Beruflich Dokumente
Kultur Dokumente
Preeti Khulbe*, Birendra Shrivastava, Pankaj Sharma and Ajay Kumar Tiwari
ABSTRACT
Article Received on
08 July 2016, Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used
Revised on 28 July 2016,
to treat rheumatoid arthritis, osteoarthritis, mild to moderate pain and a
Accepted on 18 August 2016
DOI: 10.20959/wjpps20169-7578 lots of other conditions. Although non-steroidal anti-inflammatory
drugs are widely accepted as effective agents for controlling pain, but
*Corresponding Author
their administration can lead to the development of gastrointestinal
Preeti Khulbe (GI) complications, e.g., ulcers and erosions, in susceptible individuals.
Jaipur National University, NSAIDs can cause damage to the gastric mucosa via several
Jagatpura Jaipur, Rajasthan
mechanisms, including the topical irritant effect of these drugs on the
(India).
epithelium, impairment of the barrier properties of the mucosa,
suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood flow and
interference with the repair of superficial injury. This article describes the specific
gastrointestinal complications, risk factors due to NSAIDs and management of GI
complications due to NSAIDs. In this the special emphasis provided for all the drugs used,
formulation design and its consideration along with the disadvantages of NSAIDs and
antiulcer combination therapy.
KEYWORDS: Mucosal protective agents, Comparison PPI and H2 receptor blockers, food
constituents, probiotics, buffered formulation, chiral NSAIDs.
INTRODUCTION
Non-steroidal anti-inflammatory drugs are one of the mostly prescribed drugs all over the
word. Because of their over-the counter (OTC) availability, they are also available in non-
prescription basis as well. Though reasonably safe in most cases in prescribed dosages and
for short durations, these drugs cause gastrointestinal toxicity in a large number of cases.[1]
NSAIDs are one of the most commonly prescribed medicines for number of diseases.
NSAIDs are commonly used to treat rheumatoid arthritis, osteoarthritis, mild to moderate
pain and a lots of other conditions.
NSAIDs acts by inhibiting an enzyme called cyclooxygenase (COX). The COX enzyme has
two forms known as COX-1 and COX-2. COX-1 is an enzyme that produces a product that
helps protect the lining of the stomach, and COX-2 is involved in the process of
inflammation. Hence, when NSAIDs are given to the patient, they reduce inflammation but,
at the same time, inhibit an enzyme which is responsible for protecting the lining of the
stomach. As a result, NSAIDs are associated with ulcers and gastro-intestinal bleeding. So
NSAIDs are effective for a number of conditions but side effects associated with their use
limits their usefulness, particularly in case of long term use.[2]
NSAIDs can cause damage to the gastrointstinal mucosa via several mechanisms, including
the irritant effect of these drugs on the epithelium, impairment of the barrier properties of the
mucosa, suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood
flow and interference with the repair of superficial injury. The acid present in the lumen of
the stomach also participates to the pathogenesis of NSAID-induced ulcers and bleeding, by
impairing the restitution process, interfering with haemostasis and inactivating several growth
factors that are important in mucosal defence and repair.[4]
The gastrointestinal tract (GIT) is the major part of body which targets of NSAID toxicity. It
is the major organ affected by adverse drug reactions in all over the world. Unfortunately, it
is also the most common drug-induced toxicity that can be fatal. In all over the world, 35
million people consume these drugs on a daily basis, in which 30% of these users may
develop GI toxicity requiring a physician. It has estimated that about one third of the cost of
arthritis patients treatment relates to the side effects of NSAIDs. Conservative calculations
estimate that approximately 1,07,000 patients are hospitalised annually for non-steroidal anti-
inflammatory drug (NSAID)-related gastrointestinal (GI) complications and at-least 16,500
NSAID-related deaths occur each year among arthritis patients alone.[5]
Almost all useful therapeutic NSAIDs inhibit the synthesis of PGs4. Conventional NSAIDs
cause non-selective inhibition of COX, by which there is a reduction in bicarbonate secretion
and also reduction in mucous production. It is also reported that vasoconstriction that occurs
due to NSAIDs, also causes hypoxia and consequent formation of ulcer. Mainly major group
of NSAIDs are weak acids, having low pKa value. Therefore, they are unionised in stomach
and are absorbed mainly from stomach. However, once they reach to the cell membranes of
stomach and permeate within, they encounter a basic pH (like 7.1). This causes trapping of
the drugs. This topical effect is an important mechanism of gastrointestinal damage
associated with NSAIDs. Even short-term (< 1 week) use of aspirin and other nonsteroidal
anti-inflammatory drugs (NSAIDs) can generates ulcer-related bleeding.[6]
Complications of peptic ulcer disease are much more common in patients taking NSAIDs.
