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

REVIEW ARTICLE

PATHOGENESIS OF AND CURRENT TRENDS IN THERAPY

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

¥Department of Pharmacology, *¥K.B. Institute of Pharmaceutical L.M. College of Pharmacy, and Education and Research, Sector 23, Navmngpum, Gandhinagar - 382 023 Ahmedabad- 380 009

( Received on February 14, 1996 )

Abstract: Traditionally dnlgs used in peptic ulcer have been directed mainly against a single luminal damaging agent i.e. and a plethora of dnlgs like

, anticholinergics, histamine H 2-antagonists etc. have flooded the market. An increase in 'aggressive' factors like acid and pepsin is fOlme! only in a minority of peptic ulcer patients. These factors do not alter during or after spontaneous healing. It is well­ known that the gastric mucosa can resist auto-cligestion though it is expospcl to numerous 'insults' like high concentration of hydrochloric acid, pepsin, reflux of bile, s[Jicy food, microorganisms and at times alcohol and irritant dmgs. It is thus evident that the integrity of the gastric mucosa is maintained by defense mechanisms :'Igainst these 'aggressive' damaging factors. Recently, attention has been focussed more on gastroduodenal defense mechanisms leading to the concept of 'Cytoprotection'. Th" old dictum ''no acid - no ulcer" now extends to "if acid - why ulcer"') as a fundamental question. During last rlecade more information has poured in about the prevalence and changing pattern of the disease, the influence of envirorunental factors and speculation on the role of a recently characterized bacterial organism, which colonizes in the gastric mucosa, particularly the antral region. This review briefly describes current knowledge about the pathogenesis of pel tic ulcer clisease and discusses strategies for its treatment.

Key words: gastric ulcers duodenal ulcers Helicobact.er pylori NSAIDs anti-secretory agents

INTRODUCTION one end of the disease spectrum as 93% of the patients afflicted with Zollinger Ellison Gastric and duodenal ulcer or peptic ulcer Syndrome is characterized by single or multiple disease (PUD), Zollinger-Ellison Syndrome (ZE) non-beta islet cell adenomas of the pancreas and gastroesophageal reflux disease (GRD) are which releases large quantities of in upper gastrointestinal disorders sharing a plasma resulting in a 10-20 fold increase in the common abnormality: too much acid and pepsin amount of acid secreted and a high incidence of activity for the degree of local tissue resistance. ulcers. At the opposite end of the spectrum acid Hydrolytic and proteolytic digestion of the secretion plays a lesser role and mucosal exposed mucosa occur followed by inflammation, resistance becomes more important. Gastric necrosis and ulceration. Gastric hypersecretion ulcers are typified by a reduced basal and appears to be the primary causative event at stimulated acid output. Some acid is however,

