review article pathogenesis of peptic ulcer disease

Indian J Physiol Pharmacol 1997; 41(1): 3-15

REVIEW ARTICLE

PATHOGENESIS OF PEPTIC ULCER DISEASE AND CURRENTTRENDS IN THERAPY

JAGRUTI K DESAI, RAMESH K GOYAL* AND NARAYAN S. PARMAR**

*Department of Pharmacology,L.M. College of Pharmacy,Naurangpura,Ahmedabad- 380 009

and**K.B. Institute of Pharmaceutical

Education and Research, Sector 23,Gandhinagar - 382 023

( Received on February 14, 1996 )

Abstract : Traditionally drugs used in peptic ulcer have been directed mainly againsta single luminal damaging agent i.e. hydrochloric acid and a plethora of drugs likeantacids, anticholinergics, histamine H2-antagonists etc. have flooded the market. Anincrease in 'aggressive' factors like acid and pepsin is found only in a minority of pepticulcer patients. These factors do not alter during or after spontaneous healing. It is well-known that the gastric mucosa can resist auto-digestion though it is exposed to numerous'insults' like high concentration of hydrochloric acid, pepsin, reflux of bile, spicy food,microorganisms and at times alcohol and irritant drugs. It is thus evident that theintegrity of the gastric mucosa is maintained by defense mechanisms against these'aggressive' damaging factors. Recently, attention has been focussed more ongastroduodenal defense mechanisms leading to the concept of 'Cytoprotection'. The olddictum "no acid - no ulcer" now extends to "if acid - why ulcer"? as a fundamentalquestion. During last decade more information has poured in about the prevalence andchanging pattern of the disease, the influence of environmental factors and speculationon the role of a recently characterized bacterial organism, Helicobacter pylori whichcolonizes in the gastric mucosa, particularly the antral region. This review brieflydescribes current knowledge about the pathogenesis of peptic ulcer disease and discussesstrategies for its treatment.

Key words: gastric ulcers duodenal ulcersNSAIDs anti-secretory agents

Helicobacter pylori

INTRODUCTION

Gastric and duodenal ulcer or peptic ulcerdisease (PUD), Zollinger-Ellison Syndrome (ZE)and gastroesophageal reflux disease (GRD) areupper gastrointestinal disorders sharing acommon abnormality: too much acid and pepsinactivity for the degree of local tissue resistance.Hydrolytic and proteolytic digestion of theexposed mucosa occur followed by inflammation,necrosis and ulceration. Gastric hypersecretionappears to be the primary causative event at

one end of the disease spectrum as 93% of thepatients afflicted with Zollinger EllisonSyndrome is characterized by single or multiplenon-beta islet cell adenomas of the pancreaswhich releases large quantities of gastrin inplasma resulting in a 10-20 fold increase in theamount of acid secreted and a high incidence ofulcers. At the opposite end of the spectrum acidsecretion plays a lesser role and mucosalresistance becomes more important. Gastriculcers are typified by a reduced basal andstimulated acid output. Some acid is however,

*Corresponding Author

4 Desai et al

always required as peptic ulcer disease rarelydevelops in patients of achlorhydria. The othercauses of peptic ulcer disease includeHelicobacter pylori infection, non-steroidal antiinflammatory agents (NSAIDs) and malignancy.Recent evidence relates H. pylori to thepathogenesis of chronic duodenal ulceration asH. pylori infection and antral gastritis are foundtogether in more than 95% of patients withduodenal ulcer. H. pylori is a very powerfulproducer of urease and may cause ulceration bycausing hydrolysis of urea which leads togeneration of cytotoxic ammonia. The NSAIDswhen administered orally cause local irritation,allow back diffusion of acid into the gastricmucosa and induce tissue damage, whereas,parenterally administered NSAIDs can alsocause gastric mucosal damage and bleedingcorrelated with the inhibition of the biosynthesisof gastric prostaglandins (PG) especially PGIand PGE.

Defense of normal gastric mucosa against aggressivefactors:

Three basic levels of defense underlie theremarkable ability of normal gastroduodenalmucosa to resist injury from the acid and pepticactivity in gastric juice.

1. Surface epithelial cells secrete mucus andbicarbonate, creating a pH gradient in themucus layer and change the very acidicgastric lumen to the nearly neutral surfaceof the mucosa (1).

