±61) 51 A: Control 2.27 � 0.15

9 (45±72) 48 B: Ileostomy 0.45 � 0.08

RA, OA C:NSAID 4.64 � 1.20*

3 Diclofenac (50 mg*2 daily) *

2 Naproxen (500 mg*2 + 250 mg*2 daily) *

2 Flurbiprofen (100 mg*2 + 50 mg*2 daily) *

1 Indomethacin (25 mg*3 daily) *

1 Piroxicam (20 mg *1 daily) *

Bjarnason et al. 12 29 A: Control 0.63

(1992) (6M:6F) B: Indomethacin 50 mg t.d.s.*7 d 1.20*

C: Nambumetone 1 g q.d.*7 d 0.70+

Bjarnason et al. 20 29 � 3 A: Control 5 h 0.62 � 0.3

(1992) (12M:8F) B: Indomethacin (50 + 75) )12, )1 1.54 � 0.19*+

C: Indomethacin (50 + 75) g/c/1:15:

15;)12, )1

1.15 � 0.67*+

D: Indomethacin (50 + 75) g/c/1:10:10,

)12, )1

NR

E: Indomethacin (50 + 75) g/c/1:5:5,

)12, )1

NR



patients at risk of GI disease, such as those receiving

NSAIDs. Through the clinical use of permeability tests it

could also be therapeutically possible to intervene before

clinically detectable GI disease becomes evident or

reactivates.

With the development of GI-safe NSAIDs, the

question may arise as to whether there will be a

need for a screening test for NSAIDs in the future.

Nevertheless, there may be other clinical applications

of gastric permeability tests for other xenobiotics such

as aminobisphosphonates and other diseases that

af¯ict the GI tract, including lymphocytic gastritis,

malaria, portal hypertensive gastropathy and gastric

cancer.

Table 1 (Contd.)

% 51Cr-EDTA


F: Indomethacin (50 + 75) glucose 45:1,

)12, )1

NR

G: Indomethacin (50 + 75) citrate 45:1,

)12, )1

NR

D: Control 0.79 � 0.10+

6 E: Glucose/citrate (500 + 750), )12, )1 0.75 � 0.10+

Davies et al. 40 (22±57) Group 1 A: Baseline 1.12 � 0.29

(1993) (37M:3F) B: Indomethacin (50 mg t.d.s.) + placebo*7 2.60 � 0.78*

C: Baseline 1.10 � 0.39

D: Indomethacin (50 mg t.d.s.) + metronidazole 1.55 � 0.54*

(400 mg b.d.)*7

Group 2 E: Baseline 1.31 � 0.51

F: Indomethacin (50 mg t.d.s.) + placebo*7 2.21 � 0.62

G: Baseline 1.37 � 0.70

H: Indomethacin (50 mg t.d.s.)misoprostol

(200 lg q.d.s.)*7

3.26 � 1.10*

Group 3 I: Baseline 1.48 � 0.54

J: Metronidazole 400 mg b.d.*7 1.15 � 0.70

K: Baseline 1.30 � 0.34

L: Misoprostol 200 lg q.d.s.*7 1.08 � 0.28*

Choi et al. 57 mean 30 A: Baseline 0.42 � 0.17

(1995) (28M:29F) (20±51) B: Diclofenac sodium 50 mg t.d.s.*7 0.51 � 0.28+

21 C: Baseline 0.42 � 0.17

34 D: Diclofenac sodium SR 50 mg t.d.s.*7 0.66 � 0.238

10 E: Baseline 0.39 � 0.14

13 F: Indomethacin 5O mg b.d.*7 0.95 � 0.64*

G: Baseline 0.39 � 0.11

H: Tenoxicam 20 mg q.d.*7 0.39 � 0.10+

Kremer et al. 19 (20±50) A: Baseline 2.7 � 1.14

(1996) 9 B: 8 g of omega-3 fatty acids for

16 weeks and between

2.34 � 3.2

weeks 12 and 16 indomethacin

50 mg t.d.s.

C: Baseline 2.34 � 3.2

D: Corn oil for 16 weeks and between

weeks 12 and 16 indomethacin

2.7 � 1.8

50 mg t.d.s.

a Mean age; range in parentheses, sex (# of M or F), and disease state (OA, RA) when available., Abbreviations: No.�number of subjects or

patients in study; t.d.s.�3 times daily; q.d.s.�4 times daily; q6 h (q12 h)� every 6 (12) hours; q.d.� daily. ABC:1, 2 or 3 ´ 50 mg D40 mL

2.5 mg/mL solution. a� adult; c� children; m�male; f� female; RA� rheumatoid arthritis; SR� sustained release; OA� osteoarthritis;

SpA� spondylarthropathies; IBD� in¯ammatory bowel disease; * not signi®cantly different from baseline; + not signi®cantly different frombaseline; # signi®cantly different from indomethacin alone.

308 N. M. DAVIES


METHODS OF ASSESSING GASTROINTESTINAL

PERMEABILITY

Intestine

Small bowel enteroscopy has been successfully used to

detect small intestinal lesions, erosions and ulcers

attributed to NSAIDs.13 However, the clinical use of

enteroscopy is currently not available in many centres.

Intestinal permeability tests in vivo have been assessed

by a number of analytical techniques. The three most

commonly employed markers are the urinary excretion

following oral ingestion of carbohydrates (i.e. lactulose,

cellobiose and mannitol), ethylene glycol polymers [i.e.

polyethylene glycol (PEG)], and non-degradable radio-

nuclide probes such as 51Cr-EDTA.37±39

The movement of molecules across biological mem-

branes may occur via (i) simple diffusion or (ii) speci®c

transport mechanisms. The speci®c transport mecha-

nisms include those that are carrier mediated such as

(a) facilitated diffusion, (b) exchange diffusion (counter-

transport), (c) active transport and (d) pinocytosis.40

The permeability of the intestine is highly regulated,

re¯ecting at least three distinct unmediated permeation

pathways of mucosal diffusion: (i) the intercellular

junction between adjacent enterocytes, (ii) aqueous

pores in the enterocyte brush border membrane and (iii)

the lipid-soluble rich hydrophobic pathway in the brush

border. In vivo permeability tests assess the functional

integrity of the intestinal barrier.

The requirements of an ideal passive permeability

marker include: it should be non-toxic, absorbed

entirely by passive diffusion, not modi®ed or metabolized

by enzymes, not found in the diet, not produced

endogenously, cleared from the body rapidly and

completely, hydrophilic, limited to the extracellular

compartment, non-immunogenic, and easily and rap-

idly measurable in biological ¯uids with both high

precision and accuracy.41±43 All of the current intesti-

nal permeability markers have advantages and disad-

vantages and none possess all the criteria of an ideal

marker (Table 2). Other than their non-invasive nature,

a distinct advantage of permeability tests is that they

re¯ect the functional state of a major area of the

intestinal mucosa, whereas morphological analysis may

suffer due to sampling errorÐparticularly if the GI

abnormality is randomly distributed.

Polyethyleneglycol (PEG)

Current interest in the measurement of intestinal

permeability originated from the initial work undertak-

en with PEG.41 PEG is a viscous mixture of liquid

polymers; the number corresponds to its average

molecular weight. PEG 400 has recently been exten-

sively employed as a permeability probe.44, 45

After an overnight fast, PEG (1±5 g in 50±100 mL of

water) is ingested and urine is collected, usually from 0

to 6 h.46, 47 However, it has become evident that PEG is

an unsatisfactory probe for measuring intestinal perme-

ability.48 Urinary recovery of PEG polymers is low and

variable following intravenous instillation in humans,

indicating loss to peripheral body compartments.37 PEG

is relatively lipophilic and this is re¯ected in extensive

permeation through the GI mucosal membranes (Fig-

ure 1). PEG is therefore a relatively insensitive marker

for detecting small increases in mucosal permeability

though the intercellular pathway, because the back-

ground permeation is extremely high and small changes

in permeability are not easily detectable.41, 49 Also, the

use of PEG to assess intestinal permeability in a variety

Table 2. Some ideal requirements for an

intestinal permeability marker 51Cr-EDTA

Mono-

saccharides

Oligo-

saccharides PEG

No exposure to radiation a + + +

Non-degradable + a a +

Non-toxic + + + +

Non-metabolized + + + +

No endogenous production + a + +

Complete renal excretion + a + a

Easily and reliably assayed + + + +

Hydrophilic + + + +

Lipophobic + + + a

First-order permeation kinetics + + + +

a See discussion in text.



of disorders have given results in the vast majority of

studies that are contradictory to the differential urinary

excretion of di/monosaccharides and are dif®cult to

interpret.44, 45, 50, 51 Some studies of PEG 400 intestinal

permeability are con¯icting, because both increased and

decreased permeability have been found.52, 53 Further-

more, laborious specimen preparation, an unpleasant

taste, inter-batch variation, and demanding analytical

techniques, also limit the utility of PEG as an intestinal

permeability marker.