*Corresponcling Author 4 ll"sCli et ~I Indian .r Physiol PharmClco! 1997; 4l( I) always required as peptic ulcer disease rarely The rapid repair of injury to mucosa develops in patients of achlorhydria. The other is essential to maintain the mucosal causes of peptic ulcer disease include integrity. Surface epithelial cells continually Helicobacter pylori infection, non-steroidal anti slough, and the gaps are resealed by inflammatory agents (NSAlDs) and malignancy. adjacent cells that move to fill them by cell Recent evidence relates H. pylori to the replication in response to still unknown trophic pathogenesis of chronic duodenal ulceration as signals (3). Blood flow in normal mucosa H. pylori infection and antral are found removes the acid that has diffused across a together in more than 95% of patients with compromised mucosa. Prostaglandins enhance duodenal ulcer. H. pylori is a very powerful the mucosa's resistance to injury under producer of urease and may cause ulceration by certain conditions, perhaps by increasing causing hydrolysis of urea which leads to mucosal blood flow (4,5), stimulating the generation of cytotoxic ammonia. The NSAlDs secretion of mucus and bicarbonate (6), when administered orally cause local irritation, strengthening of the gastric mucosal barrier, allow back diffusion of acid into the gastric decreasing the gastric motility (71, increasing mucosa and induce tissue damage, whereas, release of endogenous mediators of gastric parenterally administered NSAIDs can aIso cytoprotection like sulfhydryls (8) and epidermal cause ga tric mucosal damage and bleeding growth factor (9) etc., scavanging of free radicals correlated with the inhibition ofthe biosynthesis (10), decm3sing release of endogenous mediators of ga "tric prostaglandins (PG) especially PGI of gastric injury, vasoactive amines and and PGE. leukotrienes (11) and stimulation of cellular growth and repair (12). Defense of n.ormal gastric mucosa against aggressive factors: In general it can be said that there is a Three basic levels of defense underlie the plethora of mechanisms underlying the defense remarkabl ability of normal gastroduodenal of normal ga tric mucosa and their relativ mucosa to resIst injury from the acid and peptic importance and interdependence is far from activity in gastric juice. clear. This itself may be a pointer' that normal gastric defense Illay be a multifactorial 1. Surface epithelial cells secrete mucus and phenomenon. bicarbonate, creating a pH gradient in the mucus lay I' and change the very acidic Acid secretion and peptic ulcers: gastric lumen to the nearly neutral surface of he mucosa (1). Th formation of peptic ulcers depend critically on the pI' 'ence of acid and peptic 2. G stric muco al cells have a specialized activity in gastric juice. About one third of apical surface membrane that resists he patients \vith duodenal ulce', but not gastric diffusion of acid back into the cell. ulcer, secrete excess . Schwartz's (13) 3. Mucosal cells may directly resist injury by dictum "no acid - no ulcer" is more accurate if intrinsic mechanisms, such as the extrusion amplified to "no acid and peptic activity - no of back-diffused hydrogen ions by means of ulcer" a . acid without pepsin has little digestive basolateral carriers (e.g. sodium-hydrogen or power. The dependence of peptic activity sodium b' carbone t exchange) (2) is supported by the therapeutic effects Inrlian J Physiol PhRrmRcol 1997; 41(1) Pathogenesis and TreRtment of Peptic Ulcer 5 of the antacids and antisecretory drugs t Acidity in Duodenuim (anticholinergics, H 2 blockers) and also the anti­ secretory drug omeprazole which completely inhibits the secretions of acid by blocking the hydrogen-potassium adenosine triphosphatase. IslRnds of gastric metaplRsia 111 duorlc:nal CRt' However, these ulcers rapidly recur when J colonization of therapy is stopped, reflecting the non-curative H. pylori nature of anti-secretory therapy alone. urease ------,>~ Nl4-CO-Nl-I2 NH:; Impaired mucosal defense: (cytotoxic .,)

Peptic ulcer is a product of self-digestion; it results from an excess of autopeptic power in t Mucosal pH (beneath mucus layer) gastric juice over the defensive power of gastric and intestinal mucosa (13). The surface epithelial cells of the gastric mucosa have intrinsic barrier Back Diffusion Gastric Lumen property and play an important role in the first line defense of the . Davenport (14) proposed that the apical membrane or tight Duodenal Inflammation junctions between epithelial cells are relatively impermeable to hydrogen ions and therefore, t forms a physical barrier to back diffusion of acid. Chronic DuodenRI UlcerRtion

He called this the gastric mucosal barrier (14). Fig. 2 : Pathogenesis of duodenal ulceration (23). More recent studies (15) have shown the existence of surface active phospholipids which patients with duodenal ulcer (16), but whether form the hydrophobic lining on the luminal this defect is primary or secondary to other surface of the gastric epithelium and retard the factors, such as H. pylori-induced or passage of water soluble ions such as hydrogen gastric metaplasia, remains uncertain. The ions. Two major factors appear to disrupt production of prostaglandins may be abnormal mucosal resistance to injury : NSAIDs and in persons with peptic ulcer, but no consistent H. pylori infection. NSAIDs have been shown to abnormality has been confirmed. On the basis eliminate the surface hydrophobicity and disrupt of these considerations, the model depicted in the mucosal barrier to hydrogen ions. The Fig. 1 appears to be more appropriate for the duodenal secretion of bicarbonate is impaired in pathogenesis of peptic ulcer than the traditional seasaw model of acid versus mucosal defense.