2. Gastric mucosal cells have a specializedapical surface membrane that resists thediffusion of acid back into the cell.

3. Mucosal cells may directly resist injury byintrinsic mechanisms, such as the extrusionof back-diffused hydrogen ions by means ofbasolateral carriers (e.g. sodium-hydrogen orsodium bicarbonate exchange) (2),

Indian J Physiol Pharmacal 1997; 41(1)

The rapid repair of injury to mucosais essential to maintain the mucosalintegrity. Surface epithelial cells continuallyslough, and the gaps are resealed byadjacent cells that move to fill them by cellreplication in response to still unknown trophicsignals (3). Blood flow in normal mucosaremoves the acid that has diffused across acompromised mucosa. Prostaglandins enhancethe mucosa's resistance to injury undercertain conditions, perhaps by increasingmucosal blood flow (4,5), stimulating thesecretion of mucus and bicarbonate (6),strengthening of the gastric mucosal barrier,decreasing the gastric motility (7), increasingrelease of endogenous mediators of gastriccytoprotection like sulfhydryls (8) and epidermalgrowth factor (9) etc., scavanging of free radicals(10), decreasing release of endogenous mediatorsof gastric injury, vasoactive amines andleukotrienes (11) and stimulation of cellulargrowth and repair (12).

In general it can be said that there is aplethora of mechanisms underlying the defenseof normal gastric mucosa and their relativeimportance and interdependence is far fromclear. This itself may be a pointer' that normalgastric defense may be a multifactorialphenomenon.

Acid secretion and peptic ulcers:

The formation of peptic ulcers dependcritically on the presence of acid and pepticactivity in gastric juice. About one third ofpatients with duodenal ulcer, but not gastriculcer, secrete excess gastric acid. Schwartz's (13)dictum "no acid - no ulcer" is more accurate ifamplified to "no acid and peptic activity - noulcer" as acid without pepsin has little digestivepower. The dependence of peptic activityis supported by the therapeutic effects

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Indian J Physiol Pharmacol 1997; 41(1)

of the antacids and antisecretory drugs(anticholinergics, H2 blockers) and also the anti-secretory drug omeprazole which completelyinhibits the secretions of acid by blocking thehydrogen-potassium adenosine triphosphatase.However, these ulcers rapidly recur whentherapy is stopped, reflecting the non-curativenature of anti-secretory therapy alone.

Impaired mucosal defense:

Peptic ulcer is a product of self-digestion; itresults from an excess of autopeptic power ingastric juice over the defensive power of gastricand intestinal mucosa (13).The surface epithelialcells of the gastric mucosa have intrinsic barrierproperty and play an important role in the firstline defense of the stomach. Davenport (14)proposed that the apical membrane or tightjunctions between epithelial cells are relativelyimpermeable to hydrogen ions and therefore,forms a physical barrier to back diffusion of acid.He called this the gastric mucosal barrier (14).More recent studies (15) have shown theexistence of surface active phospholipids whichform the hydrophobic lining on the luminalsurface of the gastric epithelium and retard thepassage of water soluble ions such as hydrogenions. Two major factors appear to disruptmucosal resistance to injury : NSAIDs andH. pylori infection. NSAIDs have been shown toeliminate the surface hydrophobicity and disruptthe mucosal barrier to hydrogen ions. Theduodenal secretion of bicarbonate is impaired in

I NSAIDs Il' ,-H-.-PI-LO-R~IIIMPAIRED MUCOSALDEFENSE

Fig. 1: A model of the pathogenesis of peptic ulcer.

Pathogenesis and Treatment of Peptic Ulcer 5

l'Acidity in Duodenuim

Islands of gastric metaplasia 111 duodenal CR(1J colonization ofH. pylori

urease

1'Mucosal pH (beneath mucus layer)

tBack Diffusion of H+ from Gastric Lumen

tDuodenal Inflammation

tChronic Duodenal Ulceration

Fig. 2 : Pathogenesis of duodenal ulceration (23).

patients with duodenal ulcer (16), but whetherthis defect is primary or secondary to otherfactors, such as H. pylori-induced duodenitis orgastric metaplasia, remains uncertain. Theproduction of prostaglandins may be abnormalin persons with peptic ulcer, but no consistentabnormality has been confirmed. On the basisof these considerations, the model depicted inFig. 1 appears to be more appropriate for thepathogenesis of peptic ulcer than the traditionalseasaw model of acid versus mucosal defense.

