REVIEW

Phartnacotherapy of peptic ulcer disease

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

HE ETIOLCXW OF PEI"TIC ULCER DIS­ F MOLINA, MM VOHRA, CN WILLIAMS. Pharmacotherapy of peptic ulcer ease is multifoctorial (1,2), and disease. Can Gastroenterol 1991 ;5( 1):21-33. The etiology of peptic ulcer is T J factors such as environment, ethnicity, 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 pre-existing c.liscasc cone.Ii ti on (3 ), ciga­ rare increases with time for active medication and placebo, and is lower among rette consumption (4-7) and nonster­ smokers than nonsmokers for all drugs but misoprostol. Mucosa[ protectives (or oidal anti-inflammatory drugs (3 ,8) 'cytoprotectives') as a group seem to have a lower relapse rate than the Hz have heen implicated. T he patho­ receptor antagonists at one year. Combination therapy has not yet proved to be physiological mechanisms suggest an better than single drug therapy; however, the number ofs tudies is still small, and imbalance between aggressive factors more clinical trials are necessary. Resistant ulcers have demonstrated that acid (acid, pepsin anc.l Helicobacter />ylori) is one of several etiological factors and that more research is needed to elucidate and defensive factors ( mucus, bicarbo­ the reason(s) for refractoriness. The choice of therapeutic agent is generally made nate, bloodflow, epithelial cell regen­ according to patient compliance, medication cost, side effects, effectiveness, eration, gastric emptying and pyloric relapse rate and physician experience with the drug. Long term maintenance function). therapy is effective in the prevention of ulcer relapse and is especially recom­ T he importance of acid in the de­ mended for selected patient groups, including patients with recurrent or bleeding ulcer, patients with concomitant nonsteroidal anti-inflammatory drug use, and velopment of peptic ulcers is supported elderly women. Omeprazole is the treatment of choice for moderate to severe by the fact that 80% will heal after four esophagitis and should be reserved for large and resistant ulcers. to six weeks of treatment with an acid­ rec.lucing agent (9). However, maximal Key Words: Drug therapy , Duodenal ulcer , Peptic ulcer acid output in patients with duodenal ulcer overlaps that in normals (3), and Pharmacotherapie de l'ulcere gastro,duodenal basal acid output is not generally in­ RESUME: Les causes de l'ulcere gastro-duodenal sont multifactorielles; a ['ex­ creasec.l (3). In contrast, meal-stimu­ ception de l'omeprazole, tousles medicaments utilises clans le traitement de cette lated acid and nocturnal acid secretion affection provoquent la guerison sans aucune difference statistique a quatre are increased in peptic ulcer patients semaines. Le taux de guerison augmente avec le temps sous traitement actif et (3,10). The pivotal roleofacid in peptic traitement placebo, et ii est plus bas pour les fumeurs que pour les non-fumeurs ulcers is fu rther indicated by the fact dans le cas de tous les medicaments saufle misoprostol. Le groupe des cytoprotec­ that these ulcers heal when nocturnal teurs semble donner un taux de recidive inferieur a celui des anti-H2 a un an. Le acid secretion is inhibited (I 0). Duodenal ulcer patients release Department~ of Medicine and Pharmacology, Division of Ga.moenterology, Dalhousie more gastrin in response to food th::m University, Halifax, Nova Scotia Correspondence and re/)rint1 : OT CN Williams, Professor and Head , Di11L11on of people without ulcers, with less feed ­ Gastroenterology, Dalhousie Univmity. Halifax, Nova Scotia B3H 4H7. Telephone (902) back inhibition by luminal acid , and 494-2333 greater parietal cell sensitivity to the Recei11ed for publication July 17, 1990. Acce/ned August 20, 1990 secretory effect of gastrin ( l l ).

CAN] 0ASTROENTEROL VOL 5 No 1 JANUARY/FEBRUARY 1991 21 M OLINA et al

39 patients whose duodenal ulcers traitement par une association medicamenteuse n'a pas encore prouve sa su­ healed, 59% relapsed at one year. The periorite 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 relapse rate was 27% among panenrs demontrc que la secretion acidc est l'un des nombreux facteurs etiologiques et who were H pylori culture-negative hut qu'il faut poursuivre la recherche pour decouvrir les raisons de la resistance au 79% among patients who were H /))•Ion traitement. Le choix de ['agent therapcutique est generalement determine en culture-positive (32 ). In another group fonction de ['adhesion du patient, du coCit du medicament, des effets secondaires, of patients in whom H pylori was crndi­ de l'efficacite, du taux de recidive et de ['experience du medecin avec le medi­ cared, 66% had a relapse of duodenal cament prescrit. La therapie de maintien a long terme est efficace clans la ulcer with H pylori recurrence, whi le prevention des rccidives ulcereuses ct elle est surtout recommandce pour les only I 0% with no recurrence ofH pylon groupes de patients selectionnes - les malades porteurs d'ulceres recidivants ou had duodenal ulcer relapse (32). hemorragiques, ceux qui suivent un traitement concomirant d'anti-inflamma­ Antimicrobial agents and bismuth roires non stero"idiens, et Jes femmes a.gees. L'omeprazole est le traitement de compounds reduce H J>ylori infection, choix Jans Jes OCSophagites modcrees a sevcres Ct i[ devrait Ctre reserve aux which is accompanied by heali ng rares ulceres de grandes dimensions et rebelles. comparable to those obtained with acid suppression, with the added advantage that they may also reduce the relapse Without acid, pepsi n (to which plays an important role in the defence rate of duodenal ulcer (33,34). Thus,a glycoproteins in gastric mucus, collagen system. combinatio n of tinidazole (an anti­ and elastin in the gastric and d uodenal Gast ric empty ing increases in microbi al similar to met ronidazole) mucosa are susceptible) is unable to patients with duodenal ulcer, and the with colloidal bismuth subcitrnte damage the mucosa, but in combina­ normal response of decreased emptying healed a greater proportion of patient; tion with acid it produces more severe with acidification of the duodenum is with duodenal ulcer and eradicated H damage than acid alone ( 12, 13). impaired (25). In a

