Phartnacotherapy of peptic ulcer diseasedownloads.hindawi.com/journals/cjgh/1991/683517.pdf ·...

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REVIEW Phartnacotherapy of peptic ulcer disease F MOLINA, MD, MM VOi iRA, Pl ID, CN WILLIAMS, MD, FRCPC F MOLINA, MM VOHRA, CN WILLIAMS. Pharmacotherapy of peptic ulcer disease. Can J Gastroenterol 1991 ;5( 1):21-33. The etiology of peptic ulcer is multifactorial; except for omeprazole, all drugs used for the treatment of peptic ulcer result in healing with no statist ical difference at four weeks. The healing rare increases with time for active medication and placebo, and is lower among smoker s than nonsmokers for all drugs but misoprosto l. Mucosa[ protectives (or 'cytoprotectives') as a group seem to have a lower relapse rate than the Hz receptor antagonists at one year. Combination therapy h as not yet proved to be better than single drug therapy; however, the number of studies is still small, and more clinical trials are necessary. Res istant ulcers have demonstrated that acid is one of several etiological factors and that more research is needed to elucidate the reason(s) for refractoriness. The choice of therapeutic agent is generally made according to patient compliance, medica tion cost, side effects, effectiveness, relapse rate and physician experience with the drug. Long term maintenance therapy is effective in the prevention of ulcer relapse and is especially recom- mended for selected patient groups, including patients with recurrent or bleeding ulcer, patients with concomitant nonsteroidal anti-inflammatory drug use, and elderly women. Omeprazole is the treatment of choice for moderate to severe esophagitis and should be reserved for large and resi stant ulcers. Key Words: Drug therapy , Duodenal ulcer , Peptic ulcer Pharmacotherapie de l'ulcere gastro,duodenal RESUME: Les causes de l'ulcere gastro-duodenal sont multifactorielles; a ['ex- ception de l'omeprazole, tousles medicaments utilises clans le traitement de cette affection provoquent la guerison sans aucune difference statistique a quatre semaines. Le taux de guerison augmente avec le temps sous traitement actif et traitement placebo, et ii est plus bas pour les fumeurs que pour les non -fumeurs dans le cas de tous les medi ca ments sa ufle misoprostol. Le groupe des cytoprotec- teurs semble donner un taux de recidive inferieur a celui des anti-H2 a un an. Le Department~ of Medicine and Pharmacology, Di vision of Ga.moenterology, Dalhousie University, Halifax, Nova Scotia Correspondence and re/)rint1 : OT CN Williams, Prof essor and Head , Di11L11on of Gastroenterology, Dalh ousie Univmi ty. Halifax, Nova Scotia B3H 4H7. Telephone (902) 494-2333 Recei11ed for publi cation July 17, 1990. Acce/ned August 20, 1990 CAN] 0ASTROENTEROL VOL 5 No 1 JANUARY/FEBRUARY 1991 T HE ETIOLCXW OF PEI"TIC ULCER DIS- ease is multifoctorial (1,2), and factors such as environment, eth nicity, pre-exi st ing c.li scasc cone.Ii ti on (3 ), ciga- rette consumption (4-7) and nons ter- oida l anti-i nflam matory drugs (3,8) have heen implicated. The patho- physiological mechanisms suggest an imbalance between aggressive factors (acid, pepsin a nc.l Heli cobacter / >ylori) and defensive factors ( mucus, bicarbo- nate, bloodflow, epithe li al cell regen- eration, gast ri c emptying and pyloric function). T he importance of ac id in th e de- velopment of peptic ulcers is supported by the fact th at 80% will heal after fo ur to six weeks of treat ment with an ac id- rec.lucing agent (9). However, maximal acid output in patients with duodenal ulcer overlaps that in normals (3), and basal acid output is not ge nerally in- creasec.l (3). In contrast, meal-stimu- lated acid and noct urn al acid secretion are increased in peptic ulcer patients (3,10). The pivotal roleofacid in peptic ulcers is fu rther indicated by the fact t hat th ese ulcers h eal when nocturnal acid secretion is inhibited (I 0). Duode nal ulcer patient s release more gastrin in response to food th :m people without ulcers, with l ess feed - back inhibition by luminal ac id , and greater parietal cell sensitivity to th e secretory effect of gas trin ( l l ). 21

Transcript of Phartnacotherapy of peptic ulcer diseasedownloads.hindawi.com/journals/cjgh/1991/683517.pdf ·...

Page 1: Phartnacotherapy of peptic ulcer diseasedownloads.hindawi.com/journals/cjgh/1991/683517.pdf · REVIEW Phartnacotherapy of peptic ulcer disease F MOLINA, MD, MM VOi iRA, Pl ID, CN

REVIEW

Phartnacotherapy of peptic ulcer disease

F MOLINA, MD, MM VOi iRA, Pl ID, CN WILLIAMS, MD, FRCPC

F MOLINA, MM VOHRA, CN WILLIAMS. Pharmacotherapy of peptic ulcer disease. Can J Gastroenterol 1991 ;5( 1):21-33. The etiology of peptic ulcer is multifactorial; except for omeprazole, all drugs used for the treatment of peptic ulcer result in healing with no statistical difference at four weeks. The healing rare increases with time for active medication and placebo, and is lower among smokers than nonsmokers for all drugs but misoprostol. Mucosa[ protectives (or 'cytoprotectives' ) as a group seem to have a lower relapse rate than the Hz receptor antagonists at one year. Combination therapy has not yet proved to be better than single drug therapy; however, the number of studies is still small, and more clinical trials are necessary. Resistant ulcers have demonstrated that acid is one of several etiological factors and that more research is needed to elucidate the reason(s) for refractoriness. The choice of therapeutic agent is generally made according to patient compliance, medication cost, side effects, effectiveness, relapse rate and physician experience with the drug. Long term maintenance therapy is effective in the prevention of ulcer relapse and is especially recom­mended for selected patient groups, including patients with recurrent or bleeding ulcer, patients with concomitant nonstero idal anti-inflammatory drug use, and elderly women. Omeprazole is the treatment of choice for moderate to severe esophagitis and should be reserved for large and resistant ulcers.

Key Words: Drug therapy , Duodenal ulcer , Peptic ulcer

Pharmacotherapie de l'ulcere gastro,duodenal

RESUME: Les causes de l'ulcere gastro-duodenal sont multifactorielles; a ['ex­ception de l'omeprazole, tousles medicaments utilises clans le traitement de cette affection provoquent la guerison sans aucune difference statistique a quatre semaines. Le taux de guerison augmente avec le temps sous traitement actif et traitement placebo, et ii est plus bas pour les fumeurs que pour les non-fumeurs dans le cas de tous les medicaments saufle misoprostol. Le groupe des cytoprotec­teurs semble donner un taux de recidive inferieur a celui des anti-H2 a un an. Le

Department~ of Medicine and Pharmacology, Division of Ga.moenterology, Dalhousie University, Halifax, Nova Scotia

Correspondence and re/)rint1 : OT CN Williams, Professor and Head , Di11L11on of Gastroenterology, Dalhousie Univmity. Halifax, Nova Scotia B3H 4H7. Telephone (902) 494-2333

Recei11ed for publication July 17, 1990. Acce/ned August 20, 1990

CAN] 0ASTROENTEROL VOL 5 No 1 JANUARY/FEBRUARY 1991

T HE ETIOLCXW OF PEI"TIC ULCER DIS­

ease is multifoctorial (1,2), and factors such as environment, ethnicity, pre-existing c.liscasc cone.Ii ti on (3 ), ciga­rette consumption (4-7) and nonster­oidal anti-inflammatory drugs (3 ,8) have heen implicated. T he patho­physiological mechanisms suggest an imbalance between aggressive factors (acid, pepsin anc.l Helicobacter />ylori) and defensive factors ( mucus, bicarbo­nate, bloodflow, epithelia l cel l regen­eration, gastric emptying and pyloric function).

T he importance of ac id in the de­velopment of peptic ulcers is supported by the fact that 80% will heal after four to six weeks of treatment with an acid­rec.lucing agent (9). However, maximal acid output in patients with duodenal ulcer overlaps that in normals (3), and basal acid output is not generally in­creasec.l (3). In contrast, meal-stimu­lated acid and nocturnal acid secretion are increased in peptic ulcer patients (3,10). The pivotal roleofacid in peptic ulcers is fu rther indicated by the fact that these ulcers heal when nocturnal acid secretion is inhibited (I 0).

Duodenal ulcer patients release more gastrin in response to food th::m people without ulcers, with less feed ­back inhibition by luminal acid, and greater parietal cell sensitivity to the secretory effect of gastrin ( l l ).

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M OLINA et al

tra itement par une association medicamenteuse n'a pas encore prouve sa su­periorite par rapport a la monotherapie; cependant, le nombre d'essais est encore bas et ii est nccessaire de multiplier les etudes cliniques. Les ulceres rebelles ont demontrc que la secretion acidc est l'un des nombreux facteurs etiologiques et qu'il faut poursuivre la recherche pour decouvrir les raisons de la resistance au traitement. Le choix de ['agent therapcutique est generalement determine en fonction de ['adhesion du patient, du coCit du medicament, des effets secondaires, de l'efficacite, du taux de recidive et de ['experience du medecin avec le medi­cament prescrit. La therapie de maintien a long terme est efficace clans la prevention des rccidives ulcereuses ct elle est surtout recommandce pour les groupes de patients selectionnes - les malades porteurs d'ulceres recidivants ou hemorragiques, ceux qui suivent un traitement concomirant d'anti-inflamma­roires non stero"idiens, et Jes femmes a.gees. L'omeprazole est le traitement de choix Jans Jes OCSophagites modcrees a sevcres Ct i[ devrait Ctre reserve aux ulceres de grandes dimensions et rebelles.

Without ac id, pepsi n (to wh ich glycoproteins in gastric mucus, collagen and elastin in the gastric and d uodenal mucosa are susceptible) is unable to damage the mucosa, but in combina­t ion with acid it produces more severe damage than acid a lone ( 12, 13).

The mucus secreted by the surface epithelium of the stomach forms an ad­herent layer (14) that delays back dif­fu~ io n o f h yd rogen io ns into t he epitheliut;!_1 ( 15,16), and pepsin d iffuses poorly through the mucus (1 7). How­ever, the amount of mucus secreted is not likely to be enough by itself co mai ntain a neutral pH near the epi­thelia l surface when the luminal pH is 2.0 (18). Stimulated by luminal ac id, surface epithelial cells also secrete bi­carbonate (1 9 ). A lthough the amount secreted basally is no more than 10 to 15% of basal acid production (1 8 ), and thus is not suffic ien t to protect the mu­cosa alone, mucus and bicarbonate to­gether form a barrier that produces a pH gradient (neutral pH near the mucosa and an acid pH in the lumen) (20,2 1) wh ich prevents mucosa! damage from the ac id. Another c lement of defence is a hydrophobic lining of glycolipids over the epi thelium, impeding proton dif­fusion and proteolysis of the mucosa (22).

Mucosa[ ischemia is the most impor­tan t factor in acute gastric ulceration (23 ), because bloodflow is critical m the maintenance of normal mucosa! energy stores, aerobic metabo lism, buffering and d isposal of acid that enters the t is sue (24 ). Hence, gastric blood ~upply

plays an important role in the defence system.