Predisposing factors for peptic ulceration:

H. pylori infection :

H. pylori induced antral gastritis has beenfound in nearly all patients with gastric orduodenal ulcer (17,18). H. pylori has been foundin the antrum of more than 95 percent of the

6 Desai et al

patients with duodenal ulcer and in atleast 75percent of those with gastric ulcer (17.19.20).H. pylori is found in the mucus layer or beneaththe mucus adhering to gastric epithelium closeto the intercellular junctions. Besides its peculiarhabitat, H. pylori is a very powerful producer ofurease and the consequent release of ammoniamay provide a microenvironment of raised pH,enabling the organism to survive. Ammonia maybe cytotoxic. Electron microscopic studies haveshown damage to the gastric epithelial microvilliin the immediate vicinity of H. pylori (21). Areaof gastric metaplasia, arise in the duodenal cap,possibly associated in someway with high gastricoutput (22). Colonization of these heterotropicislands with H. pylori leads to mucosal injuryand subsequent ulceration (23) (Fig. 2).

Non-steroidal anti-inflammatory drugs:

NSAIDs produce a spectrum of injury to thegastro-duodenal mucosa, from hemorrhages andpetechiae to erosions and ulcers. Major biochemicalchanges induced by aspirin and other salicylatescan be briefly summarized as follows :

(a) Denaturation of mucus glycoproteins andmucus cell proteins in those areas of themucosa which are in contact with highconcentration of the drug. This leads tosloughing of the protective mucus layer(24), further, discharge of mucus fromepithelial cells (25), and celldesquamation. The buffering of the acidicdrug or gastric contents to a neutral pH,attenuates these effects,

(b) Intracellular accumulation of protonsdissociated from high concentration ofthe acidic drug which rapidly accumulatein mucus (superficial) and parietal cells.This causes localized acid accumulation(back-diffusion of acid) (26).


(c) Labilization of lysosomes in mucosa andparietal cells leading to release ofhydrolytic enzymes for cellular autolyticreactions (27).

(d) Inhibition of PG cycle-oxygenase, leadingto reduced production of PGE (28) andendothelial cell PGI (29). This causesvasoconstriction, inhibition of plateletaggregation (enhanced bleeding), andcontributes to the enhanced acidsecretion (30).

(e) Mast cell degranulation results in therelease of histamine which stimulatesthe acid secretion and causesvasodilation. Histamine produceschanges in the microvasculature of themucosa which promotes bleeding fromthe mucosa.

(f) Tissue - damaging free radicals whichare produced from the conversion ofhydroperoxy to hydroxy-fatty acids i.e.HPETE - HETE+ [0]-, further contributesto cell destruction. The hydroperoxy-fattyacids are generated from the followingreactions.

i) Diversion of arachidonic acid in thelip oxygenase pathway(s) as aconsequence of drug-inducedinhibition of the PG cyclo-oxygenasepathway (31)

ii) Degranulation of mast cells (32).

iii) Generalized lipid per oxi dat ionaccompanying cell damage.

g) Inhibition of glucose oxidation (bymitochondria) and inhibition of enzymesinvolved in anabolic reactions (eg. mucus


synthesis, protein and nucleic acidbiosynthesis in regenerating cells).Decreased glucose oxidation leads toreduction in ATP levels which in turncauses reduction in acid secretion, andenergy availability required for mucussynthesis. Decreased total ATP levelsmay also produce stimulation of adenylcyclase activity and thus increase incAMP levels (33). The exact significanceof this is unclear but may involveregulation of parietal cell acid secretion,regulation of glucolysis and mucusglycoprotein synthesis.

(h) Stress and drug induced stimulation ofcorticoid secretion from the adrenalgland could lead to an enhancement ofaspirin or other salicylate induced effectsas described above. Thus, there could beadditive/synergistic effects of both thedrug and adrenocortical stimulation onmucus biosynthesis, cellular autolysis,and nucleic acid and protein synthesis,especially in regenerating zones of themucosa.