22 CAN J 0ASTROENTEROL VOL 5 No l JANUARY/FEBRUARY 1991 Phormocotheropy of peptic ulcers

cussed: histamine H2 receptor :mrn­ gonists (cimetidine and related drugs), ACETYLCHOLJNE H z HI STA MINE GASTRI N anticholinergic drugs (pirenzepine), PIRENolNE oj sLo Rs PROGLUQDE v proton pump inhibitors (omeprnzole), 0 ~j antacids, sucralfate, bismuth com­ pounds and proscaglandins (misopros­ tol, enprostil). These agents can he \ eaom\ \ classified according to their sites of ac­ GLANOINS uon: the parietal cell ; the gastric and duodenal lumen; the gastric and duodenal mucosn. ,nGTPG, INOSITOL DRUGS THAT ACT ON THE CALr L_,.·~~rETE TRIS-PHOSPHATE PARIETAL CELL PARIETAL CELL Physiological mechanisms of acid pro­ duction: Gastric parietal cells produce j acid in response to three main stimuli: CALMODULIN CYCLIC AMP CALCIUM gastrin from G cells in the antral area; acetylcholine from the vagal endings; t::~ l l and histamine from mast-like cells in PHOSPHOPROTEIN KINASE PHOSPHOPROTEIN the fundus area ( 40). Each of these sub­ stances acts on its own receptor site on the parietal cell: muscarinic MI recep­ ~ .. ~:;p / tors for acetylcholine, histamine Hz receptors for histamine, an

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

anJ impotence (58). lt may abo cause cally significant diffe rences (73 ). How­ months of therapy. Consripation wa, confusion anJ disorientation in elderly ever, ranitid ine l 50 mg at nigh t was present in l % of patients in Lhe famo­ patients and in chose with hepatic anJ superior lo cimetidine 400 mg al night. tidine group (85). T he overall inci­ renal J ysfunction ( 59 ). C ho lesrasis, In long term treatment fo r prevenu on dence o f side effect observed in hepatitis and pancreatitis have also of duodenal ulcer relapse, 23% of pa­ patients taking famotidine is similar tu been reporteJ (56). tients receiv ing ran itidine and 37°,{l re­ that observed in pat1 ents taking ran, Most clinically significant adverse ceiving cimetiJ ine relapsed (74). In iudine; however, morl' clinical expen effects occur because cimetidinc's ac­ another study the relapse race was 15% cnce 1s need ed to d etermine tion is noc specific to gastric Hz recep­ fo r ran itid ine and 44% fo r c imetidine famo r iJinc's overall place 111 the tors (60). Thus, cimeti<.line crosses the (75) . Ranitidine 300 mg at night sup­ therapy of peptic ulcer Jisense. hlood-hrain harrier and b mJs to some pressed nocturnal acid sec retion by NizatiJinc, ltke ra111 udine, contain5 hrain rcccpw rs (6 1,62). These side ef­ 85% and 150 mg bid hy 54% (76), a fu ran ring ,md 1s a potent, specific anJ fects occur in a very small percen tage of whereas c1mctid ine 600 mg hid sup­ orally wel l tolerateJ h istamine Hz pat ients unJe r treatmen t anJ a rc pressed nocturnal acid sec retion by receptor antagon ist. It reduces ga,rnc reversed when drug administra tion is 85% (77). acid secretion fo r up to 8 h anJ is a, stoppeJ . FamotiJinc 1s a t h1azolc Jen vauve, potent as ranitiJme and three to four Ranitidinc is a secon d genera tio n different from che imidazole ringofc1m­ times mo re potent chan cimetidinc histamine I lz receptor an tagon ist. It etidine anJ the furan ring of ranitid ine. (86). N izaudine 1s excreted via the kid has highly effecti ve, specific compeu ­ O n a molccubr hasis, It is about 20 ncy, so renal impairment decreases ib tive hmding to Hz receptors m the pari ­ times more porent than c imet1dine nnJ el imination. etal cell ; mole fo r mole, it is fo ur to fi ve 7.5 rimes more potent Lhan ranitidine. Basa l, noctu rnal, an J fooJ anJ times mo re po tent th an c 1mecidine !rs acLi on can last fo r 7 h or more (78). ch em ica ll y stimulateJ gastric acid (63 ). Although ranitidine has the same Nocturnal ac1J secretion is decreased secretion is in hihned in a dose-J epcnJ, pharmacological actions as cimetidinc, by 80% with LO to 20 mg at bedtime. ent manner (87). Unlike cirnetiJ inc, side effects are much less a prohlem m Basal aciJ and pepstn output arc also niza t iJin c d ocs n ot inhib it tht patients taking ranitidine ( 46,56). Ran­ suppressed (78-8 l ). Famotid inc lacks mterosomal hepatic cytoch rome sy,, icidine also interacts with the hepatic the anr1androgenic activity and Jrug tem, and thus docs not inhibi t metabo cytochrome P450 system, bur because 1c 1nteract1ons associated with cimen d ine lism of agents affected hy this system, docs so with an affinity about 10 rimes (8 1,82 ). lts high potency makes it suit­ such as theoph ylