Research Article

InPharm Communique Vol 2, No 3 | 17

Synthesis and Pharmacological Evaluation of Gastro-sparing
Mutual Prodrug of Aceclofenac with Glucosamine

Suneela S. Dhaneshwar
* 1
, Sanal Dev
1
, B.Rathi
2
and S. L. Bodhankar
2

1
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth University, Poona College of Pharmacy,
Erandwane, Pune, India.
2
Department of Pharmacology, Bharati Vidyapeeth University, Poona College of Pharmacy, Erandwane, Pune, India.
*
Author for correspondence: Dr. Suneela Dhaneshwar E-mail: suneeladhaneshwar@rediffmail.com


ABSTARCT
Aceclofenac is a nonsteroidal antiinflammatory drug that is used to relieve pain and inflammation in arthritic
conditions like osteoarthritis, rheumatoid arthritis and ankylosing spodylitis. Aceclofenac is known to induce
erosion and ulcers in the gastrointestinal tract but in contrast to other nonsteroidal anti-inflammatory agents,
it has shown stimulatory effects on cartilage matrix synthesis. In order to lower the ulcerogenic potential and
enhance effectiveness of aceclofenac as antiarthritic agent, a mutual prodrug was synthesized with
neutraceutical carrier D-glucosamine that has shown to stimulate the biosynthesis of glucosaminoglycans
and hyaluronic acid backbone needed for the formation of the proteoglycans found in the structural matrix of
joints. The study showed that the prodrug not only lowered the ulcerogenic potential of aceclofenac but also
enhanced its analgesic, antiinflammatory and antiarthritic activities thus proving the utility of D-glucosamine
as an effective carrier in mutual prodrug synthesis.
Key words Aceclofenac, anti-arthritic, anti-inflammatory, glucosamine, gastrosparing, mutual prodrug.

INTRODUCTION

Inflammatory diseases are widely prevalent throughout the
world. Nonsteroidal anti-inflammatory drugs (NSAIDs) are
amongst the most extensively used drugs for the treatment
of pain and inflammation associated with acute and chronic
inflammatory disorders. The major drawback in the chronic
administration of NSAIDs is the occurrence of serious side
effects, mainly involving the gastrointestinal tract (GIT),
that have serious impact on the public health due to the
massive use of these drugs
[1]
. Prolonged use of these drugs
produces gastroduodenal and mucosal erosions in 35-60%
patients, ulcerations in 10-25% patients and severe
hemorrhages or perforations in about 1% of patients
[2]
.
Epidemiological studies have established that overall,
NSAIDs enhance the risk of ulcer complications such as
bleeding, perforations, hospitalization and death by
approximately 3-10 folds
[3]
. NSAID-induced gastric damage
has been attributed mainly to suppression of endogenous
prostaglandins, which have cytoprotective effect on gastric
mucosa
[4]
. Aryl acids have tendency to accumulate in the
parietal cells of stomach and in the inflamed tissue. This
pattern of preferential tissue distribution may contribute to
the direct toxic effect on gastric epithelial cells such as
apoptosis or necrosis
[5]
. These compounds inhibit the two
isoforms of cyclooxygenases (COX-1 and COX-2) and thus
suppress prostaglandin biosynthesis from arachidonic acid
[6]
. COX-1 has cytoprotective effect on GIT
[7]
while COX-2
mediates inflammation
[8]
.
Aceclofenac is a nonsteroidal anti-inflammatory drug, which
has gained a wide acceptance due to its ability to relieve pain
and inflammation in arthritic conditions. It is indicated for
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18 | InPharm Communique Vol 2, No 3
management of osteoarthritis, rheumatoid arthritis and
ankylosing spondylitis and is known to induce erosions and
ulcers in the gastrointestinal tract
[9]
. In contrast to other
NSAIDs, it has stimulatory effect on cartilage matrix
synthesis
[10]
.
Glucosamine, an amino sugar, is bodys starting material for
the production of natural joint components like critical joint
lubricants and shock absorbers
[11]
. Some scientists have
theorized that when the body becomes unable to
manufacture adequate supplies of glucosamine,
susceptibility to developing osteoarthritis dramatically rises.
Glucosamines role in halting or reversing joint degeneration
appears to be directly due to its ability to act as an essential
substrate for, and to stimulate the biosynthesis of the
glycosaminoglycans and the hyaluronic acid backbone
needed for the formation of the proteoglycans found in the
structural matrix of joints
[12]
. Apparently, as we age, many of
us lose the ability to produce the necessary levels of
glucosamine that protect our joints. Consequently, the
cartilage components of our skeletal frames lose their
capacity to hold water, therefore, joint protection
diminishes. The logical question here is, if the loss of
glucosamine leads to arthritis, would restoring glucosamine
slow the disease? In some clinical studies glucosamine was
consistently shown to relieve pain in 3-4 week, restore joint
flexibility, produce no known side effects and treat the cause
and not just
[11]
. We have reported the utility of mutual
prodrug concept in improving the safety profile of NSAIDs
using glucosamine as a carrier.
[13]

The present work reports the synthesis, physico-chemical
characterization, in vitro hydrolysis and biological
evaluation of mutual prodrug of aceclofenac with
glucosamine. The objective of this work was to evaluate the
utility of mutual prodrug concept in decreasing the
ulcerogenic potential of aceclofenac by conjugating its
carboxylic group with amino group of glucosamine. This
mutual prodrug would have the additional advantage of
producing a nutrient by-product, i.e. glucosamine on
cleavage, which after its release is expected to be available to
produce the above effects.
MATERIALS AND METHODS
Melting points were measured in open capillary tubes and
are uncorrected. IR (KBr) spectrum was recorded on
JASCO, FT- IR spectrophotometer, Model V5300 and
1
H-
NMR spectrum on FT NMR, JEOL spectrophotometer (300
MHz) at University of Pune, using TMS as internal reference
(chemical shift in , ppm). The mass spectrum was recorded
on Jeol SX-102 (FAB) spectrometer. The max was
determined on JASCO V530, UV-visible double beam
spectrophotometer. Purity of the compounds was checked
on silica gel 60F254 Merck plates using iodine vapours as
visualizing agent. Aceclofenac was procured from IPCA
Laboratories Mumbai, India as a gift sample. All chemicals
used were of LR and AR grade and were obtained from
Quali gens Fi ne Chemical s, Mumbai, India.
Synthesis of glucosamine conjugate of aceclofenac
(SA-004):
Aceclofenac, (0.02 mol) was dissolved in 50 ml of
chloroform and stirred for half an hour at 0
o
C. N, N
dicyclohexyl carbodimide (DCC) (0.0026 mol) was dissolved
in 5 ml N, N dimethyl formamide in another beaker and was
then added to a solution of aceclofenac at 0
o
C and was
stirred for 2 h. Glucosamine hydrochloride (0.026 mol) was
suspended in 30 ml of chloroform. Triethylamine (0.052
mol) was then added drop wise, to the above mixture to
liberate free glucosamine. The mixture was stirred for one
hour at 0
o
C.The solvent was distilled off to form dry residue.
To this dry residue, mixture of aceclofenac and DCC was
added drop wise at 0
o
C.The reaction mixture was stirred for
12 h at 0
o
C. It was filtered to remove the byproduct i.e.
precipitated dicyclohexylurea. The filtrate was concentrated
under vacuum. The crude product was recrystallized using
alcohol and dried under vacuum. The route of synthesis is
described in Scheme (Fig 1). C22H24Cl2N2O8, m.p130-132
o
C,
yield 83%, Rf 0.64, chloroform: methanol: acetic acid
(4:1:0.1) IR (KBr) cm
-1
; 3377 (O-H); 1055, 1255 (C-O);
1718(C=O); 3319(N-H) cm
-1
.
1
H-NMR (DMSO-d6): 2.26 (s,
4H, OH); 3.45-3.86 (d, 3H, CH, tetrahydropyran) ppm; 3.88
(s, 2H, CH2); 4.38 (s, 1H, ArNH); 4.48 (s, 1H, CH); 6.0 (d,
1H, CH); 6.82-6.84 (s, 1H, ArH); 6.92-6.98 (q, 4H, ArH);
7.28 (d, 1H, sec. amide). MS; m/z 514.09 (M+1). max: 271.0
(distilled water), 280.0 (CHCl3), 271.4 (phosphate buffer
pH 7.4), 264 (HCl buffer, pH 1.2).
Fig. 1. Scheme of synthesis


Research Article

InPharm Communique Vol 2, No 3 | 19
In vitro hydrolysis kinetics
[14]
:
The synthesized compound was subjected to in vitro
hydrolysis kinetic study. The kinetics of chemical hydrolysis
of SA-004 was studied at 37
o
C in aqueous buffer solutions of
pH 1.2 and pH 7.4. The total buffer concentration was
generally 0.05 M and a constant ionic strength () of 0.5
was maintained for each buffer by adding a calculated
amount of potassium chloride. Free aceclofenac released
after hydrolysis of conjugate was estimated on UV
spectrophotometer for the amount of free aceclofenac
released in HCl buffer and phosphate buffer at 264 nm and
at 271.4 nm respectively. The assay was carried out in
triplicate and was validated as per USP XXIV guidelines.
The kinetics of hydrolysis was monitored by increase in free
drug concentration with time and the order of reaction, half
life (t
1
/2) and rate of hydrolysis were calculated.
Hydrolysis in 0.05 M hydrochloric acid buffer (pH
1.2)
[15]
: SA-004 (10 mg) was introduced in 900 ml of HCl
buffer (pH 1.2) taken in the basket and was kept in a
constant temperature bath at 371
o
C. The solution was
occasionally stirred and 5 ml aliquot portions were
withdrawn at various time intervals and were estimated on
UV spectrophotometer at 264 nm for free aceclofenac
released after hydrolysis of SA-004.
Hydrolysis in 0.05 M phosphate buffer (pH 7.4):
Same procedure as described above was followed for SA-
004, where instead of HCl buffer; phosphate buffer (pH 7.4)
was used. Rate of hydrolysis was calculated using equation,
K= (2.303/t) log (a/a-x), where K is hydrolysis constant, t is
time in min, a represents initial concentration of prodrug, x
is the amount of prodrug hydrolyzed and (a-x) is the amount
of prodrug remaining. The K values from the plots were
calculated separately and then average K and S.D. values
were calculated.
Biological screening:
Materials:
All the experimental procedures and protocols used in this
study for pharmacological screening were reviewed and
approved by the Institutional Animal Ethical Committee
(IAEC) of Poona College of Pharmacy, Pune and were in
accordance with the guidelines of the Committee for the
Purpose of Control and Supervision of Experiment on
Animals (CPCSEA), Government of India. Healthy male
Wistar rats, weighing between 150-250 g were used. They
were divided in various groups and housed under standard
environmental conditions of temperature 231C and
relative humidity of 505%. A 12 h light/dark cycle was
followed. All animals had free access to water and standard
pelleted laboratory animal diet. Statistical analysis was
carried out by ANOVA followed by Dunnetts test to
determine the significance of the difference between the
control group and rats treated with the test compounds.
Anti-inflammatory activity by carrageenan-
induced rat paw edema method:
This activity was preformed by carrageenan-induced rat paw
edema method of
[16]
. Wistar rats of either sex having body
weight 175-200 g were used in this study. The animals were
divided randomly in four groups with 6 rats per group. A
freshly prepared solution of carrageenan (1% w/v, 0.1 ml)
solution was injected in to the planter region of right hind
paw of each rat. One group was kept as a control and the
animals of other group were pretreated with the test drugs
suspended in 1.0% CMC given orally 1h before the
carrageenan treatment. The paw volume was measured
using UGO Basile Plethysmometer 7140 at 0 h, 1 h, 2 h, 3 h
and 24 h after carrageenan treatment. Percent inhibition
was calculated according to the formula given below:
% Inhibition = {1- [(Vd Vp)/ (Vc Vp)] } 100
where, ( Vd Vp) is the difference in the paw volume after
carrageenan injection (Vd) and before carrageenan injection
(Vp) in drug treated group and (Vc Vp) is the difference in
paw volume after carrageenan injection (Vc) and before
carrageenan injection (Vp) in vehicle treated group. Data are
expressed as mean SEM.
Analgesic activity by Randall Selitto method
[17]

Following the method of Randall Selitto, male Wistar rats
weighing 100-150 g were previously selected for their
response to an increasing paw pressure delivered by an
analgesiometer (UGO Basile). Selected animals were
distributed into groups of 6 animals and 0.1 ml of 1% w/v
suspension of carrageenan in sterile saline was then injected
into the subplantar tissue of the right hind paw while the left
hind paw was taken as internal control. Test compounds
were given orally 2 h later. Immediately before (0 value) and
1 h after administration, both inflamed and non-inflamed
paws were subjected to an increasing pressure by the
analgesiometer. The pressure at which each rat responded
by withdrawing its hind paw or by struggling was recorded
and considered as pain threshold. Mean pain threshold was
calculated for each treatment group and percentage change
versus the control group was determined.
Analgesic activity by acetic acid- induced writhing
method
[18]
:
Swiss mice of either sex having body weight 24 to 26 g were
used in the study. The animals were divided randomly in
five groups with 6 mice per group. Mice were kept
individually in the test cage, before acetic acid injection and
habituated for 30 m. All compounds were dissolved in 1%
CMC solution. The controlled group received p.o.
administration of 1% CMC solution. After 1 h of drug
administration 0.10 ml of 0.6% acetic acid was administered
intraperitoneally. After five minutes they were observed for
a period of ten minutes and the numbers of writhes were
recorded for each animal. For scoring purposes, a writhe
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20 | InPharm Communique Vol 2, No 3
was indicated by stretching movements consisting of
arching of the back, elongation of the body and extension of
hind limbs. The formula for computing percent inhibition
was:
% Analgesic activity = (n - n / n) x 100
where n = mean number of writhes of control group, n =
mean number of writhes of test group.
Freunds complete adjuvant induced arthritis
model:
Antiarthritic activity was evaluated using prophylactic and
therapeutic protocols of Freunds adjuvant induced arthritis
method
[19]
. Male rats with an initial body weight of 130-200
g were used. On day 0, complete Freunds adjuvant (0.1 ml)
was injected into the subplantar region of the left hind paw.
Dosing with the test compounds or the standard was started
depending on the protocol chosen. Paw volumes of both
sides were recorded on the day of injection by using
plethysmometer (7140-UGO Basile, Italy). On day 5, the
volume of the injected paw was measured again. The
severity of the non-injected paw (secondary lesions) was
also recorded. The primary lesion was determined by
measuring the paw volume on the 0, 5
th
, 13
th
, 18
th
and 21
st
day.

% Inhibition of edema of both the injected left paw and
non-injected right paw over vehicle control group was
calculated by using the same formula as mentioned for
antiinflammatory activity by carrageenan-induced rat paw
edema method.
Assessment of gastric ulcerogenic effects in rats:
The ulcerogenic activity was determined by the cold stress
method of
[20]
. Groups of 6 male Wistar rats weighing 175
200 g were fasted for 24 h with free access to water. Test
compounds were given orally to fasted animals. After oral
administration, animals were stressed by exposure to cold (-
15
o
C for 1 h). The animals were kept in separate
polypropylene cages. After 2 h of drug administration, the
animals were sacrificed using chloroform. The stomach was
opened along the greater curvature and washed with saline
and the glandular portions were examined macroscopically
for the number and size of mucosal lesions. The severity of
the gastric damage was determined for each stomach
examined and scored accordingly to the scale: 0- no lesion;
1- redness; 2- limited number of petechiae/diffused,
pronounced lesions, 3- localized, severe lesions, more than 5
small ulcers and/or 1-2 large ulcers; 4 - extended, severe
lesions; 5- perforation. The ulcerogenic index was calculated
by using formula, UI = Un + Us + Up 10
1
where, UI- ulcer
index, Un- average of number of ulcers per animal, Us-
average of severity score, Up- percentage of animals with
ulcers.
RESULTS AND DISCUSSION
The free glucosamine was prepared by treating glucosamine
hydrochloride with triethyl amine. Aceclofenac was treated
with DCC to form a reactive intermediate o-acylisourea
which was then coupled with the free glucosamine to form
the glucosamine conjugate of aceclofenac (SA-004) (Scheme
1). The structure of the synthesized compound was assigned
on the basis of elemental analysis, IR,
1
HNMR and mass
spectral data.
The synthesized compound did not undergo hydrolysis in
0.05M hydrochloric acid buffer (pH 1.2) whereas its
hydrolysis in 0.05 M phosphate buffer (pH 7.4) followed
first order kinetics with a half-life of 84.5 min. K value was
found to be 0.009780.001.
The anti-inflammatory activity of the synthesized compound
was evaluated by carrageenan induced rat paw edema
method of Winter et al. (Table 1). The compound was tested
at equimolar dose to that of aceclofenac, which was used as
a standard. SA-004 produced 49.25% inhibition of edema
after 3 h, which was comparable to aceclofenac (46.27%). At
24 h, SA-004 produced 94.4% inhibition of edema, which
was more as compared to aceclofenac (88.8%).

Table- I. Effect of prodrug on various parameters of inflammation and pain.
Test Compound Carrageenan induced rat paw
edema model *
(% inhibition)
Analgesic activity*
(% inhibition)
FCA induced arthritis*
(% inhibition)
8 h 24 h Writhing test Randell- Selitto
test
Day 18 Day 21
Vehicle
Aceclofenac
(3mg/kg)
Glucosamine
(2.5mg/kg)
SA-004
(4.47 mg/kg)
-
46.27

50.75

49.25
-
88.89

83.33

94.44
-
44.57

48.58

51.44
-
57.1

64.3

67.9
-
45.59

10.98

54.76
-
71.37

60.03

76.89
Average of six readings; P < 0.05



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InPharm Communique Vol 2, No 3 | 21
Table - II. Gastric ulcerogenic effects of SA-004 and reference drugs after single oral administration to the rats.
Compound Dose (mg/kg) Ulcer index S.D.#
Control
Aceclofenac
Diclofenac
SA-004
----
3
2
4.47*
----
3.75 0.92
5.31 1.35
1.06 0.34
*Dose equimolar to aceclofenac, # Average of six readings.

The anti-arthritic activity of SA-004 was assessed by
Freunds complete adjuvant induced arthritis model. Few
hours after the induction of adjuvant arthritis by sub planter
injection of 0.1 ml Mycobacterium butyricum to rats, the
animals showed a local inflammatory reaction in the
injected paw (primary response) with an increase in planter
volume of about 60% over the baseline value. In addition, a
disseminated arthritic reaction (secondary response)
developed from day 1 after Freunds complete adjuvant
(FCA) injection. Thus, swelling could be observed both in
the injected paw and the non-injected contra-lateral paw.
The effect of SA-004 on the development of adjuvant
arthritis is shown in Table 1. The reduction of the planter
volume was statistically significant for both hind legs and
the reduction of edema was more pronounced in the injected
paw than in the non-injected paw.
For peripheral analgesic activity SA-004 was tested by acetic
acid induced writhing in mice. The analgesic activity of SA-
004 in this test proved to be a little more (51.44%) than that
of aceclofenac (44.57%). In the Randall-Selitto assay for
analgesic activity, SA-004 significantly raised the pain
threshold of the inflamed paw (67.9%) as compared to
aceclofenac (57.1%).
The compound was further screened for ulcerogenic activity.
The extent of gastric damage caused by SA-004 and
reference drugs after single oral administration to 24 h
fasted male rats is shown in the Table 2. Ulcerogenic effect
of SA-004 on the stomach was nonexistent at the dose at
which it showed anti-inflammatory effect. Hence gastric
tolerance to SA-004 was better than the reference drug
CONCLUSION
In conclusion, a mutual prodrug of aceclofenac was
synthesized with an objective of developing a gastrosparing
prodrug with better pharmacological profile. In order to
lower the ulcerogenic potential and enhance effectiveness of
aceclofenac as antiarthritic agent, a mutual prodrug was
synthesized with neutraceutical carrier D-glucosamine that
has shown to stimulate the biosynthesis of
glucosaminoglycans and hyaluronic acid backbone needed
for the formation of the proteoglycans found in the
structural matrix of joints. It was interesting to note that
conjugation of aceclofenac with glucosamine not only
lowered its ulcerogenic potential but also enhanced its
analgesic, antiinflammatory and antiarthritic activities
noticeably thus proving the utility of D-glucosamine as an
effective carrier and correctness of mutual prodrug
hypothesis.

ACKNOWLEDGEMENTS
The authors are thankful to IPCA Laboratories, Mumbai and
Mr. V. Mohan, Consultant, Pune, for providing the gift
samples of aceclofenac and glucosamine respectively. The
authors are also thankful to the Department of Chemistry,
University of Pune, for spectral analysis of the compound.

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