Cigarette smoking:

Gastric and duodenal ulcers occur morefrequently in smokers than in non-smokers(34,35). Peptic ulcers heal less well in smoker ascompared to non-smokers (36,37). Neither theactive tobacco component nor the mechanismby which it operates is known, but, because ofits well recognized pharmacological properties,nicotine has been widely investigated as acausative agent (38). Numerous mechanismshave been proposed to explain the effect ofsmoking on peptic ulcer (39). These include thestimulation of acid secretion (40), alteration ofblood flow or motility, induction of bile reflux(41), and reduction in the generation ofprostaglandins.


Diet:

Epidemiological evidence implicates dietaryfactors in the geographical distribution ofduodenal ulceration among people onimpoverished diets (42,43), particularly whenpolished rice forms the main component. In thepylorus ligated rat model (44) an association wasdemonstrated between gastric ulceration in ratspre-fed with diets corresponding to those areasofIndia where high and low incidence of humanduodenal ulceration are observed (45). In a studyin India, people suffering from duodenalulceration derived symptom relief bysupplementation of their diet with fresh rice bran(46,47). This observation was confirmed in therat model in which fresh rice bran and rice branoil were found to be protective against ulceration.The protective properties of rice. bran and riceoil were lost on storage, when they becameactively ulcerogenic. It was considered possiblethat on storage lipid peroxidation of unsaturatedfatty acids in the oil had given rise to theproduction of cytotoxic ketoaldehydes. Supportof this proposal was obtained by thedemonstration that cysteine suppressed theulceration induced by stored rice oil (48).

Psychological stress:

Stress ulceration of the stomach is associatedwith clinical conditions like trauma, head injury,burns, shock, sepsis and neurological disorders,and is now regarded as a multifactorialphenomenon. It is reported to result frominteractions between mucosal, vascular andneuro-humoral factors, and the autonomicnervous system plays a crucial role (Fig. 3).

Stimulation of gastric mucosa, due to stressis transmitted by cerebral marginal system andhypothalamus to the medulla oblangata andspinal cord. Medulla oblangata stimulates thevagus which increases the gastric secretions and

8 Desai et al

ISPLANC;NIC NERVE I '1

ADRENOCORTICALHYPERSECRETION

GASTRIC HYPERSECRETIONSGASTRIC HYPERMOTILITY

Fig, 3 Role of the autonomic nervous system III

the mechanism causing a peptic ulcer (49),

augments gastric motility. The spinal cord causesthe stimulation of the splanchnic nerve toproduce a disturbance in circulation due tofunctional constriction of the gastric vessels;which leads to a diminution of gastric blood flow.The function of anterior pituitary also getsdisturbed due to stress releasingadrenocorticotropic hormone (ACTH) whichultimately leads to increased gastric secretionsand reduced gastric mucosal resistance.Circulatory disturbances and the nutritionaldeficiency, are thus induced in the local tissue,which are then followed by a rapid appearanceof a deep ulcer (49).

Electrical stimulation of different regions o£the limbic area modulates gastric acid secretion,motility and mucosal blood flow - all ofwhich areimportant factors for stress ulcer development.The eNS and more importantly, the brain-gutaxis are important mediators of stressulcerogenesis, and complex neural mechanisms


are proposed (50).For example, several disruptiveand protective mediators are now recognised,and biogenic amines, amino acids , and pep tidesare implicated (51). Neurotransmitters involvedin these effects include dopamine,norepinephrine, acetylcholine, gamma-aminobutyric acid and several neuropeptides,

Alcohol:

Ethanol (50-100%) rapidly penetrates thegastric mucosa, and apparently causes cell andplasma membrane damage, that results inincreased membrane permeability leading tointracellular accumulation of sodium and water.The "leaky membrane" is a well known stage inthe development of cell injury. When theincreased membrane permeability fails tomaintain the· normal electrolyte distributionbetween intracellular and extracellularcompartments, the massive intracellularaccumulation of calcium represents a major stepin the pathogenesis of gastric mucosal injury.In the gastric mucosa. these changes result incell death and exfoliation in the superficialepithelium, i.e., erosion. Further, gastric lesionscaused by ethanol have been attributed to freeradical damage, which results in lipidperoxidation products. Clinically, also cirrhosisdue to consumption of alcohol is linked to anincreased incidence of peptic ulcer (52).