Gas t ric empty in g increases in patients with duodenal ulcer, and the normal response of decreased emptying with ac idification of the duodenum is impaired (25 ). In a<ldition , retrograde duodenal mo vements arc less frequent, less pronounced and less effective, lead­ing to a defic iency in the transport of neutra lized d uoden a l con tents and bicarbonate from dista l to prox imal duodenum, thus lowering pH in the duodenal bulb (26) . Motility abnor­malities found in experimental ulcers include decreased waves and mi.,xing waves in the proximal duodenum and increased waves in the d istal duodenum (27). Their interaction causes a diver­sion of biliary and/or pancreatic secre­tions, with increased inc idence and severi ty of posterio r wall ulce r induced by cysteamine in the ra t . Correct ion of this d iversion reverses the effect (28).

Recently H pylori has been impli­cated in the et iology of duodenal ulcer. This microorganism has been found under the gastric mucus layer, adherent to epithelia l cells and sometimes con­centra ted over intracellular junc tions (29). H pylori produces a large amount of urease, and the release of ammonia by urcase may increase gastric pH, protecting H pylori from gastric acid (30) and undermining gastric mucosa! integrity. H pylori was detected in 85% of 232 patien ts with duodenal ulcers. Ir was found in the overlying mucosa of duodenum showing gastric metaplasia, as well as in the gastric mucosa (3 1 ). O f

39 pa tients whose duodenal ulcers healed , 59% re lapsed at one year. The relapse rate was 27% among panenrs who were H pylori culture-negative hut 79% among pat ients who were H /))•Ion culture-positive (32 ). In another group of patients in whom H pylori was crndi­cared, 66% had a relapse of duodenal ulcer with H pylori recurrence, while only I 0% with no recurrence ofH pylon had duodenal ulcer relapse (32).

Antimicrobial agents and bismuth compounds reduce H J>ylori infection, which is accompanied by healing rares comparable to those obtained with acid suppression , with the added advantage that they may a lso reduce the relapse ra te of duodenal ulce r (33,34). Thus,a combinat io n of tinidazole (an anti­microbi al similar to met ronidazole) with co llo idal bismu th subcit rnte healed a greater proportion of patient; with duodenal ulcer and e radicated H pylori better than placebo or drug alone. It is likely that the concept of trealmg duodenal ulcer disease wi th an an, tibiotic will be pursued enthusiastically in the near future. The ideal agent, cor· rcct dose, dura tio n of therapy for eradication of the organism and rate of recurrence of both organism and ulcer are unknown at this time.

GOALS AND PRINCIPLES OF DRUG THERAPY FOR

PEPTIC ULCER The goals of therapy are eliminanon

of symptoms, ulcer healing, prevention of recurrence and prevention of com­plications (35).

The ideal drug for peptic ulcer treat,

ment would: have a 100% healing rate and no side effects; require only one dose every 24 h ; provide antisecretorv effectiveness for 24 h ; enhance mucosa! defence; and benefit the natural history of the disease (36). Unfortunately, no presently available drug fulfills all of these requiremen ts. Pat ients should avoid the following: foods that provoke symptoms, because although diet chan­ges cannot heal ulcers by themselves, they may a llev i,1 te sympto ms (37); smoking, because it impairs healing (38 ); and u lccrogenic medications (39) .

T he following drugs will be dis-

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cussed: histamine H2 receptor :mrn­gonists (cimetidine and related drugs), anticholinergic drugs (pirenzepine), proton pump inhibitors (omeprnzole), antacids, suc ralfate, bismuth com­pounds and proscaglandins (misopros­tol, enprostil). These agents can he classified according to their s ites of ac­uon: the parietal cell ; the gastric and duodenal lumen; the gastri c and duodenal mucosn.

DRUGS THAT ACT ON THE PARIETAL CELL

Physiological mechanisms of acid pro­duction: Gastric parietal cells produce acid in response to three main stimuli: gastrin from G cells in the antral area; acetylcholine from the vagal endings; and histamine from mast-like cells in the fundus area ( 40) . Each of these sub­stances acts on its own receptor s ite on the parietal cell: muscarinic MI recep­tors for acetylcholine, histamine Hz receptors for histamine, an<l gastrin receptors for gastrin. Their actions parallel and facil itate one anoth er ('permissive effect') ( 41 ). Receptor ac­tivation produces a second messenger (for example, calc ium is increased by gasrrin and acetylcholine, and cyclic AMP by histamine) with subsequent activation of other cellular processes, leading finally to the activat ion of the H\K+ A TPase ( the proton pump) and acid production ( 4 2 ,4 3) (Figure I ) . Histamine Hz receptor antagonists: There are now four of these drugs avail­ahle on the Ca n adian market: cimetidine, ranitidine, famotidine and nizatidine. All of them act by competi­tive binding to the Hz rece ptor.

Cimetidine, the first generation of che histamine Hz receptor antagonists, inhibits acid output in response to a ll known stimulants of ac id secretion, in­duces prostaglandin synthesis in the gastric mucosa (44), and inhibits the action of gastrin anJ acetylcholine (45). Reviews of endoscopic studies of 1he efficacy o f c imet id ine versus placebo in the healing of duodena l ulcer have found healing rates of 60 to 80% at four weeks and 85 to 95% at eight weeks for cimetiJine, compared tO 3 5 to 45% for placebo; th is Jifferencc was statistically s ignificant ( 46-48 ).

Phormocotheropy of peptic ulcers

ACETYLCHOLJNE H z HISTAMINE GASTRIN

PIRENolNE oj sLo0 Rs ~j PROGLUQDE v

\ eaom\ \ GLANOINS

,n GTPG,

PARIETAL CELL

CALr L_,.·~~rETE INOSITOL TRIS-PHOSPHATE

j CALMODULIN CYCLIC AMP CALCIUM

t::~ l l PHOSPHOPROTEIN KINASE PHOSPHOPROTEIN

~ .. ~:;p / '------~--OSPHrlLAS/--A-----~

~

~ -oMEPRAZOLE

LUMEN K H --ANTACIDS

SUCRALF/\ TE PROSTA-S <=2::UCUS-BICARBONATE BARRIER '?lJlllJl ~ BISMUTI I COMPOUNDS GLANDIN

MICROVASCULAR - ULCER CRATER MU COSA CIRCULATION

Figure I) Mechanism of acid production and mechanism of acuon of different antiulcer drugs. in GTP Gi Inhibitory GTP binding procein Gi; x Inhibit~

O riginally the recommended J ose of cimctidine was 300 mg four times a day, but a dose of 600 mg twice a Jay was later foun<l to be equally effective in the healing of peptic ulce r ( 49), and 800 mg at night time has lately proven co he as effective in lreating Juodenal ulcer as 400 mg twice a day ( 50). C imetidine's efficacy is lower among smoke rs than nonsmokers (51,52), and Jrug require­ment is increased afte r hemodialysis.

After treatment is discontinued , 80% of patients healed with c imctiJine will re lapse in one year ( 53 ); however, the relapse rate in the first year is lower among pntients receiving c imetidine 400 mg at night for two years than among patients receiving no treatment

( 54 ). Patients who received one yenr of treatment with c imetidine 200 mg twice a Jay, 300 mg twice a Jay or 400 mg at night had a symptomatic recur­rence rate of l 5% ( versus 35% among those receiving placebo), anJ relapse was more common among smokers than nonsmokers ( 5 5).

The main siJe effects of cimetidine include interaction with the hepatic cytochrome P450 system, thus inhibit­mg the metabolism and thereby in­creasing the effect of many drugs, especially theophylline, anticoagulants anJ anticonvulsants (56) . C imetidine produces hypcrprolactinemia (57) and may have amian<lrogenic effects with male breast tenderness, gynecomascia

CAN J GASTROENTEROL VOL 5 No I JANUARY/FEBRUARY 1991 23

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MOLINA cial

anJ impotence (58). lt may abo cause confusion anJ disorientat ion in e lderly patients and in chose with hepatic anJ renal J ysfunc tion ( 59). C ho lesrasis, hepa titis and panc reatitis have a lso been reporteJ (56).

Most clinically significant adverse effects occur because c imetidinc's ac­t ion is noc specific to gastric Hz recep­tors (60). Thus, cimeti<.line c rosses the hlood-hrain harrier and b mJs to some hra in rcccpw rs (6 1,62). These s ide ef­fects occur in a very small percen tage of pat ients unJe r trea tm e n t anJ a rc reversed when drug administra tion is stoppeJ .

Ranit idinc is a secon d gene ra tio n histam ine I lz receptor an tagon ist. It has highly effecti ve , specific compeu ­tive hmding to Hz receptors m the pari ­eta l cell ; mole for mole, it is fo ur to five t imes mo re po tent th an c 1mecidine (63 ). Although ranitidine has the same pharmacological actions as c ime tidinc, side effects are much less a prohlem m patients taking ranitid ine ( 46,56). Ran­icidine also interacts with the hepatic cytochrome P450 system, bur because 1c docs so with an affinity about 10 rimes lower than t, at of cimctidme, the mter­accion is of no clinical s ignificance (64). Unlike c1met1dme, 1t does not have antiandrogenic effects (65), docs not elevate prolactin leve ls at thera­peutic doses (66), and does not cause mental side effec ts even tho ugh 1t cros­ses the bloo<l-bram barrier (56). Hepa­ti t is a nd t ra nsient inc reases i n gammaglutamyltransfcrase and lactate dehydrogenase have been report<...J (67).

The healmg rate of duodenal ulce r for ranicidine 150 mg bid is 60 to 75% at four weeks and 85 to 90% al eight weeks (46,68,69). In othe r stuJics, healing rates be tween 54 and 92% have been reported at four weeks versus 8 to

46% for placebo (56). Ranitidmc 150 mg bid is as efficac ious as 300 mg at night in healing J uodenal ulcer (70). The relapse rate with 150 mg a t night 1s 38% at one year and 48% a t two years, versus 86% with placebo (71 ). Raniti­dine's effectiveness in hea ling ulcers 1s impaired by smoking (72); comparisons between ranitidine and c ime tic.line in healing duodena l ulce r in sho rt term treatment have not yielded any statisti-

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cally significant diffe re nces (73 ). How­ever, ranitid ine l 50 mg a t nigh t was superior lo cimetidine 400 mg al night. In long term treatment fo r prevenu on of duodenal ulcer relapse, 23% of pa­t ients receiv ing ran itidine and 37°,{l re­ceiving cime tiJ ine relapsed (74 ). In another study the relapse race was 15% for ran itid ine and 44% for c imetidine (75) . Ranitidine 300 mg at night sup­pressed nocturna l acid sec retion by 85% and 150 mg bid hy 54% (76), whereas c1mctid ine 600 mg hid sup­pressed nocturna l acid sec re t ion by 85% (77).

FamotiJinc 1s a t h1azolc Jen vauve, diffe rent from che imidazole ringofc1m­etidine anJ th e furan ring of rani t id ine. O n a molccubr hasis, It is a bout 20 t imes more porent than c ime t1dine nnJ 7.5 rimes more potent Lhan ranitid ine. !rs ac Lion can last for 7 h or more (78). Nocturna l ac1J secretion is decreased by 80% with LO to 20 mg at bedtime. Basal aciJ and pepstn output a rc also suppressed (78-8 l ). Famotid inc lacks t he anr1androgenic activity and Jrug 1nteract1ons associated with c imen d ine (8 1,82 ). lts high potency makes it suit­able for treatmg Zollmger-Ellison syn ­drome.

