Time course inhibition of gastric and platelet COX activity by
acetylsalicylic acid in humans
Mark
Feldman,
Kenneth
Shewmake, and
Byron
Cryer
Medical Service, Dallas Department of Veterans Affairs Medical
Center, and Department of Internal Medicine, University of Texas
Southwestern Medical School, Dallas, Texas 75216
 |
ABSTRACT |
Aspirin causes peptic ulcers
predominately by reducing gastric mucosal cyclooxygenase (COX) activity
and prostaglandin synthesis. Because aspirin circulates for only a few
hours, we hypothesized that aspirin's inhibitory effect on gastric COX
activity must be prolonged. We performed a placebo-controlled
experiment in healthy humans to determine the duration of inhibition of
aspirin on gastric mucosal COX activity (PGE2 and
PGF2
synthesis rates). Recovery of gastric COX activity
after stopping aspirin was slow and linear. Seventy-two hours after
325-mg aspirin, gastric COX activity was still reduced by 57%
(P < 0.001). Duration of inhibition of gastric COX
activity was estimated to be 7-8 days after 325-mg aspirin and 5 days after 81-mg aspirin. Recovery of gastric prostaglandin synthesis
after 325-mg but not after 81-mg aspirin occurred at slower rates in
subjects with Helicobacter pylori-associated gastritis than
in those with normal histology. In conclusion, aspirin inhibits gastric
COX activity for much longer than predicted from its pharmacokinetic
profile, explaining why aspirin at widely spaced intervals is ulcerogenic.
prostaglandins; thromboxanes; ulcer; Helicobacter
pylori
 |
INTRODUCTION |
ACETYLSALICYLIC ACID
(ASA, aspirin) irreversibly acetylates a key serine moiety of platelet
cyclooxygenase (COX)-1, reducing COX-1-derived synthesis of thromboxane
(Tx) A2, a potent platelet aggregator and vasoconstrictor
(17). As a consequence, chronic administration of low
doses of ASA protects against thrombotic occlusion of coronary
arteries, cerebral arteries, and vascular grafts (11). The
most serious side effect of chronic low-dose ASA therapy is gastric
and/or duodenal ulcer formation, sometimes accompanied by
life-threatening ulcer bleeding or perforation (11, 17,
25). Upper gastrointestinal (GI) mucosal damage results
primarily from inhibition of GI mucosal COX activity by ASA, slowing
synthesis of mucosa-protective PGs such as PGE2 and PGF2
(5, 15), although other PG-independent
mechanisms such as topical gastric injury may contribute to ulcer
formation. Inhibition of COX-mediated PG production by the human upper
GI mucosa, particularly by the gastric mucosa, has been demonstrated after doses of ASA as low as 10 or 30 mg/day (3, 15).
Because these previous studies assessed gastric PG production only
1.5-3 h after ASA administration, the duration of ASA's
inhibitory effect on gastric COX activity is unknown.
ASA is rapidly metabolized to salicylate, and within 2 or
3 h little if any ASA can be detected in the blood (6,
8). Even though the salicylate metabolite of ASA can be detected
in the blood for several hours, salicylate does not inhibit platelet COX-1 or gastric COX activity, reduce GI synthesis of mucosa-protective PGs, or cause upper GI mucosal injury (2, 5). Therefore, how administration of low doses of ASA at widely spaced intervals can
cause gastric and duodenal ulcers (3, 22, 24) has remained a mystery. Perhaps a very brief period of PG synthesis suppression may
be sufficient to predispose to ulcer formation or, alternatively, the
inhibitory effect of ASA on GI PG synthesis might extend well beyond
ASA's short serum half-life. To test the latter possibility, we
performed a placebo-controlled experiment in which we measured for
72 h the rate of recovery of gastric mucosal PGE2 and
PGF2
synthesis after exposure to ASA in healthy men and
women. Measurements were made after participants had completed a 46-day
treatment consisting of 81 mg of ASA every day or 325 mg of ASA every
third day. Because asymptomatic Helicobacter
pylori-associated gastric inflammation is common in healthy adults
(9, 18) and may be associated with significantly enhanced
mucosal PG synthesis in the gastric body (4), we also
examined whether PG synthesis rates in placebo- and/or ASA-treated
participants were affected by the presence of H. pylori-associated microscopic gastritis. We simultaneously
evaluated the rate of recovery of platelet COX-1 activity after
discontinuing ASA.
 |
METHODS |
Subjects and randomization.
A human studies subcommittee of our medical center's research
committee approved this experiment. Informed, written consent was
obtained from 32 healthy women and 29 healthy men between the ages of
18 and 61 yr (Table 1). None of the 61 participants had received aspirin, a nonaspirin nonsteroidal
anti-inflammatory drug, or a gastric antisecretory drug for at least 14 days before beginning the experiment. None had a history of peptic
ulcer, upper GI malignancy or surgery, or any chronic medical illness, and none was allergic to aspirin. We screened our study population for
antibodies to H. pylori (FlexSure HP, SmithKline
Diagnostics, Palo Alto, CA) so that approximately one-half of the
subjects were seropositive for H. pylori and one-half were
seronegative. Thus roughly equal numbers of participants with normal
gastric histology or gastric inflammation were included.
Subjects participated in a randomized double-blind study and received
an opaque capsule containing 81 mg of ASA to be taken daily
(group A); an identical-appearing capsule containing 325 mg
of ASA to be taken every third day, with an identical-appearing placebo
capsule containing methylcellulose to be taken on the other days
(group B); or a placebo capsule to be taken daily
(group C). Subjects were allocated to the three therapies in
a 3:3:2 proportion for groups A (n = 23),
B (n = 23), and C
(n = 15), respectively. Pilot studies had demonstrated
that 81 mg of ASA per day and 325 mg of ASA every third day produced
similar antiplatelet effects. Medication was administered for 46 days
to simulate long-term clinical use. This 1.5-mo duration of treatment
with low-dose aspirin in volunteers has been found to be safe
(3). Experimental measurements were made on day
46.
Measurement of gastric COX activity (PG synthesis rates).
After an overnight fast, and 2 h after the last dose of ASA or
placebo was taken on day 46, we obtained three
fluoroscopy-guided mucosal biopsies from the gastric body through a
modified nasogastric tube as previously described (1, 9).
Subjects did not receive sedation for the gastric biopsies. We then
removed the modified nasogastric tube and allowed the participants to
drink two cans of Slim-Fast (Slim-Fast Foods, West Palm Beach, FL) over
the next hour, but no other food was allowed for the next 6 h.
Eight hours after the last dose of ASA or placebo, we reintubated each
subject and obtained three additional biopsies from the gastric body. Intubation and fluoroscopy-guided biopsies were repeated after overnight fasts on the next three mornings (i.e., days 47,
48, and 49), 24, 48, and 72 h after the last
dose of ASA or placebo.
The five sets of biopsies were assessed for gastric COX activity by
measuring rates of ex vivo synthesis of PGE2 and
PGF2
, the two major PGs produced by the human gastric
mucosa (19). Freshly obtained gastric biopsies were placed
in a preweighed incubation medium, reweighed, minced, and vortexed for
3 min to liberate arachidonic acid, allowing generation of
PGE2 and PGF2
(2). The reaction
was quenched by addition of 100 µg/ml indomethacin. Aliquots from in
vitro incubations were mixed with [3H]PGE2 or
[3H]PGF2
and with antisera to
PGE2 or PGF2
(Sigma Immunochemicals, St.
Louis, MO). Antibodies were first reconstituted in 5 ml of bovine serum
albumin buffer and then diluted 1:10 (for PGE2 antibody) or
1:5 (for PGF2
antibody). After incubation, bound counts were determined by liquid scintillation. Standard curves using known
amounts of PGE2 or PGF2
were used to assay
PG concentrations in study samples. Radioimmunoassay results were
expressed as picograms of PGE2 or PGF2
(or
their sum) per milligram of tissue per minute.
Gastric histology.
Two separate gastric biopsies were obtained on day 46 from
the gastric body for microscopic examination by a GI pathologist. The
pathologist was blinded to treatment group and H. pylori
serology results. The gastric biopsies were stained with hematoxylin
and eosin and classified microscopically as either normal (i.e., no inflammation present) or inflamed (i.e., gastritis present). When gastritis was present, it was almost invariably chronic and active (i.e., containing lymphocytes and neutrophils), associated with visible
H. pylori organisms, and moderate or severe in intensity (9, 18).
Measurement of platelet COX activity (platelet-derived serum
TxB2 concentrations).
Just before each set of gastric mucosal biopsies was obtained, a venous
blood sample was collected and allowed to clot and serum was obtained
by centrifugation. Serum was later radioimmunoassayed for
platelet-derived serum TxB2 concentration as previously
described (2, 3, 6, 8, 15). Platelets use COX-1 to
generate TxB2 (2). TxB2 results
are expressed as nanograms per milliliter of serum.
Statistical analysis.
Data were entered into a Microsoft Excel spreadsheet and then imported
into Systat version 8.0 for Windows (SPSS, Chicago, IL). Results for
each treatment group were expressed as means ± SE. Differences in
mean gastric PGE2 or PGF2
synthesis rates
(or their sum) or in platelet-derived serum TxB2
concentrations among groups were tested for significance by analysis of
variance. Pairwise differences were subjected to the Bonferroni post
hoc test to determine significant differences. A general linear model of gastric PG synthesis inhibition (PGE2,
PGF2
, or their sum) as a function of time after the last
ASA dose was used. Differences in slopes of regression lines were
compared by t-tests after pooling the SEs, according to the
formula t = (slope 1
slope
2)/pooled SE. Two-tail probability (P) values <0.05
were considered significant.
 |
RESULTS |
Rate of recovery of gastric mucosal PG synthesis.
As shown in Fig. 1, gastric
PGE2 and PGF2
synthesis (and their sum) in
placebo-treated participants were quite constant over the 72-h
experiment. PGE2 synthesis was approximately twofold greater than PGF2
synthesis.

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Fig. 1.
Mean (±SE) rate of gastric mucosal synthesis of PGE2
(A), PGF2 (B), or their sum
(C) at various times after the last dose of a 46-day
treatment with placebo (Pl, open bars), 325 mg of acetylsalicylic acid
(ASA) every 3rd day (hatched bars), or 81 mg of ASA daily (solid bars)
in 61 healthy volunteers. *P 0.003 for 325-mg ASA or
81-mg ASA vs. placebo; P < 0.05 for 325-mg ASA vs.
81-mg ASA.
|
|
Gastric mucosal PGE2 and PGF2
synthesis
2 h after 325- or 81-mg ASA was much lower than after placebo
(P < 0.001). Reductions in PGE2 and
PGF2
synthesis, relative to placebo, ranged from 86% to
93%.
By 24 h after ASA, there was only slight recovery of gastric
PGE2 and PGF2
synthesis, which remained
reduced by 68-85% (P < 0.001; Fig. 1). Over the
ensuing 2 days, there was continued but very slow recovery of gastric
PG synthesis. For example, 72 h after 325-mg ASA, gastric
PGE2 and PGF2
synthesis were still reduced
by 58% and 55%, respectively (P < 0.001).
Gastric mucosal PG (PGE2 + PGF2
)
synthesis 72 h after the last 81-mg ASA dose was reduced by 34%
(P = 0.04); inhibition averaged 28% for
PGE2 alone (not significant) and 45% for
PGF2
alone (P = 0.04) (Fig. 1).
PGE2 synthesis (and the sum of PGE2 + PGF2
synthesis) had recovered to a significantly higher rate 72 h after 81-mg ASA than 72 h after 325-mg ASA
(Fig. 1).
Platelet-derived serum TxB2 concentrations.
As shown in Fig. 2, mean platelet-derived
serum TxB2 concentrations were fairly constant
(220-250 ng/ml) in subjects receiving placebo. After both 325- and
81-mg ASA, serum TxB2 concentrations were sharply reduced
throughout the 72-h experiment (P < 0.001 vs.
placebo). Serum TxB2 levels 72 h (3 days) after ASA
were still significantly reduced relative to placebo by 89% and 84%
for 325 and 81 mg, respectively (P < 0.001). Thus
platelet COX-1 activity was inhibited to an even greater extent than
gastric COX activity throughout the 72-h experiment (Fig.
3; days 0-3).

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Fig. 2.
Mean (±SE) serum thromboxane B2
concentrations at varying times after the last dose of a 46-day
treatment with placebo (open bars), 325 mg of ASA every 3rd day
(hatched bars), or 81 mg of ASA daily (solid bars) in 61 healthy
volunteers. *P < 0.001 vs. placebo.
|
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Fig. 3.
Inhibition (compared with placebo) of PG (PGE2 + PGF2 ) synthesis in the stomach and of platelet
thromboxane B2 production as a function of days after the
last dose of a 46-day treatment with 81 mg of ASA daily (A)
or 325 mg of ASA every 3rd day (B). Data from days
0-3 are derived from this experiment. Stomach PG data beyond
day 3 (dashed lines) are extrapolated using linear
regression equations (see Table 2). Platelet thromboxane B2
data beyond day 3 are actual values derived from a separate
study in 66 subjects randomly assigned to treatment with placebo or ASA
(81 or 325 mg) for 31 days before medication was discontinued, with
serum thromboxane recovery determined on days 4,
7, and 14 thereafter (M. Feldman and B. Cryer,
unpublished data).
|
|
Regression analyses.
Mean percent reductions of gastric PG (PGE2 + PGF2
) synthesis are plotted as a function of time after
the last dose of 325- or 81-mg ASA in Fig.
4. Recovery of PG synthesis after either ASA dose was linear, with correlation coefficients for the linear regression equations exceeding 0.99 (Table
2; P < 0.001). Recovery of gastric PG synthesis was also dose related, with a significantly (P < 0.001) faster recovery (steeper slope) after the
81-mg dose (Fig. 4B; Table 2) than after the 325-mg dose
(Fig. 4A; Table 2).

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Fig. 4.
Gastric mucosal PG (PGE2 + PGF2 )
synthesis (% inhibition relative to placebo) at various times after
the last dose of a 46-day treatment with 325 mg of ASA every 3rd day
(A) or 81 mg of ASA daily (B). Lines represent
best-fit regression equations. Slopes of lines and correlation
coefficients are given in Table 2, as are slopes and correlation
coefficients for PGE2 data alone and PGF2
data alone.
|
|
If the regression lines in Fig. 4 are extrapolated to no (0%) PG
synthesis inhibition, an estimate of the total duration of inhibition
of ASA on gastric PG synthesis can be obtained. The duration of
inhibition of 325-mg ASA on gastric PG (PGE2 + PGF2
) synthesis was estimated to be 7.8 days (Fig.
3B; Table 2). As shown in Table 2, similar estimates
resulted when only PGE2 data or only PGF2
data were used (7.8 and 7.5 days, respectively). The duration of
inhibition of 81 mg ASA on gastric PG (PGE2 + PGF2
) synthesis was likewise estimated to be 4.9 days
(Fig. 3A; Table 2), and to be 4.5 or 6.1 days when only
PGE2 data or only PGF2
data were used, respectively.
Role of gastritis in gastric mucosal PG synthesis.
Twenty-nine of the sixty-one subjects had H. pylori-associated gastritis on gastric body biopsies, whereas the
other thirty-two had normal gastric histology. As shown in Fig.
5, mean PG synthesis rates tended to be
slightly higher in participants with gastritis, regardless of treatment
group or the time after the last dose of medication at which
measurements were made. The difference in mucosal PG synthesis between
biopsies with normal histology vs. biopsies with gastritis was
statistically significant at 8 h (P = 0.007), and
differences approached significance at other times (P = 0.07-0.28).

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Fig. 5.
Mean (±SE) gastric body PG (PGE2 + PGF2 ) synthesis at various times after the last dose of
a 46-day treatment with placebo, 325 mg of ASA every 3rd day, or 81 mg
of ASA daily in 32 subjects with normal gastric histology and in 29 subjects with body gastritis. PG synthesis differences between the
normal histology group and the gastritis group at 8 h (all
treatments combined) were statistically significant (P = 0.007). Differences at other time points approached significance (see
text).
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|
As shown in Fig. 6B, the rate
of recovery of gastric mucosal PG (PGE2 + PGF2
) synthesis was similar in subjects treated with
81-mg ASA, whether they had gastritis or not (P = 0.51 for comparison of slopes). The duration of inhibition with 81-mg ASA was estimated by extrapolation to be 4.8 days in subjects with normal
histology and 5.2 days when gastritis was present (Table 3).

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Fig. 6.
Gastric mucosal PG (PGE2 + PGF2 )
synthesis inhibition (%, relative to placebo) at various times after
the last dose of 325-mg (A) or 81-mg (B) ASA in
32 subjects with normal gastric histology and in 29 subjects with
H. pylori-associated gastritis. Lines represent best-fit
linear regression equations. Slopes of lines and correlation
coefficients are given in Table 3.
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|
With the 325-mg ASA dose (Fig. 6A), the duration of
inhibition of PG synthesis was significantly longer in subjects with
gastritis (less steep slopes) than in subjects with normal histology
(P = 0.003 for comparison of slopes). Duration of
inhibition with 325-mg ASA was estimated to be 9.7 days in participants
with gastritis and 6.4 days in participants with normal histology
(Table 3).
 |
DISCUSSION |
ASA irreversibly acetylates a key serine residue of COX, blocking
COX activity (17). As a consequence, production of
prostanoids (PG, Tx) from arachidonic acid and from PGH2
declines, and the physiological functions that the prostanoids subsume
are impaired. COX activity returns to normal and the physiological
actions of the prostanoid products of the COX reaction are restored
only if COX is regenerated in cells or if new cells are produced.
The platelet is a unique cell in that it has no nucleus and thus cannot
regenerate COX-1 to produce TxA2 after its COX-1 activity has been irreversibly eliminated by ASA. Thus restoration of platelet COX-1 activity requires release of fresh platelets into the circulation from bone marrow megakaryocytes that have not been exposed to ASA.
Because the life span of a platelet is 10 days, only 10% of platelets
are replaced each day (17). Moreover, some of the newest
platelets to appear in the circulation soon after ASA is discontinued
undoubtedly are derived from megakaryocytes that had been exposed to
ASA and whose COX-1 activity has been inactivated. Thus it requires
12-14 days for platelet COX-1 activity and platelet-derived serum
TxB2 concentrations to return to normal after low-dose ASA is discontinued (Ref. 16; Fig. 3).
Because GI mucosal cells that produce COX are nucleated, they at least
theoretically are capable of regenerating COX mRNA and protein, thus
restoring COX activity and mucosal PG production after ASA has
disappeared from the body. However, we found that the stomach recovered
very slowly from the inhibitory effect of ASA on gastric COX activity.
For example, 3 days after 325-mg ASA, gastric COX activity was still
inhibited by nearly 60%. Recovery of gastric COX activity was linear
with time, allowing us to estimate that it would require a week or more
for gastric COX activity to return to normal after 325-mg ASA. Recovery
of gastric COX activity was significantly faster after 81-mg than after
325-mg ASA. However, after 81-mg ASA was discontinued, complete
recovery of gastric COX activity was still estimated to require 5 days. These data suggest that the regeneration of COX by the gastric mucosa
is very slow.
The gastric surface epithelium has a turnover time of 3 days, and the
turnover time for mucous neck cells and stem cells is 7 days
(13). Our PG recovery data therefore suggest that recovery of gastric COX activity is, like the platelet, dependent on production of new cells rather than synthesis of new protein by extant cells. The
somewhat faster recovery of gastric COX than platelet COX (Fig. 3)
parallels the differences in gastric and platelet cell turnover rates.
ASA serum concentrations after oral dosing peak in 20-30 min and
by 2-3 h after dosing are barely detectable by a sensitive chromatographic method (6, 8). ASA is rapidly converted to
salicylate by tissue and plasma esterases. Once the acetyl group of ASA
has been removed by these esterases, ASA can no longer acetylate COX.
Salicylate, which can circulate for
12 h after a 325-mg ASA dose,
does not inhibit gastric COX activity in vitro or in vivo (2,
5). Thus the inhibitory effect of ASA on gastric COX activity
outlasts its life in the circulation by 40- to 60-fold.
The prolonged duration of effect of low-dose ASA on gastric COX
activity helps explain the clinical observation that peptic ulcer
formation and GI bleeding are increased significantly with low-dose
ASA. In the Physician's Health Study (22), for example, duodenal ulcer formation and melena occurred significantly more often
in physicians receiving 325 mg of ASA every 48 h than in physicians receiving placebo. As shown by the 325-mg ASA data presented
here, gastric PG synthesis is still reduced by ~65% at 48 h
(Figs. 1 and 3). Likewise, in the Swedish Aspirin Low-Dose Trial
(SALT), there was more upper GI bleeding in patients receiving 75 mg of
ASA per day than in those receiving placebo treatment (23). (In Europe 75 mg of ASA is the "baby-sized"
dose, whereas in the US 81 mg of ASA is the "baby-sized" dose.)
Gastric PG synthesis 24 h after 81-mg ASA is still reduced by 70%
(Figs. 1 and 3).
It appears very unlikely from our data that an oral ASA dose regimen
will be found that produces a prolonged platelet inhibition with little
or no GI mucosal PG inhibition. In other words, GI toxicity may be an
inevitable consequence of low-dose ASA therapy. Despite this
inevitability, there may be a dose of ASA that has an optimal
benefit-risk ratio. An 81-mg ASA dose was about as effective in
inhibiting platelet COX-1 activity at 72 h as a 325-mg dose in the
present study and in other studies (3, 15, 16). Moreover,
gastric COX activity had nearly recovered by 72 h after the 81-mg
ASA dose (Figs. 1 and 3), making an ASA dose of 81 mg every third day
or twice a week worthy of consideration in future controlled clinical
trials in patients with cardiovascular disease.
The stomachs of many healthy people are infected with H. pylori, a bacterium that leads to an influx of neutrophils and
lymphocytes (chronic active gastritis) (9, 18). Although
the normal gastric mucosa predominantly uses COX-1 to generate
mucosa-protective PGs (2, 14, 20), COX-2 expression can be
upregulated in leukocytes in response to bacterial toxins, cytokines,
and growth factors, with resultant production of PGs (10,
20). For this reason, we examined whether gastric PG synthesis,
and responsiveness to ASA therapy, varied as a function of H. pylori gastritis. We found that gastric PG synthesis rates were
slightly but consistently higher in H. pylori-infected subjects with chronic, active gastritis than
in noninfected subjects with normal histology, presumably because of
COX-2-mediated PG synthesis by inflammatory cells. ASA, which blocks
both COX-1 and COX-2 (2), lowered gastric PG synthesis to
approximately the same level in infected and noninfected participants.
Moreover, PG synthesis recovery rates were significantly slower in
participants with gastritis than in participants with normal histology
after the 325-mg aspirin dose (Fig. 6 and Table 3). However, recovery
rates were similar after 81-mg ASA. Whether the P value
<0.05 with 325-mg ASA represents a type I error, the P
value >0.05 with 81-mg ASA represents a type II error, or the apparent
difference between the two aspirin doses was caused by differences in
responses of volunteers assigned randomly to the two treatment groups
is uncertain.
Upregulation of COX-2 may be an important step in colorectal adenoma
and carcinoma formation, an effect that may be antagonized by low-dose
ASA (12, 21). Oral ASA (325 mg) inhibits rectal COX
activity when measured 2 h after administration (3).
In light of the prolonged effect of ASA on gastric COX activity we observed in this study, one may speculate that inhibition of colorectal COX activity by low-dose ASA could also be prolonged. This speculation is supported by a recent study in which rectal mucosal PGE2
and PGF2
content was still slightly but significantly
reduced 3 days after a 14-day course of ASA was discontinued in healthy men (21). A prolonged inhibitory effect of ASA on
colorectal COX activity and on colorectal PG synthesis may explain why
epidemiological studies have found that even infrequent ASA use (e.g.,
twice a week or more) is associated with a reduced risk of colorectal adenomas and carcinoma (12).
In summary, antiplatelet doses of ASA, such as those used to prevent or
to treat cardiovascular diseases, likely inhibit gastric COX activity
for 5-10 days after ASA exposure, even though ASA is metabolized
to salicylate within a few hours. This markedly prolonged
pharmacodynamic effect of ASA on the gastric mucosa is most likely
caused by a slow turnover of COX (mainly COX-1) in the gastric mucosa
that appears to parallel production of new epithelial cells. Our
findings help explain how even low doses of ASA given every 24 or
48 h can be ulcerogenic in the upper GI tract (3,
22). Slow recovery of gastric COX activity after ASA therapy
occurs both in the normal gastric mucosa and, perhaps to an even
greater extent, in mucosa inflamed because of infection with H. pylori. Gastric mucosal prostaglandin depletion due to the
inhibition of mucosal COX activity appears inevitable with antithrombotic (antiplatelet) doses of ASA.
 |
ACKNOWLEDGEMENTS |
The authors thank Dr. Lori Fischbach for statistical assistance,
Kristi Rushin for technical assistance, and Vicky Robertson for
assisting in manuscript preparation.
 |
FOOTNOTES |
This work was supported by a Merit Review Award from the Department of
Veterans Affairs (M. Feldman) and by the Southland Financial
Corporation Distinguished Chair in Geriatrics (M. Feldman).
Address for reprint requests and other correspondence: M. Feldman, Medical Service (111), Dallas VA Medical Center,
4500 S. Lancaster Road, Dallas, TX 75216 (E-mail:
mark.feldman{at}med.va.gov).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10 April 2000; accepted in final form 4 June 2000.
 |
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