Carbohydrates

A number of carbohydrates have been used in studies of

permeability, including the hexoses (i.e. L-rhamnose),

sugar alcohols (i.e. D-mannitol), and the disaccharides

(e.g. lactulose, cellobiose). D-xylose has also been used in

permeability studies but as it can be transported into the

enterocyte by a carrier-mediated process, it is not an

indicator of passive permeability. Xylose absorption also

appears to be reduced after both indomethacin treat-

ment in non-arthritic subjects and in indomethacin-

treated patients with rheumatoid arthritis.54, 55

Most of the currently utilized carbohydrate permeabil-

ity studies employ differential sugar absorption tests, in

which two sugars (usually a mono- and a disaccharide)

are given concomitantly and urinary recovery of each is

determined. In differential sugar tests, patients ingest a

mixture of hyperosmolar sugars (1330 mmol/kg of

water) following an overnight fast, and urine is collected

for 5 h.39, 56 The monosaccharide shows the degree of

permeation through aqueous pores and the disaccha-

ride re¯ects the permeation of the intercellular pathway.

The ratio of the disaccharide to the monosaccharide

gives an index of relative function of the permeability

pathways.43

Travis & Menzies36 have demonstrated that perme-

ation of lactulose and oligosaccharides is temporarily

markedly increased in normal individuals when test

dose osmolarity is increased beyond 1500 mOsm/L.

This effect is evident with most readily absorbed solutes,

but these changes vary in magnitude with each osmotic

®ller and there is also considerable individual variability

in this effect.36 As a consequence there is practical

importance in controlling the osmolarity of test solu-

tions in intestinal permeability studies. The majority of

investigators now use physiological iso-osmolar tests

rather than osmotic ®llers. In order for results to be

compared directly between groups, standardization of

test dose composition is essential in permeability studies.

The use of carbohydrate probes also has some inherent

clinical problems. The osmotic ®llers may affect mucosal

permeability, because hypertonic lactulose test solutions

have been shown to decrease permeability.57 Some

carbohydrates are metabolized by intestinal ¯ora and

the brush border membrane can metabolize cellobiose,

which will lead to an underestimation of permeability.

In addition, rhamnose is incompletely excreted after

intravenous instillation, which may also underestimate

its intestinal permeability. Lactulose and mannitol may

be present in some foodstuffs, and some patients may

excrete minute quantities of endogenously produced

mannitol, which may underestimate intestinal perme-

ability.46, 58 Furthermore, sugar loads can cause abdo-

minal distention, diarrhoea and ¯atulence in some

patients.58 Additionally, quantitative analysis of carbo-

hydrates generally requires speci®c chemical analysis or

lengthy and time-consuming extraction and chromato-

graphic procedures, which are often prohibitive for

routine screening.

Studies using carbohydrate markers have produced

apparently contradictory results. These misunderstand-

ings have arisen because of the lack of insight into the

relative sensitivity of the different methods used to

assess intestinal permeability. For example, some in-

vestigators have reported that permeability measure-

ments for the disaccharide, lactulose, agree closely

(r2 � 0.82±0.98) with the permeability measurements

obtained with 51Cr-EDTA,46, 59 while other investiga-

tors have noted that NSAID-induced permeability as

measured by 51Cr-EDTA excretion did not result in a

Figure 1. 51Cr-EDTA and disaccharides pass exclusively through

the intercellular junctions between enterocytes. Monosaccharide

permeation occurs mainly through aqueous pores whereas PEG

permeation is primarily determined by the lipophilic character of

the brush border membrane.

310 N. M. DAVIES


corresponding increase in mono- or disaccharide per-

meation.56, 60, 61 Subsequently, several reports39, 62

using urinary sugar excretion have con®rmed the initial

results of Bjarnason's group17, 33, 63±69 and have dem-

onstrated abnormalities of intestinal permeability in RA

patients on NSAIDs.

In addition to the theoretical requirements of an ideal

permeability probe (Table 1), the use of excretory ratios

of markers (i.e. lactulose/mannitol; 51Cr-EDTA/man-

nitol; 51Cr-EDTA/L-rhamnose; cellobiose/L-rhamnose) to

detect an alteration in the intestinal barrier may have

advantages over a single marker by minimizing some of

the extramural factors such as intestinal motility

changes. Such extramural factors would affect both

markers identically so that their urinary excretion ratios

are unchanged, resulting in a decrease in the variability

and an increase in the reliability of the intestinal

permeability data. The value of the urine excretion ratio

speci®cally re¯ects alterations in intestinal permeability

and is largely unaffected by pre-mucosal and post-

mucosal determinants of the overall permeability of the

intestine, because each probe acts as an internal

standard for the other.

51Cr-EDTA

51Cr-EDTA was initially used as a marker of glomerular

®ltration and subsequently as a screening test for coeliac

disease.68, 70 51Cr-EDTA incorporates the analytical

advantages of a c-ray emitting isotope in a water-

soluble, highly stable, chelated compound with physi-

cochemical inertness.69 The compound is stable and has

a half-life of 1 month so that aliquots of the radioactive

material can be easily stored.

After an overnight fast, subjects drink a test solution

containing 100 lCi of 51Cr-EDTA in 10±100 mL of

distilled water, followed by 300 mL of water. Subjects

are required to fast for an additional 2 h, after which

they are allowed food and ¯uid. Adequate sensitivity of

the 51Cr-EDTA test seems to increase with a longer

collection period of up to 24 h.38 Alcohol and spicy

foods are prohibited for 3 days before and throughout

each study. Results are expressed as a percentage of the

orally administered test dose excreted in the urine

during this time interval.

The permeation of 51Cr-EDTA has been shown to be

relatively speci®c to the small intestine, given that a

comparison of peroral and intraduodenal instillation

showed no signi®cant differences in the extent of

urinary excretion in both animal and clinical stud-

ies.70±72 However, more recent studies have suggested

that there may be some degree of colonic perme-

ation.61, 73 Nevertheless, it has been suggested that the

percentage of colonic permeation is low because 51Cr-

EDTA is incorporated into faeces, limiting the availabil-

ity for colonic permeation.33 However, if there is

signi®cant epithelial damage to the colonic epithelium

(i.e. in colitis) 51Cr-EDTA permeation may increase. The51Cr-EDTA test has been shown to be reproducible and

the safety, simplicity and accuracy of the procedure

meet all the requirements for a permeability test for

NSAID-induced intestinal permeability studies.

The 51Cr-EDTA test has received criticism for high

inter-individual variability and low sensitivity.70, 74, 75

However, these studies have used small sample numbers

and the reproducibility appears to be increased with a

urine collection over 24 h. Alcohol may profoundly

affect the results of this permeability test, but this is

reversible upon abstinence.76 One may also question

the theoretical possibility that membrane integrity could

be affected by EDTA itself. However, experiments on

animal tissue suggest that the concentrations required

would need to be 1000 times that employed in

permeability tests.77, 78

51Cr-EDTA has also been criticized for being a radio-

active pharmaceutical. The estimated radiation dose of a

100 lCi (3.7 Mbq) dose is 0.12 mSv. In comparison, a

chest X-ray gives 0.05 mSv, abdominal X-ray 1.4 mSv

and the total radiation dose from natural sources is

about 2 mSv/year.43 The effective dose, therefore, is

equivalent and comparable to other standards currently

routinely employed in nuclear medicine.

