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IOSR Journal of Pharmacy and Biological Sciences (IOSR-JPBS)
e-ISSN:2278-3008, p-ISSN:2319-7676. Volume 12, Issue 6 Ver. V (Nov. – Dec. 2017), PP 80-85
www.iosrjournals.org
DOI: 10.9790/3008-1206058085 www.iosrjournals.org 80 | Page
Treatment of Peptic Ulcer; Current Status And Potential
Strategies
1Manoj G Tyagi+*, 2K Arumugamsamy, 3Privy Varshney*, 4Harsh Mishra*
5Dinesh J Vyas
Department of PharmacologyMahatma Gandhi Dental College+Jaipur,
45Rajasthan and Rama Medical College*, Hapur, Uttarpradesh, India
Author for Correspondence:Dr.Manoj G Tyagi
Abstract: Peptic ulcer is disease of the gastric mucosa in which there is erosion and inflammation. The disease
is caused by the imbalance between the bicarbonate and acid that is generated in the gastric and duodenal area
of the gastrointestinal tract. Ulcers can develop in the esophagus, stomach or duodenum, or at the margin of a
gastroenterostomy, in the jejunum, in Zollinger-Ellison syndrome, and in association with a Meckel's
diverticulum containing ectopic gastric mucosa. Peptic ulcer disease is one of several disorders of the upper
gastrointestinal tract that is caused, at least partially, by gastric acid. Gastric acid secretion is regulated by
anextensive collection of neural stimuli and endocrine and paracrine agents, which act either directly at
membrane receptors of the parietal cell or indirectly through other regulatory cells of the gastric mucosa, as
well as mechanical and chemical stimuli. In this review, we have tried to condense the current body of
knowledge about the modulating action of inflammatory mediators on the pathophysiology of gastric acid
secretion and update its significance based on recent findings in gastric mucosa and parietal cells in humans
and animal models as well the current and potential strategies for its therapy.
Keywords:Ulcer, PUFA, mucosa, inflammation, carbonic anhydrase, stem cells
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Date of Submission: 05-12-2017 Date of acceptance: 19-12-2017
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I. Introduction
Peptic ulcer disease is characterized by inflamed lesions or excavations (ulcers) of the gastric mucosa
and underlying tissue of the upper gastrointestinal tract. The ulcers are caused by the damage to the mucous
membrane that normally protects the esophagus, stomach and the duodenum from the gastric acid and pepsin.
The damage can be caused by several factors, including excessive acid and pepsin production, bile acid reflux,
advancing age, ischemia and in many cases infection with Helicobacter pylori bacteria and inhibition of the
prostaglandins (1). Oxidative stress has been found to be the major pathogenic factor in the progression of ulcer
that directly impairs the cellular functions and promotes cellular organelles damage in the cells, including
mitochondria and nucleus. The nitric oxide (NO) is accepted as a vital mediator of GIT mucosal defense as
decreased NO generation or synthesis contribute to the pathogenesis of ulcer disease (2). Recent findings show
significance of polyunsaturated fatty acids (PUFAs) in numerous clinical ailments, so observing the
consequence of PUFAs in several of the clinical situations.On the other hand it was suggested that insufficiency
of PUFAs in particular the gamma-linoleic acid, di-homo-gamma-linolenic acid and eicosapentanoic acid might
be accountable for the development of peptic ulcers (3,4). PUFAs hold the capacity to obstruct the development
of H.pylori, decrease the acid formation and release in experimental animals, in individuals and also in the
improvement in the condition by amplifying the action of PGE1 prostaglandin.There has been substantial
progress in the understanding of the peptic ulcer patho-physiology and its treatment. This review tries to
encompass some of the recent developments relating to this chronic disorder.