I NSAIDs I P-I-LO-R~I Predisposing factors for peptic ulceration: 1 r-[H-. I

IMPAIREO MUCOSAL OEFENSE H. pylori infection :

H. pylori induced antral gastritis has been found in nearly all patients with gastric or duodenal ulcer (17, 18). H. pylori has been found Fig. 1: A model of the pathogenesis of peptic ulcer. in the antrum of more than 95 percent of the G Desai et al Indian J Physiol Ph:mnacol 1!J97; 4l(.L)

patients with duodenal ulcer and in atleast 75 (c) Labilization of lysosomes in mucosa and percent of those with gastric ulcer (17.19.20). parietal cells leading to release of H. pylori is found in the mucus layer or beneath hydrolytic enzymes for cellular autolytic the mucus adhering to gastric epithelium close reactions (27). to the intercellular junctions. Besides its peculiar habitat, H. pylori is a very powelful producer of (d) Inhibition of PG cyclo-oxygenase, leading urease and the consequent release of ammonia to reduced production of PGE (28) and may provide a microenvironment of raised pH, endothelial cell PGI (29). This causes enabling the organism to survive. Ammonia may vasoconstriction, inhibition of platelet be cytotoxic. Electron microscopic studies have aggregation (enhanced bleeding), and shown damage to the gastric epithelial microvilli contributes to the enhanced acid in the immediate vicinity of H. pylori (21). Area secretion (30). of gastric metaplasia, arise in the duodenal cap, possibly associated in someway with high gastric (e) Mast cell degranulation results in the output (22). Colonization of these heterotropic release of histamine which stimulates islands with H. pylori leads to mucosal injury the acid secretion and causes and subsequent ulceration (23) (Fig. 2). vasodilation. Histamine produces changes in the microvasculature of the Non-steroidal anti-inflammatory drugs: mucosa which promotes bleeding from the mucosa. NSAIDs produce a spectrum of injury to the gastro-duodenal mucosa, from hemorrhages and (D Tissue - damaging free radicals which petechiae to erosions and ulcers. Major biochemical are produced from the conversion of changes induced by aspirin and other salicylates hydroperoxy to hydroxy-fatty acids i.e. can be briefly summarized as follows : HPETE - HETE+ [0]-, further contributes to cell destruction. The hydroperoxy-fatty (a) Denaturation of mucus glycoproteins and acids are generated from the following mucus cell proteins in those areas of the reactions. mucosa which are in contact with high concentration of the drug. This leads to i) Diversion of arachidonic acid in the sloughing of the protective mucus layer lipoxygenase pathway(s) as a (24), further, discharge of mucus from consequence of drug-induced epithelial cells (25), and cell inhibition of the PG cyclo-oxygenase desquamation. The buffering of the acidic pathway (31) drug or gastric contents to a neutral pH, attenuates these effects, ii) Degranulation of mast cells (32).

(b) Intracellular accumulation of protons iii) Generalized lipid peroxidation dissociated from high concentration of accompanying cell damage. the acidic drug which rapidly accumulate in mucus (superficial) and parietal cells. g) Inhibition of glucose oxidation (by This causes localized acid accumulation mitochondria) and inhibition of enzymes (back-diffusion of acid) (26). involved in anabolic reactions (eg. mucus ImLirm .1 Physi,,] Pharmac:ol 1997; 41(J) Pathogenesis and Treatmf'nt of Peptic: U!c,,!' 7

synthesis, protein and nucleic aCId Diet: biosynthesis in regenerating cells). Decreased glucose oxidation leads to Epidemiological evidence implicates dietary reauction in ATP levels which in turn factors in the geographical distribution of causes reduction in acid secretion, and duodenal ulceration among people on energy availability required for mucus impoverished diets (42,43), particularly when synthesis. Decreased total ATP levels polished rice forms the main component. In the may also produce stimulation of adenyl pylorus ligated rat model (44) an association wa. cyclase activity and thus increase in demonstrated between gastric ulceration in rats cAMP levels (33). The exact significance pre-fed with diets corresponding to those areas of this is unclear but may involve ofIndia where high and low incidence of human regulation of acid secretion, duodenal ulceration are observed (45). In a study regulation of glucolysis and mucus in India, people suffering from duodenal glycoprotein synthesis. ulceration derived symptom relief by supplementation of their diet with fresh rice bran (h) Stress and drug induced stimulation of (46,47). This observation was confirmed in the corticoid secretion from the adrenal rat model in which fresh rice bran and rice bran gland could lead to an enhancement of oil were found to be protective against ulceration. aspirin or other salicylate induced effects The protective properties of rice bran and rice as described above. Thus, there could be oil were lost on storage, when they became additive/synergistic effects of both the actively ulcerogenic. It was considered possible drug and adrenocortical stimulation on that on storage lipid peroxidation of unsaturated mucus biosynthesis, cellular autolysis, fatty acids in the oil had given rise to the and nucleic acid and protein synthesis, production of cytotoxic ketoaldehydes. Suppor especially in regenerating zones of the of this proposal was obtained by the mucosa. demonstration that cysteine suppressed the ulceration induced by stored rice oil (48). Cigarette smoking: Psychological stress: Gastric and duodenal ulcers occur more frequently in smokers than in non-smokers Stress ulceration of the stomach is associated (34,35). Peptic ulcers heal less well in smoker as with clinical conditions like trauma, head injury, compared to non-smokers (36,37). Neither the burns, shock, sepsis and neurological disorders, active tobacco component nor the mechanism and is now regarded as a multifactorial by which it operates is known, but, because of phenomenon. It is reported to result from its well recognized pharmacological properties, interactions between mucosal, vascular and nicotine has been widely investigated as a neuro-humoral factors, and the autonomic causative agent (38). Numerous mechanisms nervous system plays a crucial role (Fig. 3), have been proposed to explain the effect of smoking on peptic ulcer (39). These include the Stimulation of gasblc mucosa, due to stress stimulation of acid secretion (40), alteration of is transmitted by cerebral marginal system and blood flow or motility, induction of bile reflux hypothalamus to the medulla oblangata and (41), and reduction in the generation of spinal cord. Medulla oblangata stimulates the prostaglandins. vagus which increases the gastric secretions and 8 Desai et al Indian J Physiol Pharmacol 1997; 41(1)

are proposed (50). For example, several disruptive and protective mediators are now recognised, and biogenic amines, aminoacids, and peptides are implicated (51). Neurotransmitters involved in these effects include dopamine, norepinephrine, acetylcholine, gamma-amino butyric acid and several neuropeptides.

Alcohol:

1 Ethanol (50-100%) rapidly penetrates the gastric mucosa, and apparently causes cell and plasma membrane damage, that results in ADRENOCORTICAL HYPERSECRETION increased membrane permeability leading to intracellular accumulation of sodium and water. GASTRIC HYPERSECRETIONS GASTRIC HYPERMOTllITY The "leaky membrane" is a well known stage in the development of cell injury. When the increased membrane permeability fails to maintain the' normal electrolyte distribution Pig. 3 Role of the autonomic nervous system in between intracellular and extracellular the mechanism causing a peptic ulcer (49). compartments, the massive intraceHular accumulation of calcium represents a major step augments gastric motility. The spinal cord causes in the pathogenesis of gastric mucosal injury. the stimulation of the splanchnic nerve to In the gastric mucosa these changes result in produce a disturbance in circulation due to cell death and exfoliation in the superficial functional constriction of the gastric vessels; epithelium, i.e., erosion. Further, gastric lesions which leads to a diminution of gastric blood flow. caused by ethanol have been attributed to free The function of anterior pituitary also gets radical damage, which results in lipid disturbed due to stress releasing peroxidation products. Clinically, also adrenocorticotropic hormone (ACTH) which due to consumption of alcohol is linked to an ultimately leads to increased gastric secretions increased incidence of peptic ulcer (52). and reduced gastric mucosal resistance. Circulatory disturbances and the nutritional Other diseases and genetic factors: deficiency, are thus induced in the local tissue, which are then followed by a rapid appearance Certain diseases such as short bowel of a deep ulcer (49). syndrome, chronic , Crohn's disease and pulmonary disease (Chronic Obstructive Electrical stimulation of different regions of Pulmonary Disease) have also been associated the limbic area modulates gastric acid secretion, with peptic ulcer. Genetic factors may also be motility and mucosal blood flow - all of which are important. Autosomal dominant inheritance of important factors for stress ulcer development. hyperpepsinogenemia I is common in duodenal The eNS and more importantly, the brain-gut ulcer, but the nature of causal relations to the axis are important mediators of stress pathogenesis ofulcer remains uncertain. Several ulcerogenesis, and complex neural mechanisms rare genetic syndromes (Tremor nystagmus ulcer indian J Physiol Pharmacol 1997; 41(1) Pathogenesis and Treatment of Peptic U1eer ~J syndrome, familial amyloidosis, gastrocutaneous Ranitidine Bismuth Citrate: Ranitidine syndrome and stiff man syndrome) may also be bismuth citrate (RBC) is the new anti-ulcer drug associated with peptic ulcer (52). developed by Glaxo Laboratories CU.K), which when combined with clarithromycin can The changing spectrum of therapy for active peptic eradicate H. pylori in 94% of patients. This has ulcer disease: been confirmed in a clinical trial on 232 patients with duodenal ulcers. RBC was given 400 mg Conventional therapy for the prevention ofpeptic twice daily for 28 days and clarithromycin four ulcers: Cimetidine and later ranitidine times a day for first 14 days (56). revolutionized the treatment of peptic ulcers, with H 2-receptor antagonists being the most Prostaglan.(lin.~: widely used and effective novel drugs over the past decade. However, relapse ulceration In 1979, Robert (57) recognised that PGs following cessation of treatment with such agents inhibit gastric acid secretion and protect against is a frequent clinical observation. It is against experimental ulcers caused by NSAIDs, diet :1nd this background that we have to deal with the life styles (eg. alcohol, smoking and stress). current status and future advances in drug Misoprostol (Cytotec) is a synthetic prostaglandin development for the therapy of gastroduodenal E analog with acid reducing and cytoprotective ulceration. properties. Prostaglandins enhance mechanisms thought to be involved in mucosal defense of H 2-receptor antagonists: the chronic peptic ulcer (e.g., the secretion of