GASTRODUODENAL DISEASE

Sucrose

More recently, sucrose has been introduced as a marker

of NSAID-induced gastroduodenal damage.79, 80 Su-

crose permeability, unlike endoscopy, is cheap, simple

and readily accepted by patients. Increased urinary

excretion of sucrose after an oral dose indicates

abnormalities in the epithelium of the gastroduodenum.

When entering the lower intestine, sucrose is readily

cleaved to monosugars due to sucrase activity in the

brush border membrane, which makes sucrose unsuit-

able for assessing intestinal permeability because ab-

sorption of intact sucrose is restricted to the upper



gastroduodenal mucosa. Hence, detection of sucrose in

the urine indicates leakage of the GI segments proximal

to sucrase enzyme activity (i.e. stomach and duode-

num). A study using balloon pyloric occlusion has

independently con®rmed that the major site of increased

sucrose permeability is indeed the stomach.81

A test solution containing 100 g of sucrose in 350 mL

of water is consumed at bedtime after at least a 3-h fast.

All urine is collected from the subjects in a pre-weighed

container containing 5 mL of 10% thymol in methanol

as a preservative.79

It has been demonstrated that sucrose permeability

correlates with severity of the upper gastroduodenal

damage and increases with repetitive exposure of

NSAIDs.79±84 Increased sucrose permeability in man

may be useful in predicting the presence of clinically

signi®cant gastric disease seen upon endoscopy.80 The

sensitivity for detecting mild gastritis, duodenitis, severe

gastritis and gastric ulcers was 16, 29, 69 and 84%,

respectively.80 The speci®city for predicting an abnor-

mal endoscopy was 96%.80 Another study has reported

that for mild gastritis, duodenitis and severe gastritis the

sensitivity for detection was 17, 29 and 68%, respec-

tively; no gastric ulcers were seen in this latter study.81

Animal studies in dogs indicate healing of gastric

epithelial damage can also be monitored through the

use of sequential measurements of sucrose permeabil-

ity.83 Furthermore, the sucrose probe has been shown

to be able to detect differences in both NSAID formu-

lation and dose.85, 86 Moreover, economic analysis of

the sucrose test indicates that sucrose permeability is an

attractive means of stratifying elderly RA patients who

are at risk of developing complications from chronic

NSAID use.87

Patients with oesophagitis did not have elevated

sucrose permeability compared to controls; this may

be due to the small oesophageal surface area and a short

contact time with the diseased mucosa.80 In addition,

duodenal disease was erratically predicted by increased

sucrose permeability, which may be due to rapid

sucrose degradation within the duodenum, the short

contact time of sucrose solution within the affected

duodenal tissue and sucrase activity.80 Further studies

that modify the absorption rate of the sucrose test

solution could possibly be adaptable to detection of

severe oesophagitis or duodenal disease.

As indicated in the preliminary manuscript by Medd-

ings et al.,79 sucrose is a suitable and selective probe for

the gastroduodenum in a healthy intestine without

disaccharide de®ciency. Any disease state or xenobiotic

which affects sucrase activity, may affect the interpre-

tation of the permeability data and is a limitation to its

diagnostic use. Indeed, studies have utilized alterations

in sucrose urinary excretion for non-invasive in-

vestigation of intestinal disaccharidase activity caused

by a-glucosidase inhibition, primary hypolactasia and

coeliac disease.88

CLINICAL STUDIES OF NSAID-INDUCED

GI PERMEABILITY

There are few published clinical studies on NSAID-

induced gastroduodenal permeability owing to the

novelty of the sucrose probe. However, this technique

has been independently veri®ed by several groups and

has uniformly demonstrated the ability to detect

permeability changes induced by acetylsalicylic acid

and other NSAIDs.80±83, 87, 89 Furthermore, random-

ized, prospective trials evaluating sucrose permeability

in long-term NSAID users are still required to determine

the potential clinical utility.

NSAID-induced increases in intestinal permeability

have been extensively studied in humans. These

permeability changes have been detected by the oral

administration of probes such as 51Cr-EDTA, lactulose,

cellobiose and PEG. 51Cr-EDTA has been the most

frequently used probe in NSAID-induced permeability

studies. Table 2 summarizes all the available NSAID-

induced permeability data in humans using 51Cr-EDTA

as a probe. The human permeability studies have

commonly used indomethacin as the prototypical

NSAID. In general, the studies show an increase from

baseline of 51Cr-EDTA excretion in urine which is dose-

dependent and appears to be antagonized by concom-

itant misoprostol, glucose/citrate and metronidazole,

but not by H2-antagonists, in healthy volunteers and in

arthritic patients.63, 67, 90

The frequency distribution of baseline permeability

values in 65 healthy male volunteer humans from 0 to

24 h are also positively skewed with a median of 2.45%

excretion (95% CI: 2.11±2.86).38 In humans, there is a

good linear relationship between the 0±6 and 6±24 h

cumulative excretion of 51Cr-EDTA.33 Furthermore,

there does not appear to be any gender- or age-related

differences in baseline permeability values in human

studies.91, 92

The original study of NSAID-induced intestinal perme-

ability was undertaken in healthy subjects after

312 N. M. DAVIES


ingestion of two doses of aspirin (1.2 and 1.2 g),

ibuprofen (400 and 400 mg) and indomethacin (75

and 50 mg) at midnight and 1 h before a 51Cr-EDTA

permeability test the following day.17 Intestinal perme-

ability increased signi®cantly from control levels follow-

ing each drug and, in this limited example, the effect

was correlated with NSAID potency to inhibit cycloox-

ygenase in vitro. However, no estimation of systemic or

tissue cyclooxygenase-1 or -2 inhibition was attempted

in this study. Intestinal permeability also increased to a

similar extent after oral and rectal administration of

indomethacin, suggesting that this effect of NSAIDs may

be systemically mediated and/or that biliary excretion is

of importance.33

NSAIDs inhibit cyclooxygenase and therefore inade-

quate prostaglandin generation is derived from fatty

acids by the damaged cell membranes, contributing to

GI ulceration.15 Bjarnason and co-workers ®rst exam-

ined the in¯uence of concomitant prostaglandin admin-

istration on indomethacin-induced permeability chan-

ges with prostaglandin E2, a naturally occurring

prostaglandin, which did not seem to reverse perme-

ability changes. This lack of effect was postulated to be

due to the instability of the preparation. However,

prostaglandin E2 itself signi®cantly decreased baseline

permeation of 51Cr-EDTA.17 Misoprostol (a prostaglan-

din E1 analogue) alone demonstrated little or no effect

on permeation of 51Cr-EDTA,63, 90 however, coadmin-

istered with indomethacin, misoprostol in high doses for

short periods protected the small bowel mucosa from

the effects of indomethacin, as re¯ected by decreasing

indomethacin-induced increased intestinal permeation

of 51Cr-EDTA. Rioprostol, a prostaglandin analogue

given in small doses at the same time as indomethacin,

has a maximally protective action, however, the

excretion values were still signi®cantly higher than

baseline.43 The permeation of other markers (i.e. 3-O-

methyl glucose, D-xylose and L-rhamnose) was not

affected by indomethacin. Conversely, a lack of reduc-

tion of indomethacin-induced intestinal permeability

with misoprostol has subsequently been demonstrat-

ed.90 In this study only 800 lg misoprostol was

administered every 24 h for 150 mg doses of in-

domethacin. In addition, the NSAID and the prostag-

landins were administered at different times in this

study so that the intestinal protection may not have

been evident at the site of absorption, whereas in the

initial study 1200 lg misoprostol was administered

over 20 h with 125 mg indomethacin given during the

last 12 h.17 These studies therefore suggest that the

protective effects of misoprostol against indomethacin-

induced intestinal permeability may be dose-dependent

and/or that intestinal permeability may only be partial-

ly mediated by reduced mucosal prostaglandins.

Sulphasalazine and metronidazole have been clinically

used to reduce NSAID-induced enteropathy.93, 94 The

effects of indomethacin treatment (50 mg three times a

day) for 1 week with coadministered metronidazole

400 mg twice a day signi®cantly reduced in-

domethacin-induced permeability changes.90 This may

suggest a role for intestinal bacteria in the pathogenesis

of the initial permeability increase induced by NSAIDs.

A two-stage process in NSAID-induced intestinal dam-

age has been suggested.90 Initially, there is super®cial

and reversible mucosal damage, probably directly

related to NSAID effects on local prostaglandin depletion

but independent of luminal contents. The second stage

is independent of direct drug effects but follows if initial

damage to mucosal defences is not prevented or

reversed. Due to the increased epithelial permeability,

harmful luminal contents, including bacterial ¯ora,

have increased access to the GI mucosa and this may

pave the way for more severe GI damage and the

development of NSAID enteropathy.

The ability of the 51Cr-EDTA test to detect an increase

in intestinal permeability, which resulted from admin-

istration of two different doses of naproxen, has been

reported.71 There was a statistically signi®cant differ-

ence between the median increase as a percentage of

the baseline excretion for 750 mg naproxen (19%), and

1000 mg naproxen (68%). Misoprostol did not appear

to protect against naproxen-induced increased intestinal

permeability.95 However, the possibility of a dose-

dependent protective effect upon higher doses of mi-

soprostol was not examined. In addition, the small

sample numbers involved in this study (n � 6) may

have been inadequate for ®rm conclusions from these

results. The protective effects of sucralfate against

NSAID-induced GI damage have also been shown to

be con®ned to the upper gastroduodenum, because

sucralfate did not provide protection from naproxen-

induced permeability changes in the small intestine.96

Some NSAIDs are formulated as prodrugs that are

inactive as COX inhibitors until after absorption; it has

been suggested that they might cause less intestinal

damage than other NSAIDs.97 After a 1-week treat-

ment period of sulindac 200 mg daily there was no

apparent increase in intestinal permeability above



baseline, whereas an indomethacin treatment of 2 mg/

kg/day in three divided doses increased 51Cr-EDTA

permeation. Similar results have recently been reported

with another prodrug NSAID, nabumetone.65 After

taking nabumetone, 1 g at midnight for 7 days,

nabumetone did not appear to induce an increase in51Cr-EDTA permeability above baseline, whereas in-

domethacin treatment signi®cantly enhanced 51Cr-

EDTA permeation. These results could be interpreted

to suggest that the systemically mediated effect of

NSAIDs is weak and that the main damage is sustained

after drug absorption or excretion in bile. However, a

major contribution to local effects of NSAIDs in

inducing permeability changes contradicts a previous

assertion of a major systemic effect being responsible for

NSAID-induced intestinal permeability after rectal ad-

ministration of NSAIDs.33 These results may also be

attributed to either intestinal permeability being re¯ec-

tive of mechanisms other than reduction of prostaglan-

dins such as diversion of arachidonic acid metabolism

down the lipoxygenase pathway, and oxy-radical pro-

duction or direct drug cytotoxicity, or the differing

pattern of biliary excretion of nabumetone (0%),

sulindac (4%) and indomethacin (36%).98, 99 In addi-

tion, the sample numbers in these studies are small and

no dose±response relationship with this effect were

mentioned. Moreover, in the Bjarnason study65 the

collection period was only 5 h. Aabakken suggests that

a 24 h collection period increases the sensitivity of the

test.38 Furthermore, there was a trend for nabumetone

to increase permeability from baseline in several

subjects, which may reach statistical signi®cance with

a larger sample size. A recent abstract from a separate

laboratory has suggested that nabumetone increased

intestinal permeability to the same degree as in-

domethacin.100 However, these studies all used different

methods for assessing intestinal permeability, which

vary in their sensitivity; this may account for the

apparent discrepancies.

In addition to inhibiting prostaglandin synthesis it

has been suggested that NSAIDs may inhibit glycolysis

and the tricarboxylic acid cycle resulting in inhibition

of oxidative phosphorylation and damage to the

enterocyte resulting in a depletion of cellular

ATP.17, 67 The consequence of reduced ATP produc-

tion is a collapse of the cytoskeleton and, therefore,

intercellular tight-junction regulation is disrupted.

Indomethacin administered as 50 or 75 mg increased

intestinal permeability, whereas a formulation of

indomethacin containing 15 mg glucose and 15 mg

citrate to each milligram of indomethacin prevented an

increase in intestinal permeability above baseline

values.67 Unfortunately, no further clinical studies

have validated these claims. Conversely, the NSAID

azapropazone, through its incorporation into a glu-

cose/citrate formulation in proportions of 1:1:1, dem-

onstrated no signi®cant reduction in GI microbleed-

ing.101

In a validated rat model of gastrointestinal perme-

ability,72, 85, 102, 103 the ameliorative effect of orally

administered glucose/citrate on indomethacin-induced

intestinal permeability was examined after subcutane-

ous administration of indomethacin and oral adminis-

tration of glucose/citrate.104 The lack of protection of

glucose/citrate given orally when indomethacin is

administered subcutaneously suggests a possible pre-

systemic and, perhaps, physicochemical interaction.

No reduction in the indomethacin bioavailability in

humans was evident upon glucose/citrate administra-

tion.67 In this pharmacokinetic study the in-

domethacin and glucose/citrate formulation was in-

gested with 100 mL of water, whereas in their

intestinal permeability study, the indomethacin and

glucose/citrate was administered with only 50 mL of

water, which might have increased the dissolution of

the formulation in the pharmacokinetic study. In

Bjarnason's pharmacokinetic study there was a 5

and 17% reduction in the AUC and Cmax for the

indomethacin and glucose/citrate formulation, respec-

tively. This difference was, however, not statistically

signi®cant. In Bjarnason's permeability study the 51Cr-

EDTA excretion, although signi®cantly higher for

indomethacin alone, gave only small differences be-

tween the two formulations; 1.15 � 0.15% vs.

1.54 � 0.19% for indomethacin and glucose/citrate

(1:15:15) control and indomethacin treated subjects,

respectively. Bjarnason et al.15 have more recently

indicated that this cytoprotective effect of in-

domethacin and glucose/citrate to prevent permeability

changes and enteropathy is not evident upon repetitive

administration of the indomethacin and glucose/citrate

formulation.17 It is not stated, however, if this new

study found any cytoprotective effect after a single

indomethacin and glucose/citrate dose. If there is no

long-term protection then it is likely that biliary

secretion and systemic concentrations are responsible

for this effect. Further independent studies are required

to reconcile these discrepancies.

314 N. M. DAVIES


Although the deleterious effects of NSAIDs in the

intestine are becoming more common, very few studies

have examined the possible protective measures in the

distal intestine. Furthermore, differentiation between the

gastric and intestinal manifestations of NSAIDs has been

largely ignored. Hence, it is not known if the suggested

schemes for upper gastroduodenal protection also allevi-

ates NSAID-induced intestinal lesions. Aabakken's group

have examined the use of the H2-antagonists (cimetidine

and famotidine) and sucralfate, none of which seem to

possess any apparent protective or antagonizing effect on

naproxen-induced intestinal permeability.105, 106

In addition, in a latin-square crossover study, naproxen

500 mg twice daily for 7 days as plain tablets, enteric-

coated tablets or enteric-coated granules in capsules was

administered to healthy male volunteers. All formula-

tions induced a signi®cant increase in 51Cr-EDTA

permeability, but no statistical differences were detected

between them. A considerable inter-individual variation

was seen; however, it appears that the median urinary

excretion values for the enterogranulate capsules and

the enterocoated tablets were higher than after plain

tablets.107 The effect of modi®ed-release formulations on

NSAID-induced permeability has not been adequately

addressed in other clinical studies. The results of the

intestinal permeability of the sustained-release product

appear to be more variable than the regular release

product, possibly due to the sustained release of drug and

its continuous presence within the intestinal tract which

may induce more local distal intestinal damage in

addition to the systemically mediated effects. These data

are consistent with those reported by Choi et al.,108 who

found increased intestinal permeability with a sustained-

release formulation of diclofenac but did not see a

statistically signi®cant increase in intestinal permeability

with regular release diclofenac. These observations also

appear to agree with clinical observations of distal

intestinal damage induced by sustained release and

enterocoated NSAIDs. Evidence for pre-systemic distal

intestinal damage has come from the osmotically

activated slow-release formulation of indomethacin

(Osmosin; Merck-Sharpe and Dohme, UK) no longer

commercially available. Osmosin capsules were located

at the site of perforating colonic and ileal ulcers and free

in the peritoneal cavity.109 Furthermore, a more recent

report has suggested the location of possible diclofenac

pill fragments at the site of ulceration and strictures.110

This may lead to high local concentrations in the ileum

and colon, inducing distal GI damage by NSAIDs.

Although the more distal intestinal manifestations of

sustained-release NSAID formulations have been largely

ignored, the likelihood of its increased occurrence with

more frequent use of NSAID medication has been

previously predicted.111 Cost containment of pharma-

ceuticals is topical and the therapeutic rationale behind

enteric-coated and sustained-release formulations in

terms of GI side-effects is not clear-cut. These data

suggest that sustained-release NSAIDs do not solve the

problem of NSAID-induced GI toxicity but merely shift

the problem to a more distal site within the GI tract.

Mielants et al.91 report that there was no signi®cant

difference in intestinal permeability between patients

taking NSAIDs and patients taking corticosteroids. This

further suggests that alteration of intestinal permeabil-

ity may not only be accounted for by an inhibition of

mucosal COX activity but that other pathways in the

arachidonic acid cascade might be implicated.

It also appears that the effect of NSAIDs on increasing

intestinal permeability differs markedly from their

potency to cause gastric damage. Aspirin has been

shown to induce gastroduodenal permeability chan-

ges79, 82, 83 and is well-known to induce upper gastro-

duodenal damage. However, intestinal damage for

aspirin, measured as increased intestinal permeability,

has been shown to be minimal.17, 88 Conversely, it has

also been suggested that aspirin increased intestinal

permeability in a limited number of patients. However,

the type of formulation and dose administered was not

mentioned in this latter study.112 The lack of effect of

aspirin on intestinal permeability may be due to the

rapid absorption of aspirin from the upper part of the

gastroduodenum and its ef®cient hydrolysis to salicylic

acid and lack of enterohepatic recirculation which limits

both direct exposure of the more distal intestine to the

drug and the availability of aspirin for systemic

distribution into the intestinal mucosa. Salicylic acid is

a very weak inhibitor of COX and has also been shown

to be ineffective in inducing leucocyte adherence to

the vascular endothelium.113 The concentrations re-

quired for 50% inhibition of COX1 have been found to be

0.3 and 35 mg/L for aspirin and salicylic acid,

respectively.114

Omega-3 fatty acid (®sh oil) ingestion inhibits both

neutrophil LTB4 release and production of platelet

activating factor, which have been implicated in the

pathogenesis of gastrointestinal ulceration.115 The

potential protective effects of omega-3 fatty acid inges-

tion in subjects consuming NSAIDs did not demonstrate



any signi®cant differences in endoscopic gradings of

visible changes in either the stomach or duodenum and

small intestinal permeability changes as assessed by51Cr-EDTA also showed no difference between patients

consuming ®sh oil or corn oil.116

It has been postulated that there may be racial

differences in susceptibility to NSAID adverse reactions.

In 12 healthy volunteers of Afro-Caribbean (AC), Asian

(As) and Caucasian (Cs) origin the baseline differential

excretion of lactulose/L-rhamnose was 0.035 � 0.004,

0.12 � 0.046, 0.058 � 0.013 in the Cs, As and AC

groups, respectively, with a signi®cant difference be-

tween the AC and Cs groups. Following two 75 mg

doses of indomethacin, the increase was signi®cant in

the Cs and AC groups. This initial study suggests that

there is a difference in intestinal permeability between

racial groups. The non-Caucasians had increased per-

meability which may be the basis of racial variation in

adverse effects to NSAIDs.117 Further studies are

obviously required in the light of these ®ndings.

Unfortunately, due to the ethical constraints of repeat-

ed administration of radiolabelled compounds in hu-

mans and the technical dif®culty of access to the human

distal intestine these studies in humans have been

performed in the absence of any pharmacokinetic

considerations and, thus, neither the time-course of

these changes nor their relationship to drug concentra-

tion in plasma or GI tissues have been established.

Furthermore, complete characterization of the dose±

effect relationship for these NSAIDs has not been

described due to maximum ethical daily dosage regu-

lations. However, it appears that the relative effect of

indomethacin on intestinal permeability is short-lived,

with restoration of intestinal integrity within a week of

the last ingested dose.65 This contrasts with that seen in

NSAID enteropathy where in¯ammation may persist for

over 16 months after stopping NSAIDs.21

COLONIC DISEASE

51Cr-EDTA, unlike lactulose, is resistant to degradation

by bacteria in the lower intestine.61, 73 The permeation

of ingested 51Cr-EDTA is higher than lactulose in

normal adults, however, there are no signi®cant

differences in patients with ileostomies.61, 73 It has been

suggested that the simultaneous administration of

lactulose and 51Cr-EDTA may enable changes in colonic

permeability to be distinguished from changes in the

small intestine.73, 118

Further advances in gastrointestinal permeability de-

tection are still possible in both the basic and clinical

sciences. Recently, Meddings et al.119, 120 have demon-

strated the basic and clinical utility of sucralose as a

non-degradable sugar and as a suitable non-invasive

marker of colonic disease which appears to correlate

with disease severity. Utilizing sucrose, lactulose/man-

nitol and sucralose probes, respectively, non-invasive

detection of gastric, enteric or colonic damage in a single

test can be made. Sucralose is an attractive alternative to51Cr-EDTA for measuring colonic disease, because the

latter radioactive probe possesses ethical restrictions for

routine or serial tests, especially in children. Either oral

or rectal administration of sucralose could be used and

the formulation of a sucralose enema or foam is an

intriguing concept that could conceivably be instilled in

patients during a colonoscopy procedure to site-specif-

ically evaluate colonic permeability.

Although rare, NSAIDs can also induce mucosal

damage in the large intestine.16 In addition, NSAIDs

and selective COX2 inhibitors can cause reactivation of

in¯ammatory bowel disease.16, 121 The development of

selective probes of colonic permeability may have both

basic and clinical applications in the study of NSAID

toxicity in the large bowel. No clinical studies to date

have assessed colonic permeability in patients with

in¯ammatory bowel disease who are taking NSAIDs.

CONCLUSIONS

Gastrointestinal permeability tests have demonstrated

utility in both basic and clinical research in the

investigation of various intestinal diseases including

NSAID-induced alterations. An implicit advantage of

permeability tests is that they can site-speci®cally re¯ect

functional integrity over a major area of the intestinal

mucosa and sequential permeability tests may allow

non-invasive assessment of cytoprotection and prophy-

laxis approaches, as well as healing of the intestinal

barrier. These tests are safe, well tolerated, reproducible

and easy to perform and because of their non-invasive

nature can easily be applied to diagnostic screening,

research, and complement the use of invasive investi-

gations of gastrointestinal disease such as radiology,

biopsy and endoscopic procedures. Future research

should determine whether the use of gastrointestinal

permeability tests could prove cost-effective by reducing

endoscopic and radiologic workload through screening

and by selecting patients likely to bene®t from further

316 N. M. DAVIES


invasive procedures and to assess clinical progress and

response to treatment. The acceptance of these tech-

niques remains to be determined after their clinical

reliability is evaluated by primary care physicians.

REFERENCES

1 Koutsos MI, Shiff SJ, Rigas B. Can nonsteroidal anti-in¯am-

matory drugs be recommended to prevent colon cancer in

high risk patients? Drugs Aging 1995; 6(6): 421±5.

2 Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of

indomethacin in Alzheimer's disease. Neurology 1993; 43:

1609±11.

3 Blower PR. Nonsteroidal anti-in¯ammatory drugs. Br

J Rheumatol 1993; 32(Suppl. 4): 35±8.

4 Baum C, Kennedy DL, Forbes MB. Utilization of nonsteroidal

antiin¯ammatory drugs. Arth Rheum 1985; 28: 686±92.

5 Epstein AM, Read JL, Winickoff R. Physician beliefs, atti-

tudes, and prescribing behavior for anti-in¯ammatory drugs.

Am J Med 1984; 77: 313±8.

6 Wilkens RF. The selection of a nonsteroidal antiin¯amma-

tory drug. Is there a difference? J Rheumatol 1992;

19(Suppl.36): 9±12.

7 Myers ABR. Salicin in acute rheumatism. Lancet 1876; 2:

676±7.

8 Rainsford KD. Introduction and historical aspects of the side-

effects of anti-in¯ammatory analgesic drugs. In: Rainsford

KD, Velo JP, eds. Side-effects of Anti-in¯ammatory Drugs.

Part 1: Clinical and Epidemiological Aspects. Lancaster: MTP

Press, 1987: 3±26.

9 Fries JF. NSAID gastropathy: Epidemiology. J Musculoskele-

tal Med 1991; 8(2): 21±8.

10 Committee on the Safety of Medicines. Non-steroidal anti-

in¯ammatory drugs and serious gastrointestinal adverse

reactions-2. Br Med J 1986; 292: 1190±1.

11 Giercksky K-E, Huseby G, Rugstad H-E. Epidemiology of

NSAID-related gastrointestinal side effects. Scand J Gastro-

enterol 1989; 24(Suppl. 163): 3±8.

12 Silvoso G, Ivey KJ, Butt J. Incidence of gastric lesions in

patients with rheumatic disease on chronic aspirin therapy.

Ann Intern Med 1979; 91: 517±20.

13 Morris AJ, Wasson LA, Mackenzie JF. Small bowel enteros-

copy in undiagnosed gastrointestinal blood loss. Gut 1992;

33: 887±9.

14 Aabakken L. Non-steroidal anti-in¯ammatory drugsÐthe

extending scope of gastrointestinal side-effects. Aliment

Pharmacol Ther 1992; 6: 143±62.

15 Bjarnason I, Hayllar J, Macpherson AJ, et al. Side effects of

nonsteroidal anti-in¯ammatory drugs on the small and large

intestine. Gastroenterology 1993; 104: 1832±47.

16 Davies NM. Toxicity of nonsteroidal anti-in¯ammatory drugs

in the large intestine. Dis Colon Rectum 1995; 38(12):

1311±21.

17 Bjarnason I, Williams P, Smethurst P, et al. Effect of non-

steroidal anti-in¯ammatory drugs and prostaglandins on the

permeability of the human small intestine. Gut 1986; 27:

1292±7.

18 Langman MJS, Morgan L, Worall A. Use of antiin¯amma-

tory drugs by patients admitted with small or large bowel

perforations and haemorrhage. Br Med J 1985; 290: 347±

9.

19 Allison MC, Howatson AG, Torrance CJ, et al. Gastroin-

testinal damage associated with the use of nonsteroidal

antiin¯ammatory drugs. N Engl J Med 1992; 327(11),

751±6.

20 Davies NM, Jamali F, Skeith KJ. Non-steroidal antiin¯am-

matory drug (NSAID)-induced enteropathy and severe

chronic anemia in a patient with rheumatoid arthritis. Arth

Rheum 1996; 39(2): 321±4.

21 Bjarnason I, Zanelli G, Smith T, et al. Nonsteroidal antiin-

¯ammatory drug-induced intestinal in¯ammation in hu-

mans. Gastroenterology 1987; 93: 480±9.

22 Bjarnason I, Prouse P, Smith T, et al. Blood and protein loss

via small intestinal in¯ammation induced by non-steroidal

anti-in¯ammatory drugs. Lancet 1987; 2: 711±14.

23 Bjarnason I, Zanelli G, Smith T, et al. The pathogenesis and

consequence of non-steroidal anti-in¯ammatory drug in-

duced small intestinal in¯ammation. Scand J Rheumatol

1987; Suppl. 64: 55±62.

24 Bjarnason I, So A, Levi AJ, et al. Intestinal permeability and

in¯ammation in rheumatoid arthritis: Effects of non-steroi-

dal anti-in¯ammatory drugs. Lancet 1984; 2: 1171±3.

25 Rooney PJ, Jenkins RT, Smith KM, et al. 111Indium-labelled

polymorphonuclear leucocytes scans in rheumatoid arthri-

tisÐan important clinical cause of false positive results. Br

J Rheumatol 1986; 25: 167±70.

26 Mitchell JA, Akarasereenont P, Thiemermann C, et al. Se-

lectivity of nonsteroidal antiin¯ammatory drugs as inhibi-

tors of constitutive and inducible cyclooxygenase. Proc Natl

Acad Sci USA 1993; 90: 11693±7.

27 Wallace JL, Reuter B, Cicala C, et al. Novel nonsteroidal anti-

in¯ammatory drug derivatives with markedly reduced ul-

cerogenic properties in the rat. Gastroenterology 1994; 107:

173±9.

28 Lichtenberger LM, Wang ZM, Romero JJ, et al. Non-steroidal

anti-in¯ammatory drugs (NSAIDs) associate with zwitter-

ionic phospholipids: insights into the mechanism and re-

versal of NSAID-induced gastrointestinal injury. Nat Med

1995; 1: 154±8.

29 Jaszewski R. Frequency of gastroduodenal lesions in

asymptomatic patients on chronic aspirin or non-steroidal

anti-in¯ammatory drug therapy. J Clin Gastroenterol 1990;

12(1): 10±13.

30 Pounder R. Silent peptic ulceration: Deadly silence or golden

silence. Gastroenterology 1989; 96: 626±31.

31 Walt RP. Misoprostol for the treatment of peptic ulcer and

antiin¯ammatory-drug-induced gastroduodenal ulceration.

N Engl J Med 1992; 327(22): 1575±80.

32 McCarthy DM. Nonsteroidal antiin¯ammatory drug-induced

ulcers: management by traditional therapies. Gastroenter-

ology 1989; 96: 647±55.



33 Graham DY, Argawal NM, Roth SH. Prevention of NSAID-

induced gastric ulcer with misoprostol: multicentre, double-

blind, placebo-controlled trial. Lancet 1988; 2: 1277±80.

34 Graham DY. Famotidine to prevent peptic ulcer caused by

NSAIDs. New Engl J Med 1996; 335: 1322 [Letter].

35 Bjarnason I, Macpherson A, Hollander D. Intestinal perme-

ability: an overview. Gastroenterology 1995; 108: 1566±

81.

36 Travis S, Menzies I. Intestinal permeability: functional as-

sessment and signi®cance. Clin Sci 1992; 82: 471±88.

37 Tagesson C, SjoÈdahl R. Passage of molecules through the

wall of the gastrointestinal tract. Urinary recovery of dif-

ferent-sized polyethylene glycols after intravenous and in-

testinal deposition. Scand J Gastroenterol 1984; 19: 315±

20.

38 Aabakken L. 51Cr-Ethylenediaminetetraacetic acid absorp-

tion test: methodological aspects. Scand J Gastroenterol

1989; 24: 351±8.

39 Juby LD, Rithwell J, Axon ATR. Lactulose/mannitol test: an

ideal screen for celiac disease. Gastroenterology 1989; 96:

79±85.

40 Csaky TZ. Factors involved in the integrated mechanism of

intestinal absorption. In: Advances in Physiological Sci-

ences. Proceedings of the 28th International Congress of

Physiological Sciences, Budapest. Oxford: Pergamon, 1981;

22±33.

41 Chadwick VS, Phillips SF, Hoffman AF. Measurements of

intestinal permeability using low molecular weight poly-

ethylene glycols (PEG 400) I. Chemical analysis and bio-

logical properties of PEG 400. Gastroenterology 1977; 73:

241±6.

42 Cooper BT. Small intestinal permeability in clinical practice.

J Clin Gastroenterol 1984; 6: 499±501.

43 Bjarnason I, Peters TJ, Levi AJ. Intestinal permeability:

Clinical correlates. Dig Dis 1986; 4: 83±92.

44 Smith MD, Brooks PM. Increased bowel permeability in an-

kylosing spondylitis and active RA. Aust NZ J Med 1984;

14(Suppl. 1): 345±6.

45 Parke AL, Fagan EA, Chadwick VS, et al. Gut permeability in

SjoÈgren's syndrome, RA, and coeliac disease. Ann Rheum

Dis 1983; 42: 216.

46 Maxton DG, Bjarnason I, Reynolds AP, et al. Lactulose 51Cr-

labelled ethylenediaminetetra-acetate, L-rhamnose and

polyethylene glycol 500 as probe markers for assessment in

vivo of human intestinal permeability. Clin Sci 1986; 71:

71±80.

47 FaÈlth-Magnuson K, Jansson G, Stenhammar L, et al. Intes-

tinal permeability assessed with different-sized polyethylene

glycols in children undergoing small-intestinal biopsy for

suspected celiac disease. Scand J Gastroenterol 1989; 24:

40±6.

48 Peters TJ, Bjarnason I. Uses and abuses of intestinal per-

meability measurements. Can J Gastroenterol 1988; 2(3):

127±32.

49 Ukabam SO, Cooper BT. Small intestinal permeability to

mannitol, lactulose and polyethylene glycol 400 in coeliac

disease. Dig Dis Sci 1984; 29: 809±16.

50 Skoldstam L, Larsson L, Lindstrom FD. Effects of fasting and

lactovegetarian diet on rheumatoid arthritis. Scand

J Rheumatol 1979; 8: 249±55.

51 Sundquist T, Magnusson KE, SjoÈdahl R, et al. Passage of

molecules through the wall of the gastrointestinal tract. II.

Application of low-molecular weight polyethylene glycol and

a deterministic mathematical model for determining intes-

tinal permeability in man. Gut 1980; 21: 208±14.

52 Hollander D, Vadheim CM, Bretholz E, et al. Increased in-

testinal permeability in patients with Crohn's disease and

their relatives. Ann Intern Med 1986; 105: 883±5.

53 Magnusson K-E, Sundquist T, SjoÈdahl R, et al. Altered in-

testinal permeability to low-weight polyethylene glycols

(PEG 400) in patients with Crohn's disease. Acta Chir Scand

1983; 149: 323±7.

54 Kendall MJ, Hawkins CF. Xylose test; effect of aspirin and

indomethacin. Br Med J 1971; 1(5748): 533±6.

55 Dyer NH, Kendall MJ, Hawkins CF. Malabsorption in rheu-

matoid arthritis. Ann Rheum Dis 1971; 30: 626±30.

56 Struthers GR, Andrews DJ, Gilson RJR, et al. Intestinal per-

meability. Lancet; 1985; 2: 587±8.

57 Bjarnason I, Peters TJ, Veall N. 51Cr-EDTA test for intestinal

permeability. Lancet 1984; 2: 523.

58 Hamilton I, Cobden I, Rothwell J, et al. Intestinal perme-

ability in coeliac disease. The response to gluten with-

drawal and single dose gluten challenge. Gut 1982; 23:

202±10.

59 Behrens RH, Szaz KF, Northrop C, et al. Radionuclide tests

for assessment of intestinal permeability. Eur J Clin Invest

1987; 17: 100±5.

60 Bjarnason I, Peters TJ, Veall N. A persistent defect in intes-

tinal permeability in coeliac disease demonstrated by a 51Cr-

labeled EDTA absorption test. Lancet 1983; 1: 323±5.

61 Jenkins AP, Trew DR, Crump BJ, et al. Do non-steroidal anti-

in¯ammatory drugs increase colonic permeability? Gut

1991; 32: 66±9.

62 O'Mahoney S, Ferguson A. Small intestinal mucosal pro-

tection mechanisms and their importance in rheumatology.

Ann Rheum Dis 1991; 50: 331±6.

63 Bjarnason I, Smethurst P, Fenn CG, et al. Misoprostol re-

duces indomethacin-induced changes in human small in-

testinal permeability. Dig Dis Sci 1989; 34: 407±11.

64 Bjarnason I. Experimental evidence of the bene®t of mi-

soprostol beyond the stomach in humans. J Rheumatol

1990; 17(Suppl. 20): 38±41.

65 Bjarnason I, Fehilly B, Smethurst P, et al. Importance of local

versus systemic effects of non-steroidal anti-in¯ammatory

drugs in increasing small intestinal permeability in man. Gut

1991; 32: 275±7.

66 Bjarnason I, Smethurst P, Levi AJ, et al. The effect of poly-

acrylic acid polymers on small-intestinal function and per-

meability changes caused by indomethacin. Scand

J Gastroenterol 1991; 26: 685±8.

67 Bjarnason I, Smethurst P, Macpherson A, et al. Glucose and

citrate reduce the permeability changes caused by in-

domethacin in humans. Gastroenterology 1992; 102:

1546±50.

318 N. M. DAVIES


68 Bjarnason I, O'Morain C, Levi AJ, et al. Absorption of51chromium-labeled ethylenediaminetetraacetate in in¯am-

matory bowel disease. Gastroenterology 1983; 85: 318±22.

69 LoÈkken P, SoÈgnen E. 51Cr-EDTA as a reference substance in

research on gastrointestinal functions. Acta Pharmacol

Toxicol 1967; 25(4): 39.

70 Simpson LO. NSAID and the leaky gut. Lancet 1985; 1:

218±19.

71 Aabakken L, Osnes M. 51Cr-Ethylenediaminetetraacetic acid

absorption test. Effects of naproxen, a non-steroidal, antiin-

¯ammatory drug. Scand J Gastroenterol 1990; 25: 917±24.

72 Reuter BK, Davies NM, Wallace JL. NSAID-enteropathy in

rats: Role of epithelial permeability, bacterial load, and en-

terohepatic circulation. Gastroenterology 1997; 112(1):

109±17.

73 Elia M, Behrens R, Northrop C, et al. Evaluation of mannitol,

lactulose and 51Cr-labeled ethylenediaminetetra-acetate as

markers of intestinal permeability in man. Clin Sci 1987; 73:

197±204.

74 Mielants H, Vey EM. NSAID and the leaky gut. Lancet 1985;

1: 218.

75 Peled Y, Watz C, Gilat T. Measurement of intestinal perme-

ability using 51Cr-EDTA. Am J Gastroenterol 1985; 80(10):

770±3.

76 Bjarnason I, Ward K, Peters TJ. The leaky gut of alcoholism:

possible route of entry for toxic compounds. Lancet 1984; 1:

179±82.

77 Aronson AL, Rogers KM. Effects of calcium and chromium

chelates of ethylenediaminetetraacetate on intestinal per-

meability and collagen metabolism in the rat. Toxicol Appl

Pharmacol 1972; 21: 440±53.

78 Tibdall CS. Magnesium and calcium as regulators of intes-

tinal permeability. Am J Physiol 1964; 206: 243±6.

79 Meddings JB, Sutherland LR, Byles NI, et al. Sucrose: A novel

permeability marker for gastroduodenal disease. Gastroen-

terology 1993; 104: 1619±26.

80 Sutherland LR, Verhoef M, Wallace JL, et al. A simple, non-

invasive marker of gastric damage: Sucrose permeability.

Lancet 1994; 343: 998±1000.

81 Rabassa AA, Goddame R, Sutton FM, et al. Effect of aspirin

and Helicobacter Pylori on the gastroduodenal mucosal per-

meability to sucrose. Gut 1996; 39: 159±63.

82 Irvine EJ, Goodacre RL, McCullough HN, et al. Damaged

surface area of gastric mucosa correlates with urinary su-

crose excretion. Arth Rheum 1995; 38(9): A57, S162.

83 Hildsen RJ, Meddings JB, Sutherland LR. Intestinal perme-

ability changes in response to acetylsalicylic acid in relatives

of patients with Crohn's disease. Gastroenterology 1986;

110: 1395±403.

84 Meddings JB, Kirk D, Olson ME. Non-invasive detection of

nonsteroidal anti-in¯ammatory drug-induced gastropathy in

dogs. Am J Vet Res 1995; 56(8): 977±81.

85 Davies NM, Corrigan BW, Jamali F. Sucrose urinary excre-

tion in the rat measured using a simple assay: a model of

gastroduodenal permeability. Pharm Res 1995; 11: 1733±6.

86 Davies NM, Jamali F. In¯uence of dosage form on the

gastroenteropathy of ¯urbiprofen in the rat: evidence of

shift in the toxicity site. Pharm Res 1997; 14(11): 1597±

1600.

87 Steinhart AH, Detsky AS, Bombardier C. Economic analysis

of the sucrose test: a non-invasive test of gastroduodenal

mucosal damage. Gastroenterology 1996; 110(4):

A41(Abstract).

88 Bjarnason I, Batt R, Catt S, et al. Evaluation of differential

disaccharide excretion in urine for non-invasive investiga-

tion of altered intestinal disaccharidase activity caused by a-

glucosidase inhibition, primary hypolactasia and coeliac

disease. Gut 1996; 39: 374±81.

89 Ryan AJ, Chang R-RT, Gisol® CV. Gastrointestinal perme-

ability following aspirin intake and prolonged running. Med

Sci Sports Exerc 1996; 28(6): 698±705.

90 Davies GR, Wilkie ME, Rampton DS. Effects of metronidazole

and misoprostol on indomethacin-induced changes in in-

testinal permeability. Dig Dis Sci 1993; 38(3): 417±25.

91 Mielants H, Goemaere S, De Vos M, Schelstraete K, et al.

Intestinal mucosal permeability in in¯ammatory rheumatic

diseases. I. Role of antiin¯ammatory drugs. J Rheumatol

1991; 18: 389±93.

92 Mielants H, De Vos M, Goemaere S, et al. Intestinal mucosal

permeability in in¯ammatory rheumatic diseases. II. Role of

disease. J Rheumatol 1991; 18: 394±400.

93 Bjarnason I, Hayllar J, Smethurst P, et al. Metronidazole

reduces intestinal in¯ammation and blood loss in non-ste-

roidal anti-in¯ammatory drug induced enteropathy. Gut

1992; 33: 1204±8.

94 Hayllar J, Smith T, Macpherson A, et al. Nonsteroidal anti-

in¯ammatory drug-induced small intestinal in¯ammation

and blood loss. Arth Rheum 1994; 37(8): 1146±50.

95 Jenkins RT, Rooney PJ, Hunt RH. Increased bowel perme-

ability to [51Cr]EDTA in controls caused by Naproxen is not

prevented by cytoprotection. Arth Rheum 1988; 31(Suppl.

1): R11.

96 Aabakken L, Larsen S, Osnes M. Sucralfate for prevention of

naproxen-induced mucosal lesions in the proximal and

distal gastrointestinal tract. Scand J Rheumatol 1989; 18:

361±8.

97 Davies GR, Rampton DS. The pro-drug sulindac may reduce

the risk of intestinal damage associated with the use of

conventional non-steroidal anti-in¯ammatory drugs. Ali-

ment Pharmacol Ther 1991; 5: 593±8.

98 Dujovone CA, Pitterman A, Vincek WC, Drorinska MR,

Davies RO, Duggan DE. Enterohepatic circulation of sulindac

and metabolites. Clin Pharmacol Ther 1983; 33: 172±7.

99 Helleberg L. Clinical pharmacokinetics of indomethacin. Clin

Pharmacokin 1981; 6(4): 245±58.

100 Devlin J, Moots R, Andrews D, Boivin C, Emery P. High

intestinal permeability in patients with in¯ammatory ar-

thritis is more strongly associated with any NSAID therapy

than with diagnosis or disease activity. Arth Rheum 1996;

S280: 1513.

101 Rainsford KD, Dieppe PA, Pritchard MH, et al. Protection

from gastrointestinal side-effects of azapropazone by its in-

corporation into a glucose sodium acid citrate formulation.

Aliment Pharmacol Ther 1991; 5(4): 419±33.



102 Davies NM, Wright MR, Jamali F. Antiin¯ammatory drug-

induced small intestinal permeability: rat is a suitable model.

Pharm Res 1994; 11: 1564±9.

103 Ford J, Martin SW, Houston JB. Assessment of intestinal per-

meability changes induced by nonsteroidal anti-in¯ammato-

ry drugs in the rat. J Pharm Toxicol Meth 1995; 34: 9±16.

104 Davies NM, Wright MR, Jamali F. Glucose/Citrate (G/C)

gastrointestinal cytoprotective effect: a physiochemical G/C±

NSAIDs interaction. Pharm Res 1995; 12(9): A8122, S357.

105 Aabakken L, Larsen S, Osnes M. Cimetidine tablets or sus-

pension for the prevention of gastrointestinal mucosal le-

sions caused by non-steroidal anti-in¯ammatory drugs.

Scand J Rheumatol 1989; 18: 369±75.

106 Aabakken L, Bjùrnbeth BA, Weberg R, et al. NSAID-associ-

ated gastroduodenal damageÐdoes famotidine protection

extend into the mid and distal duodenum? Aliment Phar-

macol Ther 1990; 4: 295±303.

107 Aabakken L, Bjùrnbeth BA, Hofstad B, et al. Comparison of

the gastrointestinal side effects of naproxen formulated as

plain tablets, enteric-coated tablets, or enteric-coated gran-

ules in capsules. Scand J Gastroenterol 1989; 24(Suppl.

163): 65±73.

108 Choi VMI, Coates JE, Chooi J, et al. Small bowel permeabili-

tyÐa variable effect of NSAIDs. Clin Invest Med 1995;

18(5): 357±61.

109 Day TK. Intestinal perforation associated with osmotic slow

release indomethacin capsules. Br Med J 1983; 287(6406):

1671±2.

110 Whitcomb DC. Pathophysiology of nonsteroidal antiin¯am-

matory drug-induced intestinal strictures. Gastroenterology

1993; 105(5): 1590.

111 Anonymous. NSAIDs and gut damage. Lancet 1989; 2: 600.

112 Jenkins RT, Rooney RT, Jones DR, Bienenstock J, Goodacre

RL. Increased intestinal permeability in patients with

rheumatoid arthritis: a side-effect of oral non-steroidal an-

tiin¯ammatory drug therapy? Br J Rheumatol 1987; 26:

103±7.

113 Asako H, Kubes P, Wallace JL, et al. Modulation of leukocyte

adhesion in rat mesenteric venules by aspirin and salicylate.

Gastroenterology 1992; 103: 146±52.

114 Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ,

Vane JR. Selectivity of non-steroidal antiin¯ammatory drugs

as inhibitors of constitutive and inducible cyclooxygenase.

Proc Natl Acad Sci 1994; 90: 11693±7.

115 Sperling RI, Weinblatt M, Robin J-L. Effects of dietary sup-

plemenation with marine ®sh oil on leukocyte lipid mediator

generation and function in rheumatoid arthritis. Arth

Rheum 1987; 30: 988±97.

116 Kremer JM, Malamood H, Maliakkal B, Rodgers JB, Ross JS,

Cooper JA. Fish oil dietary supplementation for prevention of

indomethacin induced gastric and small bowel toxicity in

healthy volunteers. J Rheumatol 1996; 23: 1770±3.

117 Mahmud T, Scott DL, Crane R, Bjarnason I. NSAID-induced

permeability. Change in whites and non-white ethnic sub-

jects. Arth Rheum 1996; S280: 1514.

118 Jenkins AP, Nukajam WS, Menzies IS, et al. Simultaneous

administration of lactulose and 51Cr-ethylenediaminetetra-

acetic acid. Scand J Gastroenterol 1992; 27: 769±73.

119 Ens R, Bak A, Meddings JB, Sutherland LR. Sucralose: A

novel permeability marker for colonic disease. Can J Gas-

troenteol 1997; 11(Suppl. A): S37, 51A.

120 Meddings JB, Gibbons IR. Discrimination of site-speci®c al-

terations in gastrointestinal permeability in the rat. Gastro-

enterology 1998; 114(1): 83±92.

121 Reuter BK, Asfaha S, Buret A, Sharkey KA, Wallace JL.

Exacerbation of in¯ammation-associated colonic injury in

rat through inhibition of cyclooxygenase-2. J Clin Invest

1996; 98: 2076±85.

320 N. M. DAVIES


Review article: non-steroidal anti-inflammatory drug-induced gastrointestinal permeability

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