FamonJine 20 or 40 mg bid or 40 mg at night produced healing rates at two, four and e ight weeks (83, 81 and 75%, respect ive ly, at four weeb) that were nor statistically different from one an ­othe r o r from the healing rate with ran-1t idine 150 mg hid (83). S ic.le effects -Jrnrrhca, anx ie ly, JecreaseJ libiJo, and milJ elevation ofbtl1rubin - were pres­ent m a very small percentage of the paucm s, most freque ntly in those re­ceiving famotiJine 40 mg bid (83). A n ­oche r stuJy comparmg famotiJ ine with ranitidine re porteJ a healing rate of 93% for rani t idme and 90.2% for famo­t1dinc 40 mg h1J, 90. 5% for fa motidine 40 mg a l n ight , and 83.3% for famo­udmc 20 mg h1J; again, t he Jifferences we re not sta t istically significant (84 ). Famotidine 20 mg bid was founJ to

have a healing rate comparable to tha t of c 1metidine 200 mg biJ (85 ). In long term treatmen t to prevent ulcer recur­rence, 32% of patients taking famoti ­Jine 20 mg at nigh t anJ 63% of tho e takmg placebo had recurre nce at s ix

months of therapy. Consripa tion wa, present in l % of patients in Lhe famo­tidine group (85). T he overall inci­dence o f s ide effec t observed in

pat ients taking famotid ine is similar tu that observed in pa t1ents taking ran, iudine; however, morl' clinical expen cnce 1s need ed to d etermine famo r iJinc's overal l place 111 the therapy of peptic ulcer Jisense.

Nizat iJinc, ltke ra111 udine, contain5 a f uran ring ,md 1s a potent , specific anJ ora lly wel l tolerateJ h ista mine Hz receptor antagon ist. It reduces ga,rnc acid secre t ion for up to 8 h anJ is a, potent as ranitiJme and three to four t imes mo re potent chan c imetidinc (86). N izaudine 1s excreted via t he kid ncy, so rena l impairment decreases ib el imination.

Basa l, noctu rnal , an J fooJ anJ ch em ica ll y s timulateJ gast ric acid secretion is in hihned in a dose-J epcnJ, ent manne r (87). Unlike cirnetiJ inc, niza t iJi n c d ocs not inhi b it tht mterosomal hepat ic cytoch rome sy,, tem, and thus docs not inhibi t metabo lism of agents affected hy th is system, such as theoph ylline and d iazepam (88). Lt has no antiandrogenic effect anJ causes less prolacrm release than c imctid ine (89). Nocturnal acid secre­tion i:. Jecreased up co 90% with a <lose of 300 mg (90).

Nizat1dine 150 mg b1J anJ 300 mgat night were equally effect ive in healing duodena l ulcer at four weeks (67 versus 68%), and were superior to placebo (29% of healing rate, P<0.02); non, smokers' ulcers hcc1leJ more often than J id smo ke rs' (P<0.002) (91 ). In a stud\ comparing n1zat1d1ne with ran1t idme, t he heal ing races were 81 versus 80% at four weeks and 92 versus 93% at eight weeks, respectively (92).

As m a inle nancl' the rapy for duodena l ulcer Ill remission, n izat1<l111e 150 mg at nigh t was superior at one year to placebo ( recurrence rates were 34 and 64%, respecuvely, P<0.001) (93). In Lhe prevention of recurrence at six months, n muiJ inc was comparable in

efficacy (relapse rate 18%) lO ranitidinc (relapse rate 13%) (94). S 1de effects repo rceJ on these tria ls were the same anJ not statistical ly d ifferent from those reported hy patients tak ing placel-x1.

CAN J GA!>TROENTEROI VOi 5 No I j ANUARY/Fl:BRUARY 1991

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Currently, the histamine Hz recep­tor antagonists are the cornerstone of prescription peptic ulcer therapy. Effec­tive in healing and preventing relapse of duodenal ulce r, this family of drugs has revolutioni zed the treatment of peptic ulcer disease by decreasing the likelihood of complications and surgi­cal interventions. Compliance with H2 receptor antagonists is easy: most are available as a once daily Jose leading to complete ulcer healing in four to s ix weeks (although smoking decreases the efficacy of a ll of them) . Because their healing rates and mechanisms of action are similar, the selection ofan Hz recep­tor antagonist often depends on 'soft' factors suc h a~ previous response to cl1erapy, likelihood of compliance anti undesirable s ide effects. Drug intcrac­uons, patient age and the presence of other systemic disease arc also impor­tant considerations in drug selection, as is cost, since the newer Hz receptor antagonists are much more expensive than cimetidine. Anticholinergic drugs: Pirenzepine i~ an amicholinergic drug chat has a high affinity for, and inhibits relatively sclec­uvely, tile muscarinic MI receptor sites located in the parietal cell (95). T hu~ pirenzepine, which is about one-tenth as potent as atropine, inhibi ts the acid secretion stimulated by the vagus with a minimum of undesi rable cardiac, visual or urinary side effects (96,97 ). It is a tricycl ic pyridobenzod iazepine which st ru c turall y rese mbl es t h e tricyclic ant idepressants but, being quite hydrophi lic, does nor cross che blood-brain barrier and has no central effects (46). Pirenzepine 100 mg reduces noc turna l ac id secretion by 41% (98). Delayed gastric emptying has not been observed with pirenzepine (99). It has a long h alf-life ( 11 h), and most of the drug is excreted unchanged in the urine.

In duodenal ulcer treatment, piren­zepine I 00 mg has shown superiority over placebo, with a healing rate of 70 ro80% versus 32 to 57%, respectively, at four weeks ( I 00). Studies comparing pirenzepine with c imetidine (101) and raniti<line (41) showed comparable healing rates. Long term treatment with pirenzepine I 00 mg/day to prevent

re lapse of duodenal ulce r has been shown to be superior to placebo and comparable to cimetidinc ( 102). In a study comparing pi renzepine with placebo, pirenzepine 100 mg/clay for one year had a duodenal ulcer relapse rate of 58%, versus 96% with placebo; this d ifference was statistically sig­nificant ( I 03 ). Pirenzepine produces side effects at a therapeutic Jose of l 00 mg ( including dry mouth, const ipation and urinary de lay) in 7% of patients ( 104 ); h owever, doses lower than I 00 mg/Jay did nor produce as good results as 100 mg in the short term treatment of duodenal ulcers (105). The presence of troublesome side effects when ade­quate doses a re employed indicates a lesser role for this agent, especia lly when agents without these side effects a re now in routine use. Proton pump inhibitors: Omeprazole, a substituted ben zimidazole, is the most powerful inhibitor of gastric acid secre­tion ava ilable. Ir irreversibly inhibits the H + ,K+ A TPase ( the proton pump)

located in the secretory membrane of the parietal cell , which is the terminal step in the acid secretion pathway. It thus blocks a ll forms of stimulated and basal acid secretion, produc ing achlor­hy<lria independently of t he nature of the st imulus (106,107). O meprazole ap­pears co be activated at acid ic pH to a hydrogen ion-activated derivative (a sulphone) which binds irreversibly to

the H + ,K+ A TPase. This dependence

on an ac id pH makes the drug highly selective for act ive ly secreting parietal ce lls. A lso, being a weak base, omeprazole seems co concentrate in the acid environmenr of the parietal cell ([08).

O meprazole is elimina ted rapidly th rough the liver and kidney, primarily as sulphone, sulphide and hydroxy­omeprazole derivatives (mostly t he lat­ter). It inhibits reactions mediated by t he cytochrome P450 system to the same extent as an equimolar dose of c imetidine; however, as the dose of o meprazo le n eed ed fo r treat ing duodenal ulcer is 25 to 50 times lower than that of c imetidine, this interaction h as little clinical importance, although de lays in the elimination of amino­p yr ine a nd diazepam hav e been

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reported ( 4 7). O meprazole is highly protein bound (95%); its plasma ha lf­life is about 1 h; and its pharmaco­kine ric profi le is not alrereJ in chronic renal fa ilu re or by hemodia lys is. O meprazole 20 to 40 mg once a day inhibits gastric acid secretion for up to

five Jays, after which time it reaches a plateau ( 4 7 ). A J ose of 40 mg decreases acid production by 99%; after the drug has been discontinued for one week, aci<l production is still inhibited by 26% (1 07,109).

T ransient side effects include d iar­rh ea, nausea, Jry mouth , dizziness, weakness, h eada che and numbness (77, ll O). Carc ino id lesions de rived from encerochromaffin cell -like have appeared in mature rats after two years on large doses of omcprazole, but this enterochromaffin cell-like hyperplas ia seems to be species specific. These tumours are thought to be caused hy hypergas rrin e mi a, as hi gh d ose ranitidine also causes hypergasrrinemia and carcinoid tumours in rats. In addi­tion, prolonged achlorhy<lria increases gastric bacterial counts, with increased concentrati o n s o f nitrates and nitrosamines, which are carc inogenic ( 108). In another study, these changes were found to return to normal within three days after the drug was stopped ( 111 ). Hypergastrinemia also returns w normal after the drug is discont inued ( 112).

Ar present omeprazolc is only ap­proved for short tenn treatment in duo<lena l ulcer d isease. O meprazole 30 mg daily in che treatment of duodenal ulcers had a healing rate of 83% at two weeks and 98% ar fou r weeks ( 11 3 ); in another study, 78% of duodenal ulcers healed at two weeks and 94(Yo at four weeks, with 30 mg producing better results t han JO mg (109). Compared with c imetidine, omeprazole 30 mg healed 73% of ulcers at two weeks anti 92% at four weeks; cimeridine I g healed 46% at two weeks and 74% at four weeks (114 ). In a Canadian study, omeprazole 20 mg and cimeridine 600 mg bid were not statistically d ifferent in hea ling races at two and four weeks: 58 and 84% for omeprazole and 46 and 80% for c imetidine, respectively. There appeared to be a trend in favour of

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omeprazole al l wo weeks, but not at four weeks (77). Recurrence after discon­tinuation of treatment is Lhe same as with Hz receptor antagon ists (l 14).

It is likely that o meprazole will be reserved for use in patients with resis­tant Juodenal ulcers and resistant m unusual gastric ulcers (eg, large or mul­tiple ones). O meprazole is especially useful in Zollinger-Ellison syndrome and will become Lhe drug of choice for modernte to severe cases of peptic esophagitis.

DRUGS THAT ACT IN THE GASTRIC AND DUODENAL

LUMEN (ANTACIDS) Unti l 1977, when cimetidine was in­

troduced, antacids were the treatmem of choice for duodenal ulcer. T heir long term use and clinical tria ls have now proved their efficacy in this conJition. A ntacids reduce the acidity of gastric contents by neutralizing hydrochloric ac id, and this rise in pH reduces pepsin activity (pH higher than 3.5 to 4). In addition, a lumin um-containing ant­acids bind bile. A ll of these act ions de­crease damage to the Juodenal mucosa and proms.Jte heal ing of Lhe ulcer ( 104 ). Antac ids can be classified in to two groups: those whose reactivity with aciJ is defined by the anion portion of the molecule (sodium bicarbonate , calcium carbonate) and those in which the cat­ion is more important (magnesium h yJroxi d e, a luminum h yd rox id e) (115). Dose size and timing should be balanceJ LO promote ulcer healing and avoid side effects. A Jose is admini­stered I and 3 h after meals anJ at bedtime, for a total of seven da ily doses.