More than one half of patients who present with peptic ulcer or perforation report the recent
use of NSAIDs including aspirin. Many of these patients does not show any symptoms until
the life-threatening complications may develop. There are some major factors that clearly put
patients at increased risk for NSAID induced GI complications, these includes the
following.[9]
Use of NSAID has been associated with cardiovascular (CV), renal and gastrointestinal (GI)
complications and certain patients are at increased risk. NSAID use also results in small but
consistent increases in the risk of CV complications such as myocardial infarction, affected in
part by dose and potency of cyclooxygenase-2 (COX-2) inhibition. NSAID use has also long
been associated with kidney disease, resulting in both acute and chronic impairments in
kidney function.[11]
It is seen that potentially serious GI complications commonly appear with no clinical warning
symptoms suggestive of ulcers or bleeding. However, many NSAID uses complaint about the
increased frequency of various symptoms including reflux, belching, bloating and/or nausea
compared with nonusers, these symptoms do not reliably indicate the presence of significant
upper GI mucosal injury, which includes ulcers, bleeding, perforation, obstruction, and
extensive erosions. A prospective study found that bleeding complications occurred without
typical ulcer symptoms (epigastric pain or dyspepsia) in up to 80% of affected patients.
complications The rate of lower GI complications resulting from NSAID use has not been as
widely documented as that of upper GI damage, but such complications have been recognized
for decades. These injuries include bleeding in the large and small bowel, structures of the
small bowel, or exacerbation of existing illnesses such as inflammatory bowel disease.[14]
NSAIDs associated with many gastrointestinal problems, from mild to severe dyspeptic
symptoms, the development of gastric or duodenal ulceration, haemorrhage or perforation,
and other events which may lead to hospitalisation or death. Endoscopic studies have shown
a prevalence rate of 14%25% of gastric and duodenal ulcers in NSAID users, although the
difficulty of having accurate control groups makes exact figures difficult to obtain. The
endoscopic studies show more gastric than duodenal ulcers associated with NSAID use,
patients presenting with gastrointestinal bleeding on NSAIDs may have a similar frequency
of gastric and duodenal ulceration.[15]
The most common complications are bleeding and perforation present in the oesophagus,
stomach and duodenum due to NSAID effects on platelets and on a variety of mucosal
wounds. Complications arise from pre-existing peptic ulcer, NSAID-induced ulcers and
erosions and other lesions (not caused by the use of NSAIDs) caused to bleed by NSAID-
induced platelet dysfunction. There is a confusing term "NSAID gastropathy" used to
describe a variety of pathogenetically distinct mucosal wounds. Failure to differentiate
between the different forms of NSAID injury has encourage clinical investigation. This
article offers general guidelines for prevention of NSAID complications, but there remain
many unresolved issues, including the role of Helicobacter pylori infection.[16]
Described risk factors for developing NSAID related upper gastrointestinal side-effects and
complications are for example high age, previous peptic ulcer and/or bleeding, high dose of
NSAID, co-therapy with steroids and co-therapy with anticoagulants. This means, that for
example fragile and elderly patients tolerating a complication like bleeding or perforation
badly, must receive prophylactic treatment in connection with their NSAID treatment.[17]
Recent report in endoscopy, such as the development of capsule endoscopy (CE) and double
balloon (push) endoscopy, has described that small intestinal ulcerations induced by
nonsteroidal anti-inflammatory drugs (NSAIDs) in humans are more common and more
severe than previously thought. The small intestinal lesions cause bleeding, anemia, blood
loss, mal-absorption, diarrhoea, mucosal ulceration, occasional stricture due to diaphragmatic
disease, and perforation.[18]
Gastroduodenal or gastrointestinal ulceration and bleeding are the major limitations to the use
of non-steroidal anti-inflammatory drugs (NSAIDs). The development of safer NSAIDs or of
effective therapies for the prevention of the adverse effects of existing NSAIDs needs a better
understanding of the pathogenesis of NSAID-induced ulcer disease. They can affect almost
all parts of the gastrointestinal tract. In the mouth, they can cause oral ulceration, in
oesophagus, they can cause ulceration and structure deformation. In stomach and duodenum,
they can cause ulcers, severe bleeding, perforation, and obstruction. Most cases of NSAID-
induced gastrointestinal ulcers can heal spontaneously, even when the drug is continued.
However, in some they can cause serious toxicity requiring hospital admission and aggressive
management.[19]
MANAGEMENT
One of the approach to modify the NSAID structure for the prevention of such side-effects
have very less successful. For the problem of healing and preventing NSAID related
gastrointestinal problems such as ulcers and dyspeptic symptoms in patients who needed
continuous NSAID therapy is to combine the NSAID drug with an anti-ulcer drug approved
for the healing and/or prophylaxis of NSAID related gastrointestinal side-effects.[20]
Another approach for reducing side effects due to NSAIDs is the parenteral administration of
drug, but this also can cause damage and bleeding, associated by inhibition of the
biosynthesis of gastric prostaglandins, especially PGI2 and PGE2 that acts as cytoprotective
agents in the gastric mucosa. These eicosanoids, inhibits acid secretion by the secretion of
cytoprotective mucus in the intestine; inhibition of their synthesis may form the gastric region
more susceptible to damage.[21]
Mostly if the NSAIDs are stopped, majority of ulcers heal easily. If the medication cannot be
stopped, the dose may often be reduced. Even if your physician determines that continued
administration of NSAIDS is needed, healing can still occur.[22]
Anti-Ulcer Agents
Mucosal Protective Agents
It has already been described that Gastrointestinal side effects associated with NSAIDs are
caused by a decrease in PGs level in the gastric mucosa. It has therefore been proposed that
compensation for the reduction in mucosal PGs by administration of exogenous PGs may be
able to minimize NSAID-induced gastric side effects. Of the many PG derivatives that have
been synthesized to date, only misoprostol, a PGE1 derivative, is available commercially.
Furthermore, compounds with different (i.e., non-PG) chemical structures but similar
mucosal protective activity to PGs have been developed in Japan, and some of them are now
used as anti-ulcer drugs in Japan and other Asian countries. Several recent pilot studies using
CE have revealed that some of these latter drugs, as well as misoprostol, are effective in
limiting the GI side effects of aspirin and other NSAIDs.[23]
Antisecretory Agents
Though antisecretory drugs such as PPIs and H2-RAs are commonly used to prevent
gastrointestinal complications induced by NSAIDs, they are generally not considered to be
effective in mitigating NSAID-induced small intestinal lesions. However, it has been reported
that some PPIs and H2-RAs are able to prevent the formation of intestinal lesions induced by
indomethacin in rats.[24]
Food Constituents
It has also been seen that the development of intestinal complications by NSAIDs in rats, cats
and dogs depends on the feeding conditions; i.e., when NSAIDs were administered under
fasted conditions they did not cause any visible complications in the small intestine, but when
NSAIDs were administered after feeding they caused marked lesions in the small intestine.
These results suggest that food constituents may also influence the formation of intestinal
lesions.[25]
As per the most recent AGA (American Gastroenterological Association) Medical Position
Statement on the management of GERD for the treatment of patients with esophageal
GERD syndromes (healing esophagitis and symptomatic relief)PPIs are more effective than
H2RAs, which are more effective than placebo. All other recent consensus guidelines are in
agreement among them with regards to the above statement.