Other diseases and genetic factors:

Certain diseases such as short bowelsyndrome, chronic pancreatitis, Crohn's diseaseand pulmonary disease (Chronic ObstructivePulmonary Disease) have also been associatedwith peptic ulcer. Genetic factors may also beimportant. Autosomal dominant inheritance ofhyperpepsinogenemia I is common in duodenalulcer, but the nature of causal relations to thepathogenesis of ulcer remains uncertain. Severalrare genetic syndromes (Tremor nystagmus ulcer


syndrome, familial amyloidosis, gastrocutaneoussyndrome and stiff man syndrome) may also beassociated with peptic ulcer (52).

The changing spectrum of therapy for active pepticulcer disease:

Conventional therapy for the prevention of pepticulcers: Cimetidine and later ranitidinerevolutionized the treatment of peptic ulcers,with H2-receptor antagonists being the mostwidely used and effective novel drugs over thepast decade. However, relapse ulcerationfollowingcessation of treatment with such agentsis a frequent clinical observation. It is againstthis background that we have to deal with thecurrent status and future advances in drugdevelopment for the therapy of gastroduodenalulceration.

H2-receptor antagonists:

H2-receptor antagonists are capable ofreducing over 90% of basal, food stimulated, andnocturnal secretion of gastric acid stimulatedby histamine, gastrin, cholinomimetic drugs andvagal stimulation (53). Histamine antagonistsprevent occurrence of stress induced ulcers.However, their use in combination with antacidsmay be preferred. In addition, they areimportant in the medical management ofZollinger Ellison Syndrome and gastrichypersecretory states seen in systemicmastocytosis (54). As described earlier,recurrence of ulcer after healing is a frequentcomplication of therapy with H2-receptorantagonists, and therefore long term treatmentis required. H2-receptor antagonists are thusremarkable but not perfect drugs. These drugsinclude mainly cimetidine, r an it id in e,famotidine, roxatidine and nizatidine. Saltidine,mifentidine, TZU-0460, CM-57755 etc. are alsounder investigation and have shown betterantiulcer activity (55).


Ranitidine Bismuth Citrate: Ranitidinebismuth citrate (RBC) is the new anti-ulcer drugdeveloped by Glaxo Laboratories (U.K.), whichwhen combined with clarithromycin caneradicate H. pylori in 94% of patients. This hasbeen confirmed in a clinical trial on 232 patientswith duodenal ulcers. RBC was given 400 mgtwice daily for 28 days and clarithromycin fourtimes a day for first 14 days (56).

Prostaglandins:

In 1979, Robert (57) recognised that PGsinhibit gastric acid secretion and protect againstexperimental ulcers caused by NSAIDs, diet andlife styles (eg. alcohol, smoking and stress).Misoprostol (Cytotec) is a synthetic prostaglandinE analog with acid reducing and cytoprotectiveproperties. Prostaglandins enhance mechanismsthought to be involved in mucosal defense ofthe chronic peptic ulcer (e.g., the secretion ofmucus, output of bicarbonate, and blood flow)(58). It is indicated for the prevention of NSAID-induced gastric ulceration. Short term co-administration of enprostil lowered the serumgastrin levels in patients on long term treatmentwith omeprazole (59). Misoprostol does notprevent duodenal ulcer. It is contraindicated inpregnancy because of its abortifacient propertyand requires special precautions if prescribed towomen of child bearing potential. The main sideeffect is diarrhoea in 6 to 30% of users. Thesynthetic PGs currently available in market aremisoprostol, enprostil, rioprostil, arbaprostil andtrimoprostil like compounds. Several othercompounds like nocloprost, enisoprost, mexiprost,nileprost, rosaprostol etc. are undergoing clinicaltrials.

H+/K+-ATPaseinhibitors:

Blockade of the gastric proton pumpconstitutes a more direct mechanism for acidsecretion inhibition compared to blockade of

10 Desai et al

histamine and cholinergic receptors. Omeprazoleis not the active inhibitor of H+K+ ATPaseenzyme but is reversibly transformed in acidicmedia to the sulphenamide which can react withthiols to form disulfides, thus representing amodel for the covalently linked enzyme-drugcomplex. Omeprazole has been shown to inhibitthe growth of H. pylori (60). Recently,lansoprazole has been introduced in the marketsof United States of America. NC-1300, RO 18-5362, B831-56 are series of £lourinatedbenzimidazoles and are potent and long actinginhibitors of acid secretion in animals and haveshown mechanism similar to that of omeprazole.