H 2-receptor antagonists are capable of mucus, output of bicarbonate, and blood flo'w) reducing over 90% of basal, food stimulated, and (58). It is indicated for the prevention ofNSAID­ nocturnal secretion of gastric acid stimulated induced gastric ulceration. Short term co­ by histamine, gastrin, cholinomimetic drugs and administration of enprostil lowered the serum vagal stimulation (53). Histamine antagonists gastrin levels in patients on long term treatment prevent occurrence of stress induced ulcers. with omeprazole (59), Misoprostol does not However, their use in combination with antacids prevent duodenal ulcer. It is contraindicated in may be preferred. In addition, they are pregnancy because of its abortifacient property important in the medical management of and requires special precautions if prescribed to Zollinger Ell:ison Syndrome and gastric women of child bearing potential. The main side hypersecretory states seen i.n systemic effect is diarrhoea in 6 to 30% of users. The mastocytosis (54). As described earlier, synthetic PGs currently available in market are recurrence of ulcer after healing is a frequent misoprostol, enprostil, rioprostil, arbaprostil and complication of therapy with H 2 -receptor trimoprostil like compounds. Several other antagonists, and therefore long term treatment compounds like nocloprost, enisoprost, mexipl'ost, is required. H:l-receptor antagonists are thus nileprost, rosaprostol etc. are undergoing clinical remarkable but not perfect drugs. These drugs trials. include mainly cimetidine, ranitidine, famotidine, roxatidine and nizatidine. Saltidine, H+IK+-ATPase inhibitors: mifentidine, TZU-0460, CM-57755 etc. are also under investigation and have shown better Blockade of the gastric proton pump antiulcer activity (55). constitutes a more direct mechanism for acid secretion inhibition compared to blockade of 10 Desai cl at Indian J !'hy'101 Pharm:lcul 19!>7· <11\ U histamine and cholinergic l' ceptor . Omeprazole Bism.uth compounds: is not the active inhibitor of H+K+ ATPase enzyme but is reversibly transformed in acidic Bismuth subcitrate, formerly called media to the sulphenamide which can react with tripotassium dicitrate bismuthate (TDBl is the thiols to form disulfides, thus representing a most recent of the bismuth salt to be te ted model for the covalently linked enzyme-drug and found effective clinically. The sub tance is complex. Omeprazole has been shown to inhibit a colloidal suspension. When the pH is above the arowth of H. pylori (60l. Recently, 3.5 to 4.0; it forms a white precipitate in gastric lansoprazole has been introduced in the markets acid. Bismuth subcitrate ha a strong affinit.y of nited States of America. NC-1300, RO 18­ for mucosal glycopToteins) especially in the 5362, B831-56 are series of nourinated necrotic tissue in ulcer craters. Ulcer craters benzimidazoles and are potent and long acting become preferentially and visibly coated with a inhibitors of acid secretion in animals and have white layer of polymer glycoprotein complex, shown mechanism similar to that of omeprazole. which is only slowly permeated by H;{O+, such that the layer constitutes a diffusion bauier to Musc(.U"inic receptor antagonists: gastric acid. Bismuth salts also have som antimicrobial activity against H. p'ylori infection.