1.1Helicobacter Pylori and recent advances in its pathological role in ulcers
In the Western countries, the number of persons who harbour the H.pylori increases from under 5 % at birth
to about 20 % and at the age of 45 years only a small proportion of persons harbouring this bacterial organisms will
develop this disease. H.pylori induced gastritis precedes the development of peptic ulcers in most cases. H.pylori is
found at gastrointestinal tract of duodenal ulcers and 70% patients of gastric ulcers (5). The organism is known to
attach to the mucosa and mucosal epithelial cells and release enzymes that damage the mucous membrane and
mucosal cells and cause inflammation and tissue destruction. Evidence also suggests that eradication of H.pylori heals
peptic ulcers and reduces recurrence of duodenal and gastric ulcers. Approximately 10% of those infected with the
H.pylori will develop peptic ulcer disease. The bacterial genetic locus most closely associated with the development
of peptic ulcer and gastric cancer is the H.pylori Cag pathogenecity island (Cag PAI) a 40 kb DNA segment that
Treatment of peptic ulcer; current status and potential strategies
DOI: 10.9790/3008-1206058085 www.iosrjournals.org 81 | Page
encodes a type IV secretion that encodes a type IV secretion system (6).
1.2 Influence of Adenosine in gastric acid secretion
The exact role adenosine has in the parietal cell function or the gastric gland physiology in humans is
not well delineated. Although findings in the human gastric mucosa are the most attractive and important for
obvious reasons, the inference is inconclusive yet. Studies addressed adenosine deaminase (ADA) activity in
mucosal biopsies in patients with a diversity of pathologies. Adenosineis considered to have an anti-
inflammatory action (7). However, in H. pylori-infected patients or in patients with chronic gastritis (8),no
correlation between ADA activity and mucosal inflammationwas found. A positive correlation between ADA
activity and basaland maximal gastric acid output was found in the fundic mucosa, suggesting a protective,
negative influence of adenosine on acid secretion from fundic parietal cells. However, considering the low
proportion of H+/K+-ATPasepositive cells in the fundic area of the human stomach and that 95% of parietal
cells were found within the oxyntic mucosa of the stomach (9), the physiologic relevance ofthese findings may
be under scrutiny. Given the differences between species, extrapolation of the findings in animalmodels to
humans should be avoided (Fig.1).
Fig.1: Innervation of the gastric mucosa (Courtesy:Rosa M Amin et al, Front. Physiol. 8:737, 2017)
1.3 Role of Ghrelin and somatostatin
Ghrelin is a peptide that defines the anatomical body of the human stomach and seems to induce acid
secretion and hunger by stimulating histamine production by ECL cells (10). Other compounds have been also
reported to affect directly or indirectly gastric acid secretion. The effect of compounds like interleukin-1β,
neurotensin, nitric oxide, oxyntomodulin, secretin, and serotonin is most likely inhibitory, although it remains a
matter of debate (11).Somatostatin is themain negative regulator of acid secretion. It isa hormone and paracrine
peptide produced in the stomach by D cells. These cells are present in the oxyntic mucosa, where they
negatively regulate ECL and parietal cell function, and also inthe antral mucosa, where they negatively regulate
G cell function (12). The physiology and morphology of both cell populations is also different. D cells secrete
somatostatin in response to several stimuli. One of them is gastrin, which induces somatostatin secretion, which
in turn inhibits gastrin secretion from G cells. Therefore, the gastrin-somatostatin axis constitutes a negative
feedback mechanism that maintains gastrin levels and acid secretion under control. Another positive stimulus is
cholecystokinin (CCK), a peptide hormone secreted by the small intestine I cells as a response to luminal lipids;
by stimulating somatostatin secretion CCK inhibits acid secretion during intestinal digestion. Luminal pH is
probably the most important inducer of somatostatin release. Antral D cells are often called open type, because
they possess extensions that make contact with the luminal content (13).