Muscarinic receptor antagonists:

Pirenzepine, a selective muscarirnc M-1receptor antagonists, reduces basal andstimulated acid secretion, in animals and man.Its efficacy in duodenal ulcer is equivalent tocimetidine (61). It has more cytoprotective effectthan of histamine receptor antagonists againstgastric mucosal lesions induced by ethanol, HC1,NaOH and taurocholate. Telenzepine is 4-10times more potent than pirenzepine, as aninhibitor of acid secretion in rats and dogs.

Mucosal coating agents:

Sucralfate: Sucralfate IS a sulfateddisaccharide-basic aluminium sulfate complex.It forms an adherent coating with proteinaceousmaterial at ulcerated mucosal sites. When pHis low, there is extensive polymerizationand crosslinking of sucralfate. The coatingprovides barrier to hydrogen ion diffusion,reduces peptic activity and adsorbs bilesalts. Further, sucralfate can bind to bothepidermal growth factor (EGF) and fibroblastgrowth factor (FGF), which also enhance ulcerhealing (62). Recently, sucralfate has also beenreported to suppress the associated H. pyloriinfection (63).


Bismuth compounds:

Bismuth subcitrate, formerly calledtripotassium dicitrate bismuthate (TDB) is themost recent of the bismuth salts to be testedand found effective clinically. The substance isa colloidal suspension. When the pH is above3.5 to 4.0; it forms a white precipitate in gastricacid. Bismuth subcitrate has a strong affinityfor mucosal glycoproteins, especially in thenecrotic tissue in ulcer craters. Ulcer cratersbecome preferentially and visibly coated with awhite layer of polymer glycoprotein complex,which is only slowly permeated by HaO+,suchthat the layer constitutes a diffusion barrier togastric acid. Bismuth salts also have someantimicrobial activity against H. pylori infection.However, the chronic use of other bismuth saltshas caused encephalopathy and osteodystrophy(64).

Carbenoxolone:

It is a synthetic derivative of glycyrrhizicacid (a constituent of liquorice) which has beenshown to be of value in promoting healing ofpeptic ulcers. The mechanism of action is notunderstood but, is believed to involve an effecton mucus, increasing its secretion and viscosityand thus protecting mucosa from attack by acidand pepsin. Its principal adverse effect is sodiumretention which may lead to edema, hypertensionand heart failure and this limits its use especiallyin the old people. (61).

Miscellaneous group:

The anti-ulcer activity of calcium channelblockers namely verapamil, nifedipine anddiltiazem against experimental ulcers has beenestablished (65). Proglumide, a cholecystokininand gastrin receptor antagonist is also found topossess antisecretory and antiulcer activity (66).The histidine decarboxylase inhibitors like (+) -


cyanidanol-3, naringenin and meciadanol mayalso be useful in the treatment of peptic ulcerdisease (67). FPL 52694, a mast cell stabilizer,has been shown to produce a significant decreaseof overnight basal acid in dyspeptic patients afterone week treatment (66). Recently, Glavin andSzabo (68,69) have established the role ofdopamine in the gastroduodenal disease. Insupport of above contention,we have reportedthe anti-ulcer activity of the specific dopamineD1-receptor agonists (eg. SKF 38393) andselective dopamine D2-receptor antagonists (eg.sulpiride) against selected models of gastric and

cduodenal ulcers in rats (70, 71).

Treatment of H. pylori infection:

Ultrastructural studies have shown thatfollowing an exposure to bismuth preparationsH. pylori detaches from the gastric epitheliumand gets lysed within 30-90 min (72). In spite ofthe clinical suppression of H. pylori with oralbismuth, recrudescence is extremely commonfollowing monotherapy with bismuth (73).Therefore, it seems obvious that short termtreatment with bismuth alone is inadequate forH. pylori infection. Chronic administration ofbismuth for the treatment of H. pylori is notrecommended taking into consideration the riskofbismuth toxicity. In the laboratory H. pylori issensitive to a wide range of anti-microbialsincluding ampicillin, erythromycin, tetracyclines,ciprofloxacin,olfloxacin, metronidazole, tinidazole.and nitrofurantion (73). But, monotherapy withantibiotics has been shown to lead to the rapidonset of resistant organisms in somecircumstances. Acquired resistance to quinoloneshas been demonstrated in H. pylori afterolfloxacin and ciprofloxacin (74). The inadequacyof single agent therapy has led some workers topropose that a combination of bismuth withantibiotics, may provide the optimum approach(75). Combination therapy has provided the bestresults todate. Eradication rates vary from 40%