T he buffering capacities of the vari­ous antacids vary considerably ( 6 to 105 mEq); it has been suggested that a neut­ralizing capacity of 200 to 280 mmol is necessary to heal ulcers (46, 116). The healing rate using thi s neutralizing capacity was 85% at four weeks of treat­ment in patient~ with duodenal ulcer ( 117). ln three studies, the healing rates among patients Laking antacids with neutral izing capacities of 560 LO I 064 mmol for the ir Juodenal ulce rs were comparable to those in patients taking cimetidine 800 to 1200 mg ( 104 ).

Maalox TC (Rorer) three tablets bid

26

(neutra lizi ng capaciLy 162 mmol) prevented ulcer relapse about as effec­lively as c imetidine 400 mg at bedtime and better than placebo or Maalox TC al bedtime (1 18). AnLacids in liquid suspension have been considered more effective pharmacologically than am ­aciJ tablets; however, when the effect of magnesium-aluminum hyd roxide an tacid tablets or liquid on food-st imu­lated gastric acidity was evaluateJ in vivo in eigh t patients with duodenal ulcer, the durat ion of effect of tablets was greater than that of liquid suspen­sion ( 119). Smoking impairs the heal­ing of duodenal ulcer treated with antacids. The relapse rate after treat­ment is discontinued is the same as when cimetidine is discontinued ( 120).

The side effects of antacids will depenJ on the particular antacid in use. Most an tacids on the market are mix­tures of aluminum hydroxide anJ mag­nesium hydroxide, which balance the constipat ion and dia rrhea that the former and the latter, respectively, can cause. H ypernatremia, hypercalcemia, hypermagnesemia, hyperaluminemia, hypophosphatemia, alkalosis, milk­alkali syndrome, renal impairment, kid­ney stones, dec reased absorption of fluoride, iron and tetracyclines, anJ in­creased absorption of weakly basic drugs (eg, guanid ine) have all been reported (121,122). Antacids conta ining cal­cium are not recommended in the treat­ment of duodenal ulcer because they stimulate acid secretion and may thus cause acid rebound (123,1 24).

DRUGS THAT ACT ON THE GASTRIC AND DUODENAL

MUCOSA Sucralfate: S ucra lfate is a basic aluminum salt of sucrose substituted with eight sulphate groups ( 125). lt is a h ighly effect ive, essentially nonsys­temic drug for treating peptic ulcer. In the acidic environment of the stomach, a luminum h ydroxide dissociates from the sulphate residues in sucrose octasul­phonate, leaving it with a negative charge. This reaction is followed by both intra- and intermolecular bridges, producing a variety of polymers and form ing a viscous substance (active form ) ( 126) . The latter binds preferen-

ti ally to partially denatured or Jegraded proteins (positively charged) in Lhe ulcer base, forming a protective bamer against back diffusion of hydrogen ions ( 127). S ince the optimal pl I for bin<ling to the ulcer crater is 2 to 3, sucralfate should be taken when the stomach ii empty. Sucralface also inhibits pepsin activ ity and adsorbs bile salts ( 127). It increases prostaglandin synthesis and secretion in rhe gastric mucosa ( 128). It is poorly absorbed. Side effects reported are constipation (3 to 4%), diarrhea, nausea, dry mouth and hypophospha­temia; because of potentia l aluminum toxicily, its long term use in patients with renal fai lure should be approached cautiously (129, 130). Sucralfate <locs not interfere with physiological func­tions of the J igeM i ve system (acid secre­t ion or moLility) ( 13 l ). Although sucra lfate contains a luminum , aciJ neutralization does not contribute sub· stantially to its therapeutic effect ( 127).

The healing rate at four weeb m patients with duodenal ulcer Lreaied with sucralfate is 60 to 97%, compared with 24 to 64% with placebo (129). Compared with cimctidine, Lhe healing r:ue for sucralfate was sim ilar ( 132). T he relapse rate one year after treat­ment has heen disconLinueJ is 70%, similar to that of cimetiJine (133 ). Ina study using a 2.5 g daily dose of sucral­fate maintenance therapy, the relapse rate at one year was 44% compared with 82% for placebo ( 134 ); another stuJy with 2 g sucralfate daily showed a relapse rate at six months for sucralfate of 21.2% and for placebo of 50% (135). Bismuth compounds : Tripotassium dicitrare bismuthate, or colloidal bis­muth subc itrate, is a bismuth salt of citric acid. It heals ulcers by binding to proteins and necrotic debrb at the ulcer base to form a harrier to the diffusion of acid ( 136), adsorbing and reducing the concentration and output of pepsin m the stomach for at least 24 h after the last oral dose ( l37). ln the presence of acid, collo ida l bismuth subcitrate yields bismuth ox ide and an oxychlonde precip itate that forms a tenacious coagulum upon the digestive mucosa. The precipitate acts as a protective layer against erosive chemical auack by acid or pepsin. Also, colloidal bismuth

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has a marked ability co fix chloride ions, with the form;it ion of insoluble bismuth oxychloride, which prevents the J i(­fu~ion of bismuth ions into the circula­tion and thus minimizes the systemic toxicity of bismuth. le also stimu lates mucus secretion , chclares pepsin and binds bile. Jes effectiveness is highly de­pendent on the pH of the gastric juice, being greater at low ( 1.0 to 3 .5) than at high(3.5 to6.5) pH (41,129,138- 140). Bismuth compounds colour the tongue and stool black. The liquiJ p reparation has an unplca~ant ta te and ammon ia­cal smell. Bismuth compounds are potentially neurotox ic; however, chis side effect has never been reporteJ in clinical triab ( 129).

Healing rates at four weeks of 50 to

89% (versus 8 co 42% for p lacebo) have been reported; al I studies showed stat 1:,­ucal superiority in favour of bismuth compounds (36,129). Against rnn11i­Jine, no stat istical <l ifference was found at four and e ight weeks of treatment (l4l). The rates of J uodenal ulcer relapse al one year after healing with no maintenance treatment were 39'ro with bt~muth, 85% with cimcudine ( l 42, 143), 62%wich bismuth and 89% wi t h ranitid inc (l 41). These da w are ~tat i:,­rically significam in favour of bismuth . The lower relap ·e rate after treatment with bismuth compounds has been re­lated co eradicatilm of H /)ylori ( 3 3,34 ). The result was not affected hy pat ient smoking habits ( 141).

Colloida l bismuth subcitrnte is not yecavailable in Canada except fur com­passionate use, but it is likely that bis­muth subsalicylate, wh ich is avai lab le m Canada, is as effective. Bismuth sub­~1licylate is a lso the drug of choice for eraJication of H pylori. l t b the ,iuthors' practice to a<ld oral metronidazole 250 mg qid w bismuth subsalicylare 30 ml qtd to increase the like li hood of eradicating H /)ylcn·i, with rechecking after eight co 12 weeks of thernry. This ts particularly re levam for recurrent JuoJenal ulcer disease and the mnre controversial symptomatic chronic ac­tive antral gast ritis. Prostaglandins: PmsrnglanJins are a family of biolog1ca lly related unsatu­rated fatty ac ids consisting of 20 cm­hons and Jerived from arachidonic

acid. They me rresent in the gastro­intestinal tract , especially the sromach, an<l affect smooth muscle ,1C ltv1ty ,md gastric and intestinal secretion. Basal gastric acid secret1un and secretion stimulateJ by fi.1od, acecykholine, gas­lrin, h istamine anJ insulin hypogly­cemia an.' inhibited br prnsraglandins ( 144). High affinity bind ing sites for E type prnstaglandins have heen ident i­ficd m canine ranetal ce lb; l and F prosrnglandins hind (mly weakly to this si te, anJ c1metidine and histamine do not bind to it at all. These findings indicnce the existence of a ranicular receptor in the parietal cell for the E pmstaglandins ( 145). Prostaglandm E2 inhihi ts histamine-stimulmed acid se­cret ion by inhibiting adenylate cyclase via the 111h1hitnry CTP binding protein Gt, which subsequently decreases eye! ic AMP production ( 146).

Proscaglandins have a t roph ic act itlt1 on the gastric mucosa, increasing bicar­honate and mucus production in the stom;ich and dundenum ( 147- 150) and mucosa! bloodflow ( I 51 ) . A 11 of these rroperties havl' been called 'cytn­protective' ( this tl'nn ha:, heen chal­kn ged and ~ome autlrn r1rie:, recummend 'mucosa! protection', hur for the purpose of this review we shall reta111 'cywprnrecuon '). It has been proposed that a deficiency of pmsta­g la nJ ins exists 111 duudenal ulcer pauenrs. Ah lquisl er al ( 152) found rhat pro:,taglandin synthcsi:, in response w acid and (,10J was b lunted tn dundcnal ulcer patiems and was markedly higher in normals.

M boprostol is a synthetic analnguc of prnstagl;indin E1 that reduces the v,1 lume and Clmcentratiun nf pepsin and ac id production in hunwns ( 15 3 ), decreases gastric aci<l secretinn in response LO h1stam111e, penragastr in and mcab in dogs ( l 54) and docs nor in­crease gastrin levels ( l 55). Gasrrin in­hihttiun by misoprosrnl is dnse-relmed; its action scares I h after adminbtration and b negligible after 4 w 5 h ( 156). While m1snprnstnl has all of tht' proper­ties nf cycoprotection in addition co its flnti~ecretory action, the contribunon of cyroprotective activity to miso­prostol's clinical efficacy in hea li ng es­tablished ulcers 1s doubtful, since the

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drug is nm supcnor tn placcbo when a low annsecretory duse ( less than l 00 µg four times a day) has heen used ( 157). Follow111g oral aJmmistratton, the drug is rapid ly absorbed and de-esterificd into its fret' acid form, wh ich bas potent as the parent compound. Peak con­centration is reached in 30 to 60 mins. M isoprostol 1s about 85'X1 serum protein bound; it is metabolized in the liverand excreted via the kidney ( l 58).

In a study comparing misurrostol 50 llr 200 µg qid with r laceho in the heal ­ing of duodenal ulcer, t he ulcers of 42.6% of patients taking 50 µgqid, 51 % taking placebo, and 76.6% taking 200 µg qid h;id healed after four weeks of tre,Hment; the higher Jl>se ol misopros­tol was statistically supenor m the lower dllse oi misoprosttll and placeho ( l 59). Another study reported rhat, after four weeks, the ulcers of 64. 9lX, of patients taking misopmstol 100 µ g q1d and 4 7.4% of patients taking placebo had healed, with significant statist ical dif­ference in favour of misoprostol ( 160). Diarrhea has been the side effect most frequently reported wirh misoprosrol; its frequency 1s dose-dependent: 4% with 50 µg qid, 8.5% with 100 µg q1d and I 3. l % with 200 µg qid, against placebo (5%). The diarrhea resolves when the drug ts discontinued ( l 59,160). Other side effects reported include ahJommal cramps, dyspepsia, nausea and headache . Note chat misoprosrol, like che E prosragl~mJins, c..in srnnulate uterine contracti lity and hence is contraindicated during preg­nancy nr 111 women ar risk of becoming pregnant. Misopn1stol 400 µg bid has been rerorced to he as effective as 200 µg lliJ in the 1 reatmenr of duodenal ulcer; 200 µg hid, however, was no bet­ter th an placebo (161). After four weeks of treatment, c1mctidine 300 mg qid, misopro~tol SO µg qid and misnprostol 200 µg qid produced hea l­ing rates of 6 7, 4 l and 60°;(,, respective­ly. There was no statistically significant d iffe rence between misoprostol 200 µg ;:ind cimetidine; both drugs were supe­rior to nusoprostol 50 µg q id ( 162). Cigarette smoking Joes not impair the healing action oi misoprostol in duodemil ulcers ( 16 3). Studies are not yet available cnnct·rning the use of

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CIMETIDINE I I - : RANITIDINE I --- 1

MMOTIDINE I - NIZATIDINE I ..____. I - PIRENZEPINE 1- 1 - OMEPRAZOLE : I - ANTACIDS I - 8UCRALMTE I I - 818MUTHI I - Ml80PR08TOL 1-1 - I PLACEBO----+ I

I I I I I

0 20 40 60 80 100 HEALING RATE (%)

Figure 2) Healing rates of duodenal ulcer with differe nc antiulcer drugs afcer four weeks of treatment. Arrows show rhe ranges amon![ mulriJ)le swdies

misoprosto l, wh ic h is approveJ in Canada for rhe t reatment of duodenal ulcer, as main tenance therapy for the prevention of recurrence.

Enprosti l is a synthetic ana logue of prostaglandin Ei with the same proper­t ies as misoprosto l. A lthough not yet approved for the treatment of duoJena l ulcer in Canada, enprost il has been shown to be superior to placebo in duodena l ulcer healing, and a J ose of 35 µ g bid is as effective as c imet idine 400 mg bid ( l 57 ). However, a fter four weeks of trea tme n t, ran itidine 150 mg bid produced a healing rate of 93%, versus 46% with enprostil 35 µ g bid; rani tidine was stat istically superior ( 164). S ide ef­fec ts and con traindication s a re the same as with misopmsto l (164).

Nicholson et a l (165 ) reviewed 49 tria ls of treatment of duodenal ulcer with cytoprotective d rugs or Hz recep­tor antagonists. Th e relapse rate at one year was lower for cytoprotective drugs. As Figure 2 shows, the healing rates in patients with J uodenal ulcer are com­parable for all drugs except omeprazolc.

COMBINATION THERAPY Theore tically, using two antiulcer

drugs with d ifferent mechanisms of ac­tion should result in a syne rgistic effect and a better healing rate than using a s ingle drug. W ork re po rted thus fa r, howeve r, has nor substantia ted this h yp o th es is . O n e s tud y compa red cimetidine 300 mg qid, sucralfa te I g

qid a combination of both anJ found no stat ist ica ll y s ign ifican t d iffe rence among the three groups at rwo, four and e ight weeks of treatme nt, although at two weeks the re was a trend in favour of the combination ( 166).

In an othe r study, ranJomly assign ­ing patients whose ulce rs h ad no t healed after eight weeks of treatment with c imetidinc 800 to 1000 mg/day or ranitid in e 300 mg/day to rece ive c imeridinc 800 mg/day or c imetid ine 800 mg plus pirenzepine LOO mg/day for s ix weeks, produced a healing rate of 70% for hoch groups (1 67). Investiga­tions of combined the rapy have in­volved small patient samples, so further stud ies with larger samples arc neces­sary hefore any generalizations for or against combined therapy can confi­dently be made.

REFRACTORY DUODENAL ULCER

Bardhan (1 68) has defined a refrac­tory duodena l ulcer as one that fa ils to heal afte r t reatment wi th c imetid ine 1 g daily for three mon ths. He found a 7% fa ilure in h ealing of duodenal ulcers after con tinuous treatment for three mon ths. ln a study of 66 patients with re fractory duoden al ulcers, 42% did not heal after an average of 9 .4 mo nths of treatment, despite inc rement to 2 o r 3 g of cimeti<line da ily. Nine underwent surgery - fi ve of these h ad poor resul ts. Patients with refractory ulcers were

younger than 40 years and had longer histories, frequent episodes of bleeding, a family history of peptic ulcer, previous treatment with cimetidine, ulcer~ of med ium or large size, and moderate or seve re duoden it is com pared w1th pat ients who responded tn cimcti<lmc treatment ( 168).

The cause of refractoriness is un­known. Noncompliance, genuine rcsis• Cance ( 168) and excessive vagal <lnve ( L69) have been proposcJ as explana­tions of the phenomenon. A pnthn­physiological fa ilure of Hz blocker~ to suppress acid secretion , e~pecia lly at night, has been implicated ( 170). Meas­urements of in tragastr ic aci<li ty indi­cated thm acid inhibit ion was lower from midnight to midday anJ over 24 h in 10 pa tien ts whose ulcers did not heal after three months of t reatment with famotid ine 40 mg nr ranitid ine 300 mg at bedt ime than in controls (l 71 ). In this situation , o meprazole may be the a nswer. H oweve r , t h e finding hy Deakin and W illiams ( 172) that some patien ts' ulcers d id not heal after six weeks of treatment with cime tid inc 400 mg tw ice a day produced overn ight achlorhydria, serves to reinforce the mul t ifactorial nature of duodenal ulcer etio logy. T hus, when 25 pat ients whose duodena l ulcers did not heal after four weeks of treatmen t with a standard dose of ci metidine were randomized to re­ceive collo idal bismuth suhcitratc one tablet qid or cimetidine 400 mg qid for four weeks, after which patients whose ulcers did not heal in either treatment were crossed over, the c umulative heal­ing rate was 85% for colloida l bismuth subcitrate a nd 40% fo r c im eci<line ( 171 ). S imilarly, afte r patients whose d uodena l ulcers had not healed after 10 weeks of treatment with c imetidinc or ran iti<line were random ized to receive misoprostol 200 µ g q id o r placebo for four weeks, 42% of those receiving misoprostol and 17% of t hose receiving placebo haJ their ulcers heal ( 174 ).

In 1990, very few patien ts have truly refractory Juodenal ulcers, so Lhe need for su rgery is minimal in uncomplicated duoJ ena l ulcer disease. With frequent recurrence, however, a maintenance program is required, and in this situa­tion a case can be made for highly selec-

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tive vagotomy to reduce the ac id load permanently and thus reduce the risk or recurrent dut)Jemd ulceration, par­ucularly if the patient is a young adult who might otherwise face years of drug therapy. A lso, the lesson co be learned is: if a patient docs not respond to one

ACKNOWLEDGEMENTS: The authors aregrnteful to Mr Peter King for hi> c<licnm1l assistance.

REFERENCES I. Lam S-K, Sircus W. SruJ1cs un

ducx.lenal ulcer. I. The clinical evi<lence for the ex u,tence of two populations. Q J Med l 975;44:369-87.

2. Rotter JI, Rimotn DL. Peptic ulcer disease - A hcterogcnous group of disorders? Gastrol.'nterokigy l 977; 73:604-7.

}. Hamson AR, Elashoff JD, Grossman Ml. Peplic ulcer Jiseasc. In: Smoking anJ Health: A Report of the Surgeon General. (DHEW Puhlicacion no. PHS 7950066.) Washington: Un ired Srntes Department of Health , Education, and Welfare, l 979:9.1-9.21.

4. Doll R, ]lll1es AF, Pygott F. Effect of smoking on the produl.tion ,rnd main,enancc of gastric anJ duodenal ulcers. Lancet 1958;i:657-62.

5. Shepherd AMM, Stewart WK, Wormsley KG. Pepric ulcerntinn in chronic renal foilure. Lancet I 973;i: 1357-9.

6. Benner JR. Smoking and the gastmimestinal tract. G ut 1972; 13:658-65.

7. Massarrat S, Eisenmann A. Factors affecting the hea ling rate of Jmxlenal and pyloric ulcers with low-Jose antacid treatment. Gut 198 l ;22:97- l 02.

8. Tenenbaum J. Non-steroidal anti-inflammatory drug, (NSAll>..) cause gastrointestmal 111tolcrance and major hleeding-or Jo they? Clin Invest Med 1987;10:246-50.

9. Misiewicz JJ . Histamine Hz-receptl>r antagonist in short and long-term treatment of ducxlenal ulcer. In: Holtermuller KH, Malagelada JR, nb. Advances tn Ulcer Disease. Am,terdam: Excerpra Medica, I 980.

JO. Lam SK, Lai CL, Lee NW, et al. Effective healing of duodenal ulcer with single night time dose nf oxmetidine -A double-hi ind controlled study. Gasrmenterulogy 1983;84: l 221. (Abst)

I I. Walsh JH, Lam SK. Physioloi.,,y and pathology of gamm. C l111

class of antiulcerdrug, increase Lhe dose (in t h e ahsence of s id e effects) or prescrihe a drug with a different mechanism of action.

In conclus ion, there arc many effica­cious drugs for the treatment of peptic ulcer disease. The cho ice nf the drug(s)

Gnstroenreml I 980;9:567-9 I. 12. Samloff IM, Taggart RT. Pcpsinogcn,,

pepsins, and peptic ulcer. Clm Invest Med 1987; I 0:215-21.

I 3. Pearson J, Allen A, Venables C. Gastric mucus: Isolation and polymeric strnclllre of the undegraded glycoprml'in: Its hreakdown by pepsm. Gastroenteroloi.,,y I 980;78:709-15.

14. McQueen S, Hutton D, Allen A, Gamer A. Gastnc and du,x.icnal surface mucus gel thickness 111 rat: Effects of prostaglandins and damaging agents. Am J Phys,ol l 983;245:0388-91.

15. Heatley NG. Mucosuhstance as a barrier to diffusion. G;istmenterology 1959; 3 7: 3 I 3-7.

16. Pfeiffer CJ. Experimental ,malys1s of hydrogen ion diffusion in gastrointest inal mucus glycoprotem. Am J Phy,iol 1981;240:676-82.

17. Allen A. Structure and funcrnm of gastrointc~t inal mucus. In: John,on LR, Christensen J, Grossman Ml, Jacobson ED, Schultz SG, eds. Physiology of the Gastrointestina: Traer. New York: Raven Press, 1981 :617-.39.

l 8. Turn berg LA. Gastric mucus, bicarbonate and pH grndicnts in mucosa! protection. C lin lnvc,t Med 1987; I 0: 178-80.

19 Isenberg JI, 1 logan DL, ScllingJA, Koss MA. Duo<lenal h1carbonace secrellt>n m ntmnal subjects and duodenal ulcer pm1ents. Dig Db Sc, 1985; 30: 381. (Abst)

20. Q uigley EM M, Tumberg LA. Ncurrnl m,cm-climarc lines human gastroduoJenal mucosa 111 viv1,. Gu t 1985;26: I J 17. (Abst)

21. W illiams SE, T umberg LA. Demonstration of a pH gradient across mucus adherent to rabbit gastric mucusa: Ev idence fo r .i 'mucus-bicarbonate' harrier. Gut 1981 ;22:94-6.

22. Lichtenberger LM. Membranes and barriers: With a focus on the gastric mucosa! barrier. Clin Invest Med 1987;10:181-8.

2 3. K1v1laakso E, Silen W. Pathogenesis of cxpcrnncntal ga,tric mucosal mjury. N Engl J Med I 979;301:364-9.

24. Chcung LY, Ashley SW. Gastric bkx,d flow and muco,al defense mcch,m isms.

(AN J GASTROENTEROL VOL 5 No l JANUARY/FEBRUARY l 99 l

Pharmacotherapy of peptic ulcers

is based on individual preferences and other medical history of the patient, particularly smoking, concomitant medications, age and cost of the medicat ion, which can vary up to th ree to fo urfold for the treatment of duodenal ulcers.

Clin Invest Med. l 987; 10:201-8. 25. M,1lageh1da J-R, L:mich JR. Gastric

emptying m dutxlem1l ulcer. Scand J Gastrocnterol 1980;63: l 15-30.

26. Rorgsrri\m S, Arborelius M Jr. Duodenal motility pattern in duodenal ulcer disease. Scand J Gastroentcml 1978;!3: 349-52.

27. Monto GL, Ashworth WD, Malecki M, Thompson AB, Englert E. Duodenal contraction w,ive pattern, 111 patlcnts with and without ulcer. Am J Gastroenterol l 976;65:52-6.

28. Pih,tn G, Gallc1gher GT, Szabo S. Biliary and p::mcrearic secretions mfluence experimental du(xlcnal ulcer without affecting gastric secretion in the rat. Dig Dis Sci l 986;30:240-6.

29. l lazell SL, Lee A, Brady L, l lennessy W. Cam/)ylohacter pyloridi.~ :ind gastritis: Association with interccllular ,paces ,md adapt:-m on roan environment of mucus as important factors tn colon izat ion of the gastric epithelium. J Infect Dis 1986;153:658-63.

30. Bartlett JG. Campylobacter /rylari: Fact or fancy? Gastrocntcmlogy l 988;94:229-12. (Edit)

31. Slom, any BL, Bilski J, Muny VLN, ct al. Campylohacter pyloridis degrn<les muctn and undermines gastric mucmal integrity. Gastmentcrolo1.,ry 1987;92:1645. (Abst)

32. Coughlan JG, Gi lligan D, l lumphrics H, ct al. Cam/>ylobacter /)ylori and recurrence of duodenal ulcers - A 12-month fo llow-up ~t udy. Lancet l987;ii:l 109-I I.

l 3. Coughlan G, Gi lligan D, l lumphries H, ct al. Campylobacter pylondis and relapse of duodenal ulcers. Gastmcnterology 1987;92: 1355. (Abst)

34. Eberhardt R, Kasper G, Dettmer A, I-fochtcr W, Hagena D. Effect of oral b1smuthsubsal icylatc on Cam/)ylolmcier />ylorrdis and on duodenal ulcer. Gastroenterology 1987;92: 1379. (Ahst)

15. Sturdevant RAL, Walsh JH. Duodenal ulcer. In: Sle1senger Ml l, Fordtran JS, eds. Gastromtcsunal Obeasc: P,1thnphysiology, Diagnosis, Management, 2nd cdn. Philadelphi,1: WB Saunders Company, 1978:840-60.

16. S:-1lcna BJ , Hunt RI I. The lim1tanon, of current therapy in peptic ulcer disease. C lin In vest Med 1987;10:17 1-7.

29

Page 10: Phartnacotherapy of peptic ulcer diseasedownloads.hindawi.com/journals/cjgh/1991/683517.pdf · REVIEW Phartnacotherapy of peptic ulcer disease F MOLINA, MD, MM VOi iRA, Pl ID, CN

MOLINA et al

37. Thomp~on ABR, Mahachai V. Pharmacological management of patient~ with pepuc ulcer Jisease: Prospects for the late 1980\. Clin Invest Med 1987; I 0: 152-70.

.38. Lam S-K, Koo J. Accurate prediction of duodenal-ulcer he.1ling rate by discriminant analysis. Gastroenrerology ! 983;85:403- 12.

39. Piper OW, McIntosh JH , Anmti DE, Fenton BH, Maclennan R. Analgesic ingestion and chronic peptic ulcer. Gastrocnrerology 1981 ;80:427-32.

40. Soll AH, Grossman Ml. Cellular mechanisms in acid secretion . Annu Rev Med I 978;29:495-507.

41 . De Garn CJ, Jones DB, Hunt RH . A physiological basis for the rational therapy of peptic ulcer. Mod Concepts Gastrocnterol l986;l:l-32.

42. Saccomani G, Helander I IF, Crago S, Chang HH, Dailey OW, Sachs C. Characterization of gastric mucosa I membranes. X. Immunological studies of gastric (H+ K+) ATPase. J Cel l Biol 1979;83:27 l -83.

43. Sachs G, Chang 11, Rabon E, Shackm:rnn R, Sar::iu HM, Saccomani G. Metabolic and membrane aspects of gastric 1-l + transport. Gastroentcrology l 977;73:93 l-40.

44. Branski D, Sharon P, Karmcli F, Rachmilewicz D. Effect of cimetidinc on human gastric and duodenal prostanoid synthesis. Scaml J Gastrocnterol 1984; 19:45 7-60.

45. Wollin A. Regulation of gastric acid secretion at the cellular level. C lin Invest Med 1987; I 0:209-1 4.

46. Dcbas HT, Mulholland MW. New horizons in the pharmacologic management of peptic ulceration. A m J Surg 1986; 151:422-30.

47. Weir DG. Peptic ulceration. Br Med J 1988;296: 195-200.

48. Thompson ABR, Mahachai V. Medical management of uncomplicated peptic ulcer disease. In: Berk JE, ed. Bockus Gamocnterology, 4th edn. Philadelphia: WB Saunders, 1985: 111 6-54.

49. Navert 1-l, Archambault AP, C learor IGM, ct al. The efficacy of two therapeutic regimens of c imetitlinc in the treatment of duodenal ulcer disease - A Canadian multicentcr tria l. Annu Rev Coll Phys Surg Canada 1983; 16:332. (Abst)

50. Kildebo S, Aronscn 0, Bcmcrscn B, ct al. Cimetidinc, 800 mg at night, in the treatment of duodena I u leers. Scand J Gastmcntcrol 1985;20:] 147-50.

51. Korman MG , Shaw RG, Hansky J, Schmidt GT, Stem Al. Influence of smoking on hea ling rate of Juodcnal ulcer in response to cimetiJine or

30

high-dose antac id. Gastrocntero logy 1981 ;80: 1451 -3.

52. Gugler T, Rohner H-G, Kratochv il P, Brandstatter G, Schmitz H. Effect of smoking on duodenal ulcer healing with c11netidine and oxmctid ine. Gut l 982;23:866-71.

53. Bardhan KO. Long term manage1nent of duodenal ulcer. A physician's view. In: Baron JH, ed. C imctidine in the 80s. Edinburgh: C hurchill-Livingstone, 1981.

54. Walan A, Porro GB, Hentschel E. Maintenance cirnctidinc fo r up to three years. Lancet l 985;i: 11 5-6.

55. Sontag S, Graham DY, Bclsiro A, ct al. C imetidine, c igarette smoking, and recurrence of duodenal ulcer. N Engl J Med l 984; 311 :689-93.

56. Thomas JM , Misiewicz G. Histamine I Ii receptor antagonists in the shortand long-rerm treatment of duodenal ulcer. C lin Gastroenterol 1984; 13:50 l-4 l.

57. DclitalaG, Stubbs WA, Wa~JAH, Jones A, William S, Besser GM. Effects of the 112 receptor ,mtagon ist cimctid inc on pitui tary hormones in man. C lin Endocrinol l 979; 11: 161-7.

58. Jensen RT, Collen MJ, Pando! SJ , et al. C imetidine-induccd impotence and breast changes in patients with gastric hypcrsccrcrory states. N Engl J Med 1983; 308:883-7.

59. McMillen MA, Ambis D, Sicgcl JH. C1metidine and mental confusion. N Engl J Med l 978;298:284-5.

60. McGuigan J E. A consideration of the adverse effects of cimecitlinc. Gasrroenterology 198 1 ;80: 181-92.

61. Smith JR, C leverley MT, Gancllin CR, Metters KM. Binding of 13 H] cimctidinc to rat brain tissue. Agents Act ions 1980; I 0:422-6.

62. Lakoski JM, Aghl1janian GK, Gallager OW. Interaction of histamine H2 receptor antagonists with GABA and bcnzodiazcpine binding sites in the CNS. Eur J Pharmacol l 983;88:241 -5.

63. Peden NR, Saunders JHB, Wom1sley KG. Inhibi tion of pcnragastrin-stimularcd and nocturnal gastrin secretion by ranitidine: A new H2 receptor antagonist . Lancer 1979;i:690-2.

64. Rcndic S, Alebic-Kolbah T, Kajfez F, Ruf H -H. Interaction of ranitidinc with liver m1crosomes. Xcnobiorica 1982;12:9-l 7.

65. Pearce P, Funder JW. Histamine H 2 receptor antagonist: Radioreceptor assay for antiandrogenic side effects. C lin Exp Phanm1col Physiol 1980;7:442. (Abst)

66. Nelis GF, van de Mcenc JGC. Comparative effect of cimetidine and ranitidine on prolactin secretion. Postgrad Med J 1980;56:4 78-80.

67. Colin-Jones DG. Med ica l treatment of peptic ulcer. In: Misiewicz JJ , Pounder RE, Venables CW, eds. Diseases of the G ut and Pancreas. Oxford: Blackwell Scientific Publications, l 987:288-315.

68. Peden NR, Boyd EJS, Saunders JI IB, Wormslcy KG. Rnnmdine 111 the treatment of duodenal ulcernrion. Scand J Gastrocnrcrol 1981; 16:325-9.

69. MacKay C, Mohammed R, Lee Fl, Fielding JD, I lolmes GKT, Hine K. The effect of ranitidine, a new h1stammc 112 receptor antagonist on che healing rate of duodenal ulceration. Gastroenrenllogy 198 l ;80: 1219. (Alm)

70. Dobrilh1 G, Granata F, Fclelcr M, Piazzi L, Castelli G. A smgle nocwrnal JlJSe of ranitidirie for the shon -tcrm treatment of Juodenal ulcer: lntcnm results of an Italian multicentre stud)'· In: Misiewicz JJ, Wmxl JR, eds. Ranitidine: Thernpcuric Advances. Amsterdam: Excerprn Metlirn, 1984: 154-67.

71. Boyd EJS, Wibon JA, Wormslcy KG. Safety of ranitidinc mamtcnance rreatmenr of duodenal ulcer. Scanc!J Gascroenrerol 1984; 19: 394-400.

72. Korman MG, H ansky J, Merren AC, Schmid t GT. Ranitidine in duodenal ulcer: Healing rate anti effect of smoking. Gastrocntcrology 198 l ;80: 1197. (Alm)

73. Boyd EJ, Wilson JA, Wormslcy KG. Review of ulcer treatment: Role of ranitidinc. J C lin Gasrrocntcrol I 983;5(Suppl I) : 13 3-4 J.

74. Gough KR, Konnan MG , Bardhan KD, ct al. Ranitidinc and c imetidmc in

prevention of duodenal ulcer relapse: A double-blind, ra ndomised, mulciccntre, comparative trial. Lancet I 984;ii:659-62.

75. Silvis SE. Final report on the United States multicentcr trial comparing ran itidine to cimeridinc as maintenance therapy following healing of duodem1l ulcer. J C lin Gastrocmercil 1985;7:482-7.

76. Gledhill T, Howard OM, Buck M, Paul A, Hunt RH. Single nocturnal dose of an H2 receptor anragonisr for the treatment of duodenal ulcer. Gur I 983;24:904-8.

77. Archambault AP, Pare P, Bailey RJ, ct al. Omeprazole (20 mg daily) vcrsu, cimetitlinc ( 1200 mg daily) in duodenal ulcer healing and pain relief. Gastroentcrology 1988;94: 11 30-4.