1.4 Nanolipobead based drug delivery system for treating peptic ulcer
Artificial particulate systems such as the polymeric beads and liposomes are finding a variety of
biomedical applications in drug delivery, drug targeting, protein separation, enzyme immobilization and in
Treatment of peptic ulcer; current status and potential strategies
DOI: 10.9790/3008-1206058085 www.iosrjournals.org 82 | Page
blood cell substitution. Liposomes have a flexible, cell‐like lipidbilayer surface which acts as a permeability
barrier such that compounds can be entrapped in their aqueous interior. However, liposomes can be
mechanically unstable and their loading capacitylimited by the water solubility of the material to be loaded.
Polymeric beads, although mechanically more stable and having a larger loading capacity then liposomes, lack
many of the useful surface properties of a lipid bilayer shell (14-15). Recently the preparation and
characterization a new hybrid vesicle system with structural similarity to natural cells that combines
complementary advantages of liposomes and polymeric beads this system which have been called 'Lipobeads'
consists of a lipid bilayer shell that is anchored on the surface of a hydrogel polymer core. H. pylori was shown
previously to bind to a specific alkylacyl glycerolipid derived from human erythrocytes, HEP2 cells and human
antral epithelium. Furthermore cultured human cells with less PE show minimal attachment of H. pylori in
vitroemphasizing the importance of PE–H. Pylori interaction. In bacterial adhesion PE is a predominant lipid in
the antrum of the human stomach and functions as a receptor for H. pylori adhesion. Correlation of the ability of
H. pylori to adhere to eukaryotic cells with the detected presence of the PE receptor, however underscores the
importance of this lipid as a major receptor in promoting H.pylori adhesion to intact cells. PE bacterial adhesin
exists as a cell surfaceassociated ligand (16,17). On the basis of the above facts, anti-adhesion drug delivery
system based on PE has been developed as a receptor‐mediated drug delivery system for use in blocking
adhesion of Helicobacter and thereby preventing the sequelae of chronic gastric infections.
1.5 Gastroprotective role of PUFAs
Amongst the long chain PUFAs theOmega-3 (n-3) polyunsaturated fatty acids [n-3
PUFAs,eicosapentaenoic acid (EPA 20:5n-3), and docosahexaenoic acid (DHA 22:6n-3)] are the PUFAs, which
are essential fatty acids as they can be synthesized by mammals from other dietary precursors which contain n-3
PUFAs. They are sufficiently found in fish. Fatty acids are key nutrients affecting early growth and
development and preventing chronic disease in later life (18). PUFAs that contain more than one carbon double
bond are divided into two major classes, namely, the n-6 and n-3 (Figure 1). Several lipid metabolites can be
made from these PUFAs. Linoleic acid (LA 18:2n-6) is a representative n-6 PUFA, which is the precursor of
arachidonic acid (AA 20:4n-6) that is involved in inflammation, inducing cardiovascular diseases, diabetes,
cancer, and age-related diseases. n-3 PUFAs suppressed the activation of EGFR, PKC and interleukin levels.
Sardine oilcontains comparatively high amount of PUFA and n-3 PUFA dominant among fatty acids (19). The
gas chromatographic analysis of Sardine (Sardinella longiceps) fish oil highlighting nutritionally significant n-3
PUFA (like EPA and DHA) and they contribute to the major bioactivity of the oil. The protective effects were
linked to their anti-oxidant properties.The the anti-inflammatory activity of these n3 and n6containing PUFA
containing oils reduced the TNF alpha levels and increased the PGE2 levels(20). This treatmentoffers
cytoprotection by increasing inhibition of TNF-α andneutrophil infiltration in mucus. Thus these PUFA
containingoils ultimately inhibit tissue destruction by reactive oxygenshowed good gastro-protective anti-
ulcerogenic activityspecies.The data obtained from studies carried out by this author suggests that thePUFA
containing oils used in this study i.e. the fish oil andArasco oil the n-6 PUFA contained in Arasco oil were able
toattenuate the ulcer formation as calculated based on the ulcerindex (21). Dietary supplementation with n-6
fatty acid rich inLA has been found to influence the physiological function of various blood components,
producing an inhibitory effect onleucocyte adhesion, platelet count, platelet aggregation andcollagen formation.
Dietary supplementation with n-3PUFAs improved colonic anastomoses healing. n-3 PUFAsenhance the
colonic wound healing in a rat model. Actually,n-3 PUFAs may prompt faster resolution of inflammationwithin
the wound microenvironment, which leads tofacilitated regeneration and re-epithelialization.A smallrandomized
controlled trial evaluated a formula supplementedwith fish oil in patients with pressure ulcers and
noteddecreased progression of pressure ulcers in those receivingfish oil supplementation. There is growing
evidence that thediverse biological roles of n-3 PUFAs contribute to theirregenerative actions against chronic
inflammatory disease.
1.6 Carbonic Anhydrase (CA) Activity in the Intermediate Level of Acid Secretion
Carbonic anhydrase is an important enzyme regulating the acid-base balance in the body. The involvement of
CA I and CA IV in gastric acid secretion, effect of CA inhibitors in reducing HCl secretion and their healing
eٴوect ongastric and duodenal ulcers is now well documented (22). In vivo results,performed in humans, show
that omeprazole inhibits not only H+/K+ATPase, but also CA II and CA IV, isozymes present in large
quantitiesin the cytosol, in the walls of the secretory canaliculi, and in theparietal cell membrane. Further,
gastric acid secretion is inhibited inhumans after oral administration of acetazolamide in therapeuticdoses of 25
mg/kg of body weight (23). Acetazolamide exhibit anti-ulceraction in acute experiments because of inhibition of
CA-II, but itseffect on Gastric ATPase is not clear.Sulfonamides with the general formula RSO2NH2 constitute
a wideclass of inhibitors of the zinc enzyme carbonic anhydrase (CA). Acetazolamide, a classic sulfonamide
drug has also been reported toreduce gastric acid secretion commensurate with gastric carbonic anhydrase
Treatment of peptic ulcer; current status and potential strategies
DOI: 10.9790/3008-1206058085 www.iosrjournals.org 83 | Page
inhibition (23). Correlating in vivo results with the dataobtained in vitro suggests that gastric mucosa CA I, II,
and IVinhibition is induced by sulfenamide, the active form of omeprazole, thus this class of compound can be
interesting leads for furtherexploration of anti-ulcer action (Table 1).
1.7 Association of peptic ulcer disease with anthropometric, blood parameters and nutrition:
Recent findings areconsistent with the results of previous studies; specifically, as it was found that
weight, hip circumference (HipC), and BMI in women and HipC in men were highly associated with peptic
ulcer disease (PUD) in both thecrude and adjusted analyses. Therefore, it was suggested that PUD may be
associated with anthropometric indices such as weight, BMI, and HipC in women, but not in men, although
therewas not a strong association between PUD and anthropometric indices in the Koreanpopulation (24-
26).Regarding nutritional components, some studies have argued that high dietary fiber intakeis associated with
PUD, gastric cancer, and gastroesophageal reflux disease, when comparedwith low dietary fiber intake, and that
intake of vitamin A and C is related to PUD. Anderson and colleagues suggested that a high intake of dietary
fiber reducedthe risk of gastrointestinal and duodenal ulcer, coronary heart disease, diabetes, obesity, andstroke.
Additionally, Ryan-Harshman and Aldoorireported that a high-fiber diet andsoluble fiber intake appeared to
decrease the risk of duodenal ulcer (27).Aldoori and colleaguesreported that dietary fiber intake was inversely
related to the risk of duodenal ulcer in USmen when comparing the highest and lowest quintiles of dietary fiber
intake. In another study, Aldooriand colleagues found that vitamins A and E were associated with the risk of
duodenalulcer and that vitamin A and fiber could possibly reduce the development of duodenal ulcer.They
argued that vitamin B2 and potassium were inversely associated with the risk of duodenalulcer. Miyake and
colleagues reported that a lack of water-soluble vitamins could accelerate the development of PUD in Japanese
adults (28). Additionally, Aditi and Graham documented that Vitamin C (ascorbic acid) plays a very important
role in the conservation andtreatment of the gastric mucosa and that deficiency in vitamin C has repeatedly been
linked with PUD (29).