As per the ACG (American College of Gastroenterology) Updated guidelines for the
diagnosis and treatment of gastroesophageal reflux disease: The OTC [over the counter]
H2RAs are particularly useful when taken prior to an activity that may potentially result in
reflux symptoms (heavy meal or exercise in some patients). Many patients can predict when
they are going to suffer from reflux and can premedicate with the OTC H2RAs. Comparisons
between OTC H2RAs and antacids are limited. It has been suggested that antacids provide a
more rapid response, but gastric pH begins to rise less than 30 min after taking a dose of
H2RA so this does not seem to be a major factor. The peak potency of OTC H2RAs and
antacids are similar, but the H2RAs have a much longer duration of action (up to 10 h).[26]
Both the two majorly used antiulcer drugs PPIs and H2RAs were more effective than placebo
in maintaining a reestablishment of esophagitis and in maintaining symptom relief. However,
PPIs were more effective than H2RAs in maintaining a remission of esophagitis and in
maintaining symptom relief. On the other hand, there is also found to be statistically
significant increase in headache with PPIs compare with H2RAs. According to the Cochrane
review Healing doses of PPIs are more effective than all other therapies, although there is
an increase in overall adverse effects compared to placebo, and headache occurrence
compared to H2RAs. H2RAs prevent relapse more effectively than placebo, demonstrating a
role for PPI-intolerant patients.[27]
However, H2RAs have a faster onset of effect on the symptoms of GERD and NYD,
compared to PPIs. This time period is in the order of minutes or 1-2 hours. Of note, onset of
effect (when a patient has a noticeable improvement in his/her symptoms) is different from
complete resolution of symptoms (when a patient is completely symptom free, even from
mild, not-bothersome symptoms).
Pipkins et al reported that, in GERD patients, oral ranitidine or famotidine had a faster onset
of action compared to oral omeprazole or a lansoprazole: The H2RAs achieved a significantly
greater and more rapid rise in intragastric pH in the hour immediately after dosing and
offered a faster relief of symptoms. This suggests that H2RAs may be more effective than
PPIs for on-demand treatment for episodic heartburn or episodic dyspepsia.[28]
Two methods are commonly employed to prevent the development of peptic ulceration and
mucosal injury in patients taking NSAIDs: (i) co-therapy with a PPI, high-dose histamine- 2-
receptor antagonist (H 2 RA), or the synthetic prostaglandin E1 analogue, misoprostol; and
(ii) substitution of a COX-2 inhibitor for a traditional NSAID. Although co-therapy with a
standard-dose H 2 RA may prevent duodenal ulcers, it has not been shown to prevent NSAID-
related gastric ulceration. Enteric coating or buffering of NSAIDs and co-therapy with
sucralfate have not been shown to be effective in preventing NSAID-related gastric or
duodenal ulceration. Misoprostol was the agent approved for the prevention of NSAID-
related ulceration.[29]
COX-2 inhibitors - research for a less gastrotoxic NSAID led to the development of the
COX-2 inhibitors. It had been known for some time that NSAIDs inhibited the enzyme
cyclooxygenase (COX), leading to a significant decrease in prostaglandin production. COX
exists as two isozymes, COX-1 and COX-2. COX-1 is a constitutive enzyme and exists in
many body tissues, including the stomach, where it facilitates the production of those
prostaglandins considered to be important in gastric mucosal protection. COX-2, on the other
hand, is an inducible enzyme and is associated with inflammation in the joints. It was
postulated that the selective inhibition of COX-2 should lead to decreased inflammation in
musculoskeletal tissues and, by sparing COX-1, to a decrease in the incidence of GI mucosal
injury.[30]
A fixed combination also limits the choice of the anti-inflammatory component, which is an
issue for some patients who are allergic to a particular drug.[31]
FORMULATION DESIGN
For making an effective therapy of NSAIDs it is necessary to administer NSAIDs along with
an antiulcer drug. As above described that the most effective antiulcer drugs used in case of
NSAIDs related gastrointestinal complications are proton pump inhibitors. So here the
antiulcer drug refers to proton pump inhibitor (PPIs). Concurrent administration of antiulcer
drug with NSAIDs reduces the chances of gastrointestinal side effects associated with
NSAIDs. But the main fact is that the release of antiulcer drug in the formulation is optimized
so that the ulcerogenic effect of the NSAIDs can be reduced. The following release patterns
may be possible:
Buffered Formulation
Buffered formulation is one of the current approach which is available in combination of
NSAIDs and antiulcer drugs. These are the formulation containing agents which immediately
buffer the internal environment of the body and increases the stability of acid labile drugs
inside the body. Because most of the antiulcer drugs are acid labile. So for making such type
of formulation increases the stability of drug on the mean time it will also relief from the
gastrointestinal pain and stress due to ulcer by its buffering action.[34]
Lower-dose NSAID
New formulations of NSAIDs may reduce risks of adverse events by using lower doses while
providing effective analgesia. Some NSAIDs, such as diclofenac, could provide effective
pain relief at lower doses than are currently used, assuming 80% inhibition of COX-2 is
necessary for therapeutic efficacy. This would hypothetically provide effective pain relief
with an improved GI safety profile due to lessened inhibition of COX-1.20 A diclofenac
potassium liquid-filled capsule using a formulation designed to deliver diclofenac more
rapidly than conventional tablets was approved by the FDA in 2009.
The liquid-filled capsules is absorbed faster than that of diclofenac potassium immediate-
release tablets, and the capsules produce greater pain relief compared with placebo at lower
doses of diclofenac (25 mg four times daily) then that are generally used; however, it is
unclear whether they produce more rapid or effective pain relief than other diclofenac
formulations. Lower-dose capsules that contain finely milled, rapidly absorbed NSAID
particles may also provide analgesia at lower systemic doses. Low-dose diclofenac capsules
and indomethacin capsules (20 mg TID or 40 mg two times daily or TID) containing fine-
milled particles have been approved by the FDA for treatment of mild-to-moderate acute pain
in adults and have been found to provide effective relief of acute, postoperative pain in Phase
III studies.
Topical NSAIDs
NSAID-associated GI complications are dose dependent, so the development of topical
formulations is an effective approach that lower systemic exposure while providing pain
relief may reduce gastrointestinal pain and injury. Topical NSAID formulations can produce
higher concentrations of drug in local tissue with very low systemic exposure as measured via
plasma concentrations. Although topical NSAID formulations have been shown to be
effective in treatment of acute pain, and for short-term use in treating chronic pain, there are
conflicting results regarding whether topical NSAIDs provide effective long-term pain relief.
Further study is necessary to determine the long-term benefits and risks of topical NSAID
use.[35]
Moreover, PPIs can reduce NSAID absorption from GI tract; they can reduce the gastric acid
output to almost nil. Therefore, newer ways to modify the drugs have been developed.
Zwitterion phospholipids
One of the effective approach is to combining NSAIDs with phospholipids is that the
combination prevents the interaction of hydrophobic portion of cells to the drugs. This can
help in reducing damage. One such combination of acetylsalicylic acid and
dipalmitophosphatidylcholine retains analgesic and anti-inflammatory effects while
exhibiting more antipyretic effects. Its tendency to cause gastrointestinal damage is
significantly reduced.
Trefoil peptides
It is the family of cysteine-containing protective peptides normally secreted in GI tract. Oral
administration of these peptides has been shown to abrogate the GI damage produced by
indomethacin.[36]
Chiral NSAIDs
Another attempt is to purify some of the commonly used drugs such as ibuprofen that exist as
racemic mixtures. This is done following realisation that GI damage is caused by one of the
isoforms, while the other one is safer. Experiments in mice show that the S isoform leads to
usual mucosal damage, while R has substantially less propensity to do so.
Nitro-aspirins
Nitric oxide is responsible for most of the mucoprotective properties of prostaglandins.
Therefore, several NSAIDs like flurbiprofen, naproxen and diclofenac have been combined
AVAILABLE COMBINATIONS
S. No. Combination Reference
1. Aspirin- Omeprazole 41
2. Naproxen-Omeprazole 42
3. Naproxen-Esomeprazole 43
4. Diclofenac sodium/Misoprostol 44
5. Ibuprofen/Famotidine 44
6. Naproxen-Famotidine 45
7. Naproxen-pantoprazole 45
8. Aspirin- esomeprazole 46
9. Celecoxib-esomeprazole 47
10. Indomethacin-Omeprazole-Folic acid 48
CONCLUSION
The use of NSAIDs continues to increase, especially in the elderly. NSAIDs may have
adverse effects in any part of the gastrointestinal tract: oesophagus, stomach, duodenum,
small intestine, or colon. Risk factors for gastrointestinal damage due to NSAIDs include age,
previous ulcer history, first three months of treatment, smoking, underlying cardiovascular or
respiratory disease, concomitant drug use with corticosteroids and anticoagulants, high dose
and multiple NSAIDs and possibly in some cases H pylori. Low dose prophylactic aspirin
may also be associated with adverse gastrointestinal effects.[38]
Healing of NSAID related ulcers can be achieved while NSAIDs are continued by the use of
H2-receptor antagonists in high doses, or more effectively by proton pump inhibitors.
Prevention of NSAID related gastrointestinal problems may be achieved by identifying and if
possible reducing risk factors, the co-prescription of prostaglandin analogues or acid
suppressive drugs (especially proton pump inhibitors), or by using the currently being
developed and promising COX-2 specific inhibitors. The development of COX-2 specific
inhibitors offers the hope of real progress in producing much safer and effective NSAIDs.
Misoprostol, when given in full doses (800 mcg / day) is very effective in preventing ulcers,
and ulcer complications in patients taking NSAIDs. Unfortunately, its usefulness is limited by
its GI side effects. When given in lower doses its side-effect profile is the same as that of
PPIs and it is equally effective.[39]
PPIs significantly reduce gastric and duodenal ulcer sand their complications in patients
taking NSAIDs or COX-2 inhibitors. Although superior to placebo, high-dose H2RAs can
reduce the risk of NSAID-induced endoscopic peptic ulcers. -are significantly less effective
than PPIs, however, there is no clinical outcome data to prove that this strategy prevents ulcer
complications.[40]
ACKNOWLEDGEMENT
I acknowledge my colleagues, seniors, parents and my dear husband for their support and
motivation.
REFERENCES
1. Vikas Dhikav, Sindhu Singh, Swati Pande, Atul Chawla, Kuljeet Singh Anand Non-
Steroidal Drug-induced Gastrointestinal Toxicity: Mechanisms And Management,
JIACM, 2003; 4(4): 315-22.
2. Rajneesh Taneja, patent WO 2004060372 A1, Dosage forms containing a proton pump
inhibitor, a nsaid, and a buffer, 2004.
3. Plachetka, patent US 6,926,907 B2, Pharmaceutical compositions for the coordinated
delivery of NSAIDs, 2005.
4. Best Practice & Research Clinical Gastroenterology, 2000; 14(1): 147159.
5. Singh G. Recent considerations in non-steroidal anti-inflammatory drug gastropathy. Am
J Med, 1998; 105(1B): 31S-38S.
6. Wilcox, C Mel et al. Striking prevalence of over-the-counter non-steroidal anti-
inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Intern
Med, 1994; 154: 42-6.
7. Kurahur K, Matuhot, Iide M et al. Clinical and endoscopic features of non-steroidal anti-
inflammatory drug-induced colonic ulceration. Am J Gastroenterol, 2001; 96: 473-80.
8. R I Russell, Non-steroidal anti-inflammatory drugs and gastrointestinal damage problems
and solutions, Postgrad Med J., 2001; 77: 8288.
9. Soll AH, McCarthy D., NSAID-related gastrointestinal complications. Clin
Cornerstone. 1999; 1(5): 42-56.
10. Yeomans YD, Tulassay Z, Juhsz L et al. A Comparison of omeprazole with ranitidine
for ulcers associated with nonsteroidal anti-inflammatory drugs. The acid suppression
trial: ranitidine versus omeprazole for NSAID-associated ulcer treatment (ASTRONAUT)
study group. N Eng J Med, 1998; 338: 719-26.
11. Bjarnason I, Zanelli G, Smith T et al. NSAID induced intestinal inflammation in human.
Lancet, 1987; 2: 711-4.
12. Jay L Goldstein, Byron Cryer, Gastrointestinal injury associated with NSAID use: a case
study and review of risk factors and preventative strategies, Drug, Healthcare and Patient
Safety, 2015; 7: 3141.
13. Chan FKL, Sung JJY, Suen R, et al. Does eradication of H pylori impair healing of non-
steroidal anti-inflammatory drug associated bleeding peptic ulcers? A prospective
randomised study. Aliment Pharmacol Ther, 1998; 12: 12015.
14. Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer
bleeding. BMJ, 1995; 310: 82730.
15. DeWitt DL, Meade EA, Smith WL. Prostaglandin H synthase isoenzyme activity: the
potential for safer nonsteroidal anti-inflammatory drugs. Am J Med, 1993; 95: 40S6.
16. Ehsanullah RSB, Page MC, Tildesley G, et al. Prevention of gastroduodenal damage
induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine. BMJ,
1988; 297: 101721.
17. Russell RI. Endoscopic evaluation of etodolac and naproxen and their effects on gastric
and duodenal prostaglandins. Rheumatol Intern, 1990; 10(suppl): 1721.
18. Patent US 6365184 B1, Oral pharmaceutical dosage forms comprising a proton pump
inhibitor and a NSAID.
19. H. Satoh and K. Takeuchi, Management of NSAID/Aspirin-Induced Small Intestinal
Damage by GI-Sparing NSAIDs, Anti-Ulcer Drugs and Food Constituents, Current
Medicinal Chemistry, 2012; 19: 82-89.
20. Guess, H.A. et al. "Fatal upper gastrointestinal hemorrhage or perforation" J. Clin.
Epidimol, 1988; 41: 35-45.
21. Hawkey C. "Non-steroidal anti-inflammatory drugs and peptic ulcers.", 1990; 300:
278-284.
22. Larkai, E.N. et al. "Gastroduodenal mucosa and dyspeptic symptoms" Am. J.
Gastroenterology, 1987; 82: 1153.
23. Bjarnason, I.; Smethurst, P.; Fenn, C.G.; Lee, C.H.; Menzies, I.S.; Levi, A.J. Misoprostol
reduces indomethacin-induced changes in human small intestinal permeability. Dig. Dis.
Sci., 1989; 34: 407-411.
24. Watanabe, T.; Sugimori, S.; Kameda, S.; Machida, H.; Okazaki, H.; Tanigawa, T.;
Watanabe, K.; Tominaga, K.; Fujiwara, Y.; Oshitani, N.; Higuchi, K.; Arakawa, T. Small
bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot
study. Clin. Gastroenterol. Hepatol., 2008; 6: 1279-1282.
25. Watanabe, T.; Higuchi, K.; Kobata, A.; Nishio, H.; Tanigawa, T.; Shibata, M.; Tominaga,
K.; Fujiwara, Y.; Oshitani, N.; Asahara, T.; Nomoto, K.; Takeuchi, K.; Arakawa, T. Non-
steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4
dependent. Gut, 2008; 57: 181-187.
26. American College of Gastroenterology, ulcer and gastrointestinal bleeding: protecting
your health, report.
27. Scarpignato, C. NSAID-induced intestinal damage: are luminal bacteria the therapeutic
target? Gut, 2008; 57: 145-148.
28. Pipkin GA, Mills JG. Onset of action of antisecretory drugs: beneficial effects of a rapid
increase in intragastric pH in acid reflux disease. Scand J Gastroenterol Suppl. 1999; 230:
3-8.