78. Muller P, Dammann HG, Schmitlc-Gayk H , LichtwalJ K, Stmg~r C, Simon B. Famotidinc (MK-208): Duration of action, 24-hour inrragastric tic idity, antipyrinc kincncs and basal honnonc levels in man. Gastroenterology 1984;86: 1190. (Ab~t)

79. Smi th JL, Camal MA, Chrcmos AN,

CAN J GASTROENTEROL VOL 5 No I JANUARY/FEBRUARY 1991

Page 11: Phartnacotherapy of peptic ulcer diseasedownloads.hindawi.com/journals/cjgh/1991/683517.pdf · REVIEW Phartnacotherapy of peptic ulcer disease F MOLINA, MD, MM VOi iRA, Pl ID, CN

Graham DY. FammiJme, ,1 new I lz receptor antagonist: Effect on parietal, nonpariernl, anJ pepsm ,;ccrction in man. Dig Dis Sci 1985;30: 308-12.

80. Ryan R. C linica l pharmacology of famotidinc: Summary of J arn from the United States. Ital J Gastroenterol 1984; 16: 171-4.

SI. Ohc K, Miyoshi A, Yach1 A, ct al. Famotidinc clinical pharmacology: Japanese studies. I rnl J Gast roentcrol 1984;16:1250.

82. Staiger C, Korodnay B, Devries J. Comparative effect~ of famotidme anJ cimctidinc on antipyrinc kinetics in healthy volunteer~. Br J C lin Pharmacol 1984;18:105-6.

83. Barbara L, Corinaldcsi R, Bianchi Porro G, et al. Famotidmc in the management of duodenal ulcer: Experience in Italy. Digestion l985;32(Suppl I ):24-31.

S4. Simon B, Dammann HG. Jakob G, ct al. Famotidine versus rnnitidinc for che short-term treatment of dunJenal ulcer. Digestion 1985;32(Suppl I ):32-7.

85. Bianchi Porro G. F,1mmiJmc in the treatment of gastric anJ duodern1I ulceration: Overview of clinical experience. Digestion 1985; 32 (Suppl I ):62-9.

86. Morron DM. Phannacology and toxicology of nizaridmc. ScanJ J Gastrocnterol l 98 7; I 36: 1-8.

87. Calla~han JT, Bergstrom RF, Ruhm A, et al. A pharmacokinccic profile of nizaudmc in man. Scand J Gastrocnccrol 1987; I 36:9-1 7.

88. Klotz U. L ick of effect of ni:atidine on drug metabolism. Scand J Gastroentcrol 1987; 136: 18-23.

89. Van Thie l DH, Gavab JS, Heyl A. Suscn B. An evaluation of the antiandrogcn effects associated with Hz antagonist therapy. Scand J Gastrocnterol 1987; 136:24-8.

90. Kovacs TOG, Van Dcvcnter GM. Maxwell V, Symik B, Walsh J H. The effect of an oral evening Jose of nizatidinc on nocturnal rmd pcpwncstimulated gastric acid and gastrin secretion. Sc;md J Gastrocncerol 1987; 136:41-6.

91. Dyck WP, C loud ML, Offen WW, Matsumoco C, C hern1sh SM. Treatment of Juodcnal ulceration m the United States. Scand J Gastroentcrol 1987;136:47-55.

92. Simon B, Cremer M, Damm,mn HG, ct al. 300 mg nizaciJinc at night versus JOO mg ranitidine at night in patients with c.luodenal ulcer: A mult1ccntrc trial in Europe. Scand J Gasrrocnccml 1987;136:61-70.

93. Cerulli MA, Cloud ML. Offen WW, Chem1sh SM, Matsumoto C. Nizatidine as maintenance therapy of duodenal ulcer disease m rem1ss1on.

ScanJJ Gascrocnrerol l987;136:79-83. 94. I lcntschcl E, Schiitzc K, Reichel W,

ct al. Nizatidinc versus rnnicidine in the prevention of duodena I ulcer relapse: Six-month interim results of a European multiccntrc stu<ly. Scand J Gastroencerol I 987;136:84-8.

95. Carmine AA, Brogden RN. Pircnzepinc: A review of its pharmacodynamic nnJ pharmacokmctic properties and therapeutic efficacy in peptic ulcer J1scase and mher all1eJ d1sc::ises. Drugs l 985;30:85-126.

96. Hirschowitz Bl, Fong J, Molina E. Effects of pirenzepinc and atropme ,m vagal and cholinergic gastric secretion and gastrin release and on heart race m the Jog. J Pharmacol Exp Ther I 983;225:263-8.

97. Bianchi Porro C, Prada A, Parente F, Sangaletti 0, Lazzaroni M. The effect of pirenzcpinc on meal-stimularcJ gastric acid secretion, gastric relem,c and gastric emptying. Scaml J Gastrocntcrol 1982; 72: 159-62.

98. Dammann I IG, Simon B, Mtillcr P, Kruger HJ. Hcmmung der nachtlichcn N(ichtcrnsckrction <lurch P1renzepm. Armeimittclforschung 1982; 32:309-10.

99. Jaur BH. Stu<lies on the mode of action of pircnzcpine in man with special reference co its ancicholincrg1c muscarinic properties. Scand J Gastrocnccrol 1981 ;68: l-26.

100. Texter EC Jr, Reilly PA. The efficacy and selectivity of pircnzcpinc: Review and commentary. Scand J Gasrroenccrol 1982; 72:2 3 7-46.

IOI . Giorg1-Conciaro M, Daniotti S, Ferrari PA, er al. Efficacy and safety of p1rcnzepmc in peptic ulcer and 111 non ulcerous gnstroduodenal disern,cs: A muluccnrre controllcJ clinical trial. Scand J Gastroenterol 1982;8 l : l-42.

102. Visconti GP, Spotti D, Grasso GA, Pnpelli G. Manni U. Long-term trial of pircn:erinc, cimetidinc and placcb,, in the management of duodcm1l ulccr. Curr Ther Res l 983;34:853-6.

103. Dal Monce PR, Bianchi Porro G, Petrillo M, Giuliani-Piccari G, D'lmpcrio N, Daniom S. Long-term treatment of duodenal ulcer with p1renzcpme: A double-blind, placebo-controlled trial. Scand J Gamocmcrol l 982;72:225-8.

104. Walan A. Antacids and anticholinergics in the trcai mcnt of duodenal ulcer. Clin Gastroenterol i 984;13:473-99.

105. Barhara L, Bclsasso E, Bianchi Porro G, ct al. Pirenzcpinc m duodenal ulcer: A mulriccntre double-blinJ ClmtrolleJ clinical trial: Second of rwo pares. Scand J Gastrocnterol 1979; 5 7: l 7-9.

106. Fcllenius E, Bcrglindh T, Sachs C, cc al. Suhsmured henzim1dazoles

CAN J GASTROENTEROL VOL 5 No I JANUARY/FEBRUARY 199 l

Pharmacotherapy of peptic ulcers

inhibit gastnc acid secretion by hlocking (11• + K+)ATPasc. Naturl' 1981 ;290: 159-61.

107. Londong W, Londong V, Cederberg C, Steffen 11. Dosc-rcspon,c study of omcprazolc nn mcal-stimularcd gastric acid secretion and gastrin release. G:mrocntcro logy 1983;85: 13 73-8.

108. Borg KO, Olbe L. Omcprnzole: Survey of preclinical data. Scand J Gastroenterol 1985; I 08: 1-1 20.

109. Prichard PJ, Yeomans ND, Mihr1ly GW, er al. Omcprnzolc: A study nf its inhibition of gastric pH and oral pharmacokineucs after mornmg or even mg dosage. Gastrocncemlogy L 985;88:64-9.

110. Prichard PJ, Ruhinstcin D, Jones DB, ct al. Double hlind comparative study of omcprazole 10 mg and 30 mg daily for healing duodcnc1l ulccrs. Br Med J l 985;290:601-3.

111. Sharma BK, Santan..i lA, Wood EC, er al. lnrragasmc bacterial activity and nicrosation before, c.luring, anJ ,ifte r treatment with omcpramlc. Br Med J 1984;289:717-9.

112. Festcn 11PM, Thijs JC, Lamers CBHW, ct al. Effect of oral omcprnmlc un serum gastrin and scrum pcpsinogcn I levels. Gastrocntcrology 1984;87: IO 30-4.

113. Bianchi A, Rotenberg A, Soule JC, ct al. T raitcmcnt de l'ulcerc duodenal en poussfr par l'omcprazole: Resulcats J'une etude non conrrolee multiccntriquc. Gastrocntcrol C lin Biol l 984;8:943-6.

114. Lauritsen K, Rune SJ, Bytzer P, ct ,11. Effect of omcprazolc and cimcti<linc on duodenal ulcer: A double-hi ind comparative trial. N Engl J Med I 985;312:958-61.

11 5. Malagclada J-R, Carlson GL. Antacids and I IC I. Scand J Gascrocnterol 1982;75:10-2.

11 6. Lam SK, Lam KC, Lai CL, Yeung CK, Y nm L YC, Wong WS. T reatmcnt <>f duodenal ulcer with antac1J anc.l sulpi ridc: A double-hlinJ controlled study. Gastrocnccrology l 979;76:315-22.

117. Kumar N. ViJ JC, Karol A, AnanJ BS. Cnncrollcc.l therapeutic trial rn detcrmmc the optimum dose of antacids in duodenal ulcer. Gut 1984;25:1199-202.

118. Bardhan KD. Arc antacids as effective as cirnetidinc in preventing duodenal ulcer relapse? A multicenter study. Gastroentcrology 1986;90: 13 36. (Ab~t)

119. Barnett CC. Richardson CT. In vivo and in vitro cvaluauon of magnes1um-alum111um hydroxide antacid tablets and liquid. Dig Dis Sci 1985;30: 1049-52.

120. lppoliti AF. Antacid therapy for duodenal anc.l gastric ulcer; The

3 l

Page 12: Phartnacotherapy of peptic ulcer diseasedownloads.hindawi.com/journals/cjgh/1991/683517.pdf · REVIEW Phartnacotherapy of peptic ulcer disease F MOLINA, MD, MM VOi iRA, Pl ID, CN

MOLINA eta/

experience in the United Scates. Scam! J Gasrrocnterol I 982;75:82-5.

121. Herzog P, HoltcrmLillcr K-1-1. Antacid therapy - Changes in mineral metabolism. Scnnd J Gastroentcrol I 982;75:56-62.

122. Walan A. Metabolic sidc-effem and interactions. Scand J Gasrrocntcrol 1982;75:6 3-8.

123. Barreras RF. Acid secretion after calcium carbonate in patients with duodenal ulcer. N Engl J Med 1970;282: 1402-5.

124. Fordtran JS. Acid rebound. N Engl J Med I 968;279;900-5.

125. Brogden RN, Heel RC, Speight TM, Avery GS. Sucralfote: A review of its pharmacodynamic properties and therapeutic u;,e in peptic ulcer c..liseasc. Drugs 1984;27: 194-209.

126. Naga~hima R, Yoshida N. Sucralfate, ;1

basic aluminum salt of sucrose , ul fatc. I. Behaviors in gastroduodenal pl-I. Arzneimittelforschung 1979;29:1668-76.

127. Nagashima R. Mech,misms of acnon of sucralfate. J Clin Gastroenterol 198l;3(Suppl 2): 17- 127.

128. Konturek SJ, Kwiecien N, Obrulowicz W, Kopp B, Olesky J. Double blinc..l controlled swc..ly on the effect of sucralfate on ga~1 ric prosraglandin formation and microbleeding in normal and aspirin treated man. Gur 1986;27: 1450-6.

129. Tytgat u'NJ, Hameeteman W, V,111 O lffen O H. Sucralfatc, bismuth compounds, substituted benzimidazoles, trimipraminc and pirenzepine in the short and long-term treatment of duodenal ulcer. Clin Gastroenterol 1984;1 3:543-68.

130. Sherman RA, Hwang ER, Walker JA, Elsinger RP. Reduction in scrum phosphoms due m sucralfate. Am J Gastrocntcrol 1983;78:210-1.

131. Fixa B, Komarkova 0. Aluminum sucrose sulphate (sucralfatc) in the treatment of peptic ulcer (double blind study). In: Caspary WF, ed. Sucralfate: A New Therapeutic Concept. Baltimore: Urban anc..l Schwarzenberg, 198 1:80-4.

132. Hentschel E, Schlitze K, Dufek W. Controlled comparison of sucrnlfate and cimetidine in duodenal ulcer. ScandJ Gastroenterol 1983;83:3 1-5.

133. Marks IN , Wright JP, Lucke W, G irdwood JH. Relapse rntcs after initial ulcer healing with sucrnlfatc and cimetidine. Scand J Gastrocntcrol 1982; 17:429-32.

134. Mosha[ MG, Spitacls J-M, Mnnion CL. Double-blind placebo-controlled evaluation of one year therapy with sucralfo te in healed duodenal ulcer. Scand J Gascrocnterol 1983;83:57-60.

135. C lassen M, Bethge H, Brunner G,

32

et al. Effect of sucralfate on peptic ulcer recurrence: A controlleJ double-blind multicenter study. Scand J Gascroentcml l 983;81:61-8.

136. Brogden RN, Pinder RM, Sawyer PR, Speight TM, Avery GS. T ri -potassium di-citrato bismuthate; a repon on its pharmacological properties anc..l therapeutic efficacy in peptic ulcer. Drugs 1976; 12:401-11.

137. Baron JH, Barr J, Batten J, SiJebotham R, Spencer J. Acid, pepsin and mucus secretion in patients with gastric and duodenal ulcer before and after colloidal bismuth subcitratc (De-Nol). Gut l 986;2 7 :486-90.

118. Bekker J, Pinatsis A. Information about De-Nol chewing tablets. J Drug Res 1982;7: 1541-5.

139. Lee SP. A potential mechanism of action of colloidal bismuth subcitratc: Diffusion barrier to hydrochloric acic..l. Scand J Gastroencerol 1982;80: 17 -2 1.

140. Wilson TR. The phannacology of tri-potassium di-citraro bismuthate (TDB). Postgrad Med J J 975;5 I (Suppl 5):18-21.

141. Lee Fl, Samloff IM, Hardmarn M. Comparison of tri-porassium di-citraco bismuthatc tablets with ranitidinc in healing and relapse of duodenal ulcer. Lancet 198S;i:1299-302.

142. Martin DF, Hollanders D, May SJ, Ravenscroft MM, Tweedle DEF, Miller JP. Difference in relapse rates of dutxlenal ulcer after healing with cimetidine or tripotassium dicitrnto bismuthatc. Lancet 1981;i:7- l0.

143. Vantrnppen C, Schuunnans P, Rutgeerts P,JanssensJ. A comparative study of colloidal bismuth subcitrate and cimetic..line on the healing :m<l recurrence of duodenal ulcer. Scand J Gastrocntcrol l 982;80:23-30.

144. Cohen MM. Role of endogenous prostaglandins in gastric secretion and mucosa] defense. C lin Invest Med 1987;10:226-31.

145. Tsai BS, Kessler LK, Schoenhard 0, ct al. E-typc prostaglandin binding sites in isolated canine parietal cells: Elucic..lation with ( 11-1) misoprostol free acid. Z Gastroentcrol l 987;25:201-6.

146. Chen MCY, Amirian DA, Toomey M, S,mdcrs MJ. Soll AH. Prosranoid inhihirion of canine parietal cells: Mediation by the inhibitory guanosinc triphosphate-binding protein of adcnylate cyclase. Gasrroencerology 1988;94:11 21-9.

147. Garner A, HeylingsJR. Stimulation of alkaline secretion in amphibian-isolated gastric mucosa by 16, 16-dimcthyl PGE2, anJ PGF2a: A proposed explanation for some of the cywprotecrivc actions of prostagland ins. Gastroenterology l 979;76:497-503.

148. Kauffman GL, Grossman Ml. Gastric alkal inc secretion: Effect of topical and intravenous 16-16 dime1 hyl prostaglandin Ei. Gastrocnccwlogy 1979;76: 1165. (Abst)

149. HclanJcr I IF, Johansson C, Blom 11, Uribe A.Trophic actions of E2 pmstaglimdins in the rat gastmintestinal mucosa: A quantitative morphologic study. Gastrocncerology 1985;89: 1393-9.

150. Bolton JP, Palmer D, Cohen MM. St11nulation of mucus and nonparicrnl cell secretion by the E2 prostaglandin,. Am J Dig Dis J 978;23: 359-64.

IS I. Leung FW, Robert A, Guth PI I. G;iscric rnucos;il blood flow in rats after ac..lministration of 16, J 6-dimethyl prostaglnndin Ez at a cy1oprotcctive dose. Gastroentemlogy 1985;88: 1948-53.

152. Ahlquist DA, Dozois RR, Zinsmeister AR, Malagelada J -R. Duodenal prostagland in synthe~is and acid load in health and in duodenal ulcer disease. Gastroentcrology I 983;85:522-8.

153. HowJen CW, Burget DW, van Ecdcn A, Hunt RH. Enisoprost : Marked inhibition ofhistamine-stimulateJ <1c1J and pepsin secretion in man. Gasuoenterology 1986;90: 1466. (Abst)

154. Bauer RF. Misoprostol: Preclinical phnrmncology. Dig Dis Sci 1985;30: l 18S-25S.

155. McGuit,ian JE, Chang Y, Dajani EZ. Effect of misoproscol, an ,1ntiulccr prostaglandin, on scrum gasrrin in patients with du(xlcnal ulcer. Dig Dis Sci 1986;3 I : 120S-5S.

156. Steiner JA. Misoprostol clinical pharmacology: Establ ishmcnr of activity in mnn. D1g D,~ Sci 1985;30: I 36S-4 1 S.

l 57. Hawkey CJ, Walt RP. Prostaglandim for peptic ulcer: A promise unfulfilled. L111cet 1986;ii:1084-7.

158. Schoenhard C, Oppcrmann J, Kohn FE. Metabolism and pharmacokinctic studies of misoprostol. Dig Dis Sci 1985; 30: 126S-8S.

159. Brand DL, Roufail WM, Thompson ABR, Tapper EJ. Mboprostol, a synthetic PGE1, analog, in the tremrncnt of dmxlenal ulcers: A multicentcr c..louble-blind study. Dig DbSci 1985;30: 147S-58S.

160. Sontng SJ, Mazurc PA, Pontes JF, Beker SC, Dajani EZ. Mboprostol in the treatment of c..luodenal ulcer: A multiccntcr double-bl ind placebo-controlled study. Dig Dis Sc, 1985;30: I 59S-63S.

161. Bright-Asare P, Sontag SJ, Gould RJ, ct a l. Efficacy of misoprostol (twice daily dosage) in acute healing of duodenal ulcer: A multiccnter double-hlind controlled trial. Dig Dis

CAN J 0ASTROENTEROL VOL 5 NO I JANUARY/FEBRUARY 1991

Page 13: Phartnacotherapy of peptic ulcer diseasedownloads.hindawi.com/journals/cjgh/1991/683517.pdf · REVIEW Phartnacotherapy of peptic ulcer disease F MOLINA, MD, MM VOi iRA, Pl ID, CN

Sci 1986; 31:63S-7S. 162. Nicholson PA. A muluccntcr

mtemariona I conrrollcd companson of two dosage regime, of ml'oprostol anJ c1metidine in the trefltment of duodenal ulcer 111 ouc-pauenr,. Dig D1, Sc1 1985; 30: 171 S-7S.

161. Lam SK, Lau WY, Choi TT, ct al. Prostagl.111d111 Et (misopn>stol) overcome, the .,dverse effect nf chrome cigarette smokmg on Jundenal ulcer healing. Dig Dis Sci 1986;3 I :68S-74S.

164. Bimlhan KD, Bose K, l linchliffe RFC, ct al. Enprostil (E) ver<,tts ran1t1dinc (R) Ill duodenal ulcer (DU). Gut 1985;26:1149. (Ahsr)

165. Nicholson P. Swahh E, Clay G, Souched. J. Duodenal ulcer rcl.tpsc followmg acute heal mg hy misoprrn,col or Hz antagonist: A global amily,1., of 49 trials. In: Symposium on Cl1111c.1l Dcvclopmcnt1, nn MtM)prostol: Peptic

Ulcer D1sca,c anJ NSAI[) lnJuccJ Gastropmhy. Chicago: GD Searle and Co, 1987.

166. Van devcnter GM, Schneidman D, Walsh JI 1. Sucralfote and c1mctidine as ,111gle agents and 111 combination for treatment of ;"tCttvc Juo<len,11 ulcers: A Joublc-blind, placebo-cont rolled trial. AmJ Med 1985;79(Suppl 2C):39-44.

167. flardhan Kl), Thomp,on M, flose K, ct al. Combmcd anrt-muscminic anJ 112 receptor hlockade 111 the healing of refr.1ctory duodenal ulcer: A double blind study. Out 1987;28: 1505-9.

168. Bardhan KD. Refracrory drn xlcna I ulcer. Gut 1984;25:711-7.

169. Gledhill T, Fluck M. Hum RI I. Eff~ct of no treatment, c1meuJinc I g/day, umcndme 2 g/day and c11nettdmc comhincd with atropmc on nocturnal g,Mric ,cul'lilln 111 cimctidme non-responders. Gut 1984;2 5: 1211-6.

170. flardh.in KD. Kapur B, Hinchliffe

CAN J GA~TROENTEROL VOL 5 N() I jANUAR Y/FEnRl,AR Y 199 1

Pharmacotherapy of peptic ulcers

RFC. Cimcudmc or vagmomy? fir J Surg 1984;7 I :402-3. (Leu)

171. Savanno V, Mela GS, Scalahrm1 P, Celk G. J lz receptor ,tntagom,1 nonrespomlers. Lann't 1987;11: 1281. (Leu)

172. Deakm M, W11liam,JO. Hz-receptors anrngonbt non-responders. L1m:et I 988;i: 127-8.

171. Lam SK, Lee NW, Ko,iJ, Hui WM, Fok Kl 1, Ng M. Randomised crossover mal of tnpotas,ium d1C1trnro bismuthate versus high do5e c11nct1Jinc for duodenal ulcers res1'tant to

standard dose of c1meud111c. Gur 1984;25:703-6.

174. Gi tl in N. Tlw role of misoprrn.tol in the management of pcpuc ulcl·r d1~e.i,e. Sympo'1um ofCltn1l.,tl Dcvdopmems on Mboprmtnl: Peptic Ulcer Disc,1se and NSAlll lndun·J Gascropachy. Chicago: GD Searle and Co, 1987.

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