Pireozepine. a selective muscarImc M- I However, the chronic use of other bismuth salt receptor antagonists, reduces basal and has caused encephalopathy and osteodystrophy stimulated acid ecretion in animals and man. (64), Its efficacy in duodenal ulcer is equivalent to cimetidine (61). It has more cytoprotective effect Carben~xolone: than of histamine receptor antagonists against gastri mucosal lesions induced by ethanol, HCl, It is a synthetic derivative of gl cyrrhizic NaOH and taurocholate. Telenzepine is 4-10 acid (a constituent of liquorice which ha been times more potent than pirenzepine, as an shown to be of value in promoting healing of inhibitor of acid secretion in rats and dogs. peptic ulcers. The mechanism of action is not understood but, is believed to involve an effect Mucosal coating agents: on mucus, increasing its secretion and viscosity and thus protecting mucosa from attack by acid Sllcralfate: Sucralfate IS a sulfated and pepsin. Its principal adverse effect is sodiulll disaccharide-basic aluminium sulfate complex. retention which may lead to edema, hypertension It forms anadherent coating with proteinaceous and heart failure and this limits its use especially material at ulcerated mucosal sites. When pH in the old people.(6n is low, there is extensive polymerization and crosslinking of sucralfate. The coating },-liscellaneous group: provides barrier to hydrogen ion diffusion, reduces peptic activity and adsorbs bile The anti-ulcer activity of calcium channel salts. Further, sucralfate can bind to both blockers namely veTapamil, nifedipine and epidermal growth factor (EGFI and fibroblast diltiazem against experimental ulcers has been growth factor FGF), which also enhance ulcer established (65). Proglumide, a cholec tokinin healing (62). Recently, sucralfate has also been and gastrin receptor antagonist i also found to reported to suppress the associated H. pylori possess antisecretory and antiulcer activity (66), infection (63). The histidine decarboxylase inhibitor like (+ - Indian J Physiol Pharmacol 1997; 41(1) Pathogenesis and Trefltment of Peptic Ulcer LJ cyanidanol-3, naringenin and meciadanol may with TDB and amoxycillin to 80% with TDB and also be useful in the treatment of peptic ulcer metronidazole (76). TTiple therapy has been found disease (67). FPL 52694, a mast cell stabilizer, still more effective and 96% of patients will has been shown to produce a significant decrease eradicate the organism with TDB, metronidazole of overnight basal acid in dyspeptic patients after and tetracycline (or amoxycillin) combination (75). one week treatment (66). Recently, Glavin and Further, it is reported that the efficacy of muny Szabo (68,69) have established the role of antibiotics is pH dependent (77). Hence, there is dopamine in the gastroduodenal disease. In a rationale for combination of acid inhibitory support of above contention, we have reported drugs with antibiotics in the treatment of the anti~ulcer activity of the specific dopamine H. pylori infection. A controlled study of Dt-receptor agonists (eg. SKF 38393) and combination therapy with omeprazole and selective dopamine Dz-receptor antagonists (eg. amoxycillin in patientwith duodenal ulcer showed sulpiride) against selected models of gastric and eradication of H. pylOli in 82% of patients (78). duodenal ulcers in rats (70, 71). Over the past five years, several workers havp suggested that eradication of H. pylori Treatment ofH. pylori infection: significantly reduces the rate of duodenal ulcer relapse (79-80). Recently, National Institute of Ultrastructural studies have shown that Health (NIH) Consensus Conference following an exposure to bismuth preparations recommended H.pylori eradication regimen as H. pylori detaches from the gastric epithelium the first line medical therapy for patients with and gets lysed within 30-90 min (72). In spite of peptic ulcer disease who are H. pylori positive the clinical suppression of H. pylori with oral (81). bismuth, recrudescence is extremely common following monotherapy with bismuth (73). Therapy and prevention ofNSAlD-associated ulr.ers: Therefore, it seems obvious that short term treatment with bismuth alone is inadequate fOT Ulcers associated with NSAIDs usually heal H. pylO1i infection. Chronic administration of spontaneously when the NSAIDs are withdr8wn. bismuth for the treatment of H. pylOli is not Even with the continued use of NSAIDs, ulcers recommended tabng into consideration the risk may heal spontaneously. Limited studies suggest of bismuth toxicity. In the laboratory H. pylori is that Hz-blockers, prostaglandins, and omeprazole sensitive to a wide range of anti-microbials accelerate healing as compared to placebo (82, 831. including ampicillin, erythromycin, tetracyclines, Omeprazole is emergirig as the most promising ciprofloxacin, olfloxacin, metronidazole, tinidazole agent for troublesome ulcers, especially when and nitrofurantion (73). But, monotherapy with NSAIDs cannot be discontinued (82). A few trials antibiotic~ has been shown to lead to the rapid have tested regimens for the prophylactic onset of resistant organisms in some treatment of NSAID-associated ulceration. A circumstances. Acquired resistance to quinolones three month trial indicated that misoprostol has been demonstrated in H. pylori after prevented NSAID-associated gastric ulcer, but olfloxacin and ciprofloxacin (74). The inadequacy data is lacking on the efficacy ofPGs in preventing of single agent therapy has led some workers to NSAID-associated duodenal ulcer (84). One short propose that a combination of bismuth with term study prov~d higher efficacy of PGs than antibiotics, may provide the optimum approach Hz-blockers in preventing NSAID-associated (75). Combination therapy has provided the best gastric damage whereas Hz-blockers were results todate. Eradication rates vary from 40% effective in preventing duodenal damage (85l. 12 Indian .J l'hysiol Pbarmaco[ 1.~)97; 41.(1)

Treatment of refractory ulcers: The relapse rates are higher after healing

with H 2-antagonists as compared to tri-potassiuIl1 Regardless of the mode of therapy, the di-citrato bismuthate therapy 86). Maintenance healing of ulcers is time dependent; 90 to 95 therapy with an H2-receptor antagonists reduces percent of all ulcers heal if therapy is continued this rate to 40o/t. Pabents with complications of for 12 weeks. Mter that, ulcers or symptoms (or recurrence or those taking NSAlDs, and those both) can be considered refractory to therapy. who have pulmonary, renal or heart disea. es Since persistent symptoms may not be due to are considered to be at a higher risk and should persistent ulcer disease, is essential be placed on maintenance therapy to avoid to establish the diagnosis. Ifpersistent ulceration recurrence. A single night time administration is found on endoscopy, a few possibilities warrant of H 2-antagonist at a dose of one half of the consideration. Poor patient compliance, use of normal therapeutic dose is appropriate. This NSAlDs, smoking and are common should be continued for one year. Sucralfate, eauses of refractory ulceration. The role of 1 g at bedtime, is also an effective maintenanc 0 If. pylori infection in refractory ulceration also regimen. Patients should be then reassessed for remains uneertain. A 40 mg dose of omeprazole further therapy. Patients who have a minimal or .~ f1JIl dose antisecretory therapy will probably risk and who experience a recurrence should be have 0 b continued to maintain the healing of reevaluated and reassigned to maintenan' refractory ulcers, since it does not alter the therapy. Maintenance therapy is also appropriate natur::ll history of ul er disease. Treatment with for recurrent gastric ulcer, but he I' . ponse rate bi muth or th eradication of H. pylori (or both) may not be as high as that for duodenal ulcer d serve' consideration for pa ients who do not (87), re pond to conventional therapy (52). ACKNOWLEDGEMENTS Recurrence of duodenal ulcers: Our work mentioned in the review was Duodenal ulcers recur 111 70 to 90% of supported by the Council of Scientific and patients within 1 year of the cessation of drug Industrial Research, New Delhi, which is highly therapy. The evidence suggests that the rate of ackno·wledged. The financial assistance was r 'url'ence differs depending on the initial provided by them as Senior Research Fellowship therapy used. awarded to J.K.D.

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