1.8Stem cell based therapy for peptic ulcer
Stem cell based transplantation has been found to be effective for the treatment of various
disorders.Engevik and colleagues show that gastric stem cells isolated from young mice can be transplanted into
sites of injury within the stomachs of older mice, and that this results in accelerated repair (30). The ability of
the transplanted young mouse cells, but not stem cells from older mice, to differentiate into a specialized cell
type, termed SPEM, which is central to the healing process, appears to be a key component of this intervention.
While more work needs to be done, it is clear that this approach, or other means of inducing older cells to
differentiate into SPEM, would be powerful in treatment of gastric injury.Gastric stem cells isolated from young
mice have been experimentally transplanted into older mice with stomach ulcer (31-32). The transplanted cells
which replaced cells at the site of injury were observed and found to speed-up the healing process. These stem
cells from older mice were unable to differentiate into the specialized cell type which is responsible for the
healing process.
II. Conclusions
The advent of peptic ulcer disease with time is both complex and interesting. Although its incidences
were rare before the 18th century, withtime and change in life style its incidences have increased significantly.
Various therapeutic strategies have evolved over time for itsclinical management. However, considering the
involvement of multiple factorsin its etiology, it has not been possible to provide an ideal solution tocompletely
cure its manifestations. Traditional use of antacids and use ofhistamine inhibitors are important for the
management ofpeptic ulcer disease. Irreversible inhibition of proton pump although reducesulceration, but in the
long run leads to adverse issues. It has not been possible to develop an ideal proton pump inhibitor. In this
scenario,search for alternatives by capitalizing on the multifactorial etiology ofulceration holds promise.
However, these searches are far from overand require further investigations to develop ideal antiulcer agents,
although the disease can be substantially controlled by pharmacotherapeutic interventions.
Table 1: Current treatment regimen for H.pylori infected peptic ulcer
Therapy
Drugs
Dose
Duration
Triple therapy
1.Lansoprazole
2.Amoxicillin
3.Clarithromycin
60 mg/12 hourly
1g/ 12 hourly
500mg/12 hourly
10-15 days
Triple therapy
(Penicillin allergy)
1.Omeprazole
2.Metronidazole
3.Clarithomycin
40mg/12 hourly
500mg/12 hourly
500mg/12 hourly
10-15 days
Quadrapule therapy
1.Lansoprazole
2 Amoxicillin
30 mg/12 hourly
500mg/12 hourly
10-15 days
Treatment of peptic ulcer; current status and potential strategies
DOI: 10.9790/3008-1206058085 www.iosrjournals.org 84 | Page
3.Clarithromycin
4.Metronidazole
500mg/12 hourly
500mg/12 hourly
Therapy in resistant cases I
1.Lansoprazole
2 Amoxicillin
3.Levofloxacin
30 mg/12 hourly
1g/12 hourly
500mg/12 hourly
10-12 days
Therapy in resistant cases II
1.Lansoprazole
2Bismuth
3.Tetracycline
4.Metronidazole
30 mg/12 h
120 mg/6 h
500 mg/6 h
500 mg/8 h
10-15 days
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Manoj G Tyagi*,."Treatment of Peptic Ulcer; Current Status And Potential Strategies." IOSR
Journal of Pharmacy and Biological Sciences (IOSR-JPBS) 12.6 (2017): 80-85.
IOSR Journal of Pharmacy and Biological Sciences (IOSR-JPBS) is UGC approved Journal
with Sl. No. 5012, Journal no. 49063.