29. Grigorios I. Leontiadis, Antiulcer medicines: Review for section update, WHO
Secretariat, Division of Gastroenterology, McMaster University, Hamilton ON, Canada
pg:1-18.
30. DeVault K.R., Castell D.O. Updated guidelines for the diagnosis and treatment of
gastroesophageal reflux disease. Am J Gastroenterol. 2005; 100(1): 190-200.
31. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890976 accessed on 16 June 2016.
32. Peura DA, Freston JW, Haber MM, et al. Lansoprazole for long-term maintenance
therapy of erosive esophagitis: double-blind comparison with ranitidine. Dig Dis Sci.
2009; 54: 955-63.
33. Park, S-H.; Cho, C-S.; Lee, O-Y.; Jun, J-B.; Lin, S-R.; Zhou, L-Y.; Yuan, YZ.; Li, Z-S.;
Hou, X-H.; Zhao, H-C.; Kachintorn, U.; Kositchaiwat, C.; Lertkupinit, C. Comparison of
prevention of NSAID-induced gastrointestinal complications by rebamipide and
misoprostol: a randomized, multicenter, controlled trial-STORM study. J. Clin. Biochem.
Nutr., 2007; 40: 148-155.
34. The theory and Practice of Industrial Pharmacy, Leon Lachman, Herbert A. Lieberman,
Joseph L. Kanig. Third Indian Edition, Varghese Publishing house Hind Rajasthan
Building, Dadar Bombay 400014, 1987.
35. United States Patent 8999384.
36. Micheal MW. Future trends in the development of safer NSAIDs. Am J Med. 1998;
15(5A): 44S-52S.
37. Carbaza A, Carbre F, Rotten E et al. Stereo-selective inhibition of cyclooxygenase by
chiral NSAIDs. J Clin Pharmacol. 1996; 505-12.
38. Satoh, H.; Inatomi, N.; Nagaya, H.; Inada, I.; Nohara, A.; Nakamura, N.; Maki, Y.
Antisecretory and antiulcer activities of a novel proton pump inhibitor AG-1749 in dogs
and rats. J. Pharmacol. Exp. Ther., 1989; 248: 806-815.
39. Takeuchi, K.; Tanigami, M.; Amagase, K.; Ochi, A.; Okuda, S.; Hatazawa, R.
Endogenous prostaglandin E2 accelerates healing of indomethacininduced small intestinal
lesions through upregulation of vascular endothelial growth factor expression by
activation of EP4 receptors. J. Gastroenterol. Hepatol., 2010; 25(suppl 1): S67-S74.
40. Frank L. Lanza, Francis K.L., Eamonn M.M. Guidelines for Prevention of NSAID-
Related Ulcer Complications, Am J Gastroenterol. 2009; 104: 728 738.
41. Bliden KP, Brener M, Gesheff MG, Franzese CJ, Tabrizchi A, Tantry U, Gurbel PA, PA
tablets: investigational compounds combining aspirin and omeprazole for
cardioprotection. Future Cardiol. 2013 Nov; 9(6): 785-97.
42. Marc Hochberg, Jay L. Goldstein, John G. Fort, Mark Sostek, John Plachetka, A novel,
single-tablet formulation that delivers immediate-release omeprazole followed by enteric-
coated (EC) naproxen significantly reduces the incidence of gastric ulcers compared with
EC naproxen alone: results of a prospective, randomised, double-blind, 6-month study
including patients with OA and RA, 2Department of Medicine, University of Illinois at
Chicago, Chicago, Illinois, USA.
43. Philip miner, john plachetka, eric orlemans, Pharmacokinetics of naproxen and
esomeprazole in PN400, a single tablet multilayer formulation of enteric coated naproxen
couples with immediate release esomeprazole. Oklahoma foundation of digestive disease
research, Oklahoma city USA.
44. Therapeutic Class Overview: nonsteroidal anti-inflammatory drug/anti-ulcer agent
combinations, catamaran, university of Massachusetts medical school, review.
45. John R. Plachetka, patent US6926907, Pharmaceutical compositions for the coordinated
delivery of NSAIDs, 2005.