with TDB and amoxycillin to 80% with TDB andmetronidazole (76).Triple therapy has been foundstill more effective and 96% of patients willeradicate the organism with TDB, metronidazoleand tetracycline (or amoxycillin) combination (75).Further, it is reported that the efficacy of manyantibiotics is pH dependent (77). Hence, there isa rationale for combination of acid inhibitorydrugs with antibiotics in the treatment ofH. pylori infection. A controlled study ofcombination therapy with omeprazole andamoxycillin in patient with duodenal ulcer showederadication of H. pylori in 82% of patients (78).Over the past five years, several workers havesuggested that eradication of H. pylorisignificantly reduces the rate of duodenal ulcerrelapse (79-80). Recently, National Institute ofHealth (NIH) Consensus Conferencerecommended H.pylori eradication regimen asthe first line medical therapy for patients withpeptic ulcer disease who are H. pylori positive(81).

Therapy and prevention of NSAID-associated ulcers:

Ulcers associated with NSAIDs usually healspontaneously when the NSAIDs are withdrawn.Even with the continued use of NSAIDs, ulcersmay heal spontaneously. Limited studies suggestthat H2-blockers, prostaglandins, and omeprazoleaccelerate healing as compared to placebo (82, 83).Omeprazole is emerging as the most promisingagent for troublesome ulcers, especially whenNSAIDs cannot be discontinued (82). A few trialshave tested regimens for the prophylactictreatment of NSAID-associated ulceration. Athree month trial indicated that misoprostolprevented NSAID-associated gastric ulcer, butdata is lacking on the efficacy ofPGs in preventingNSAID-associated duodenal ulcer (84). One shortterm study proved higher efficacy of PGs thanH2-blockers in preventing NSAID-associatedgastric damage whereas H2-blockers wereeffective in preventing duodenal damage (85).

12 Desai et al

Treatment of refractory ulcers:

Regardless of the mode of therapy, thehealing of ulcers is time dependent; 90 to 95percent of all ulcers heal if therapy is continuedfor 12 weeks. After that, ulcers or symptoms (orboth) can be considered refractory to therapy.Since persistent symptoms may not be due topersistent ulcer disease, endoscopy is essentialto establish the diagnosis. If persistent ulcerationis found on endoscopy, a few possibilities warrantconsideration. Poor patient compliance, use ofNSAIDs, smoking and gastrinoma are commoncauses of refractory ulceration. The role ofH. pylori infection in refractory ulceration alsoremains uncertain. A 40 mg dose of omeprazoleor a full dose antisecretory therapy will probablyhave to be continued to maintain the healing ofrefractory ulcers, since it does not alter thenatural history of ulcer disease. Treatment withbismuth or the eradication of H. pylori (or both)deserves consideration for patients who do notrespond to conventional therapy (52).

Recurrence of duodenal ulcers:

Duodenal ulcers recur in 70 to 90% ofpatients within 1 year of the cessation of drugtherapy. The evidence suggests that the rate ofrecurrence differs depending on the initialtherapy used.


The relapse rates are higher after healingwith H2-antagonists as compared to tri-potassiumdi-citrato bismuthate therapy (86). Maintenancetherapy with an H2-receptor antagonists reducesthis rate to 40%. Patients with complications ofrecurrence or those taking NSAIDs, and thosewho have pulmonary, renal or heart diseasesare considered to be at a higher risk and shouldbe placed on maintenance therapy to avoidrecurrence. A single night time administrationof H2-antagonist at a dose of one half of thenormal therapeutic dose is appropriate. Thisshould be continued for one year. Sucralfate,1 g at bedtime, is also an effective maintenanceregimen. Patients should be then reassessed forfurther therapy. Patients who have a minimalrisk and who experience a recurrence should bereevaluated and reassigned to maintenancetherapy. Maintenance therapy is also appropriatefor recurrent gastric ulcer, but the response ratemay not be as high as that for duodenal ulcer(87).

ACKNOWLEDGEMENTS

Our work mentioned in the review wassupported by the Council of Sci ent.ific andIndustrial Research, New Delhi, which is highlyacknowledged. The financial assistance wasprovided by them as Senior Research Fellowshipawarded to J.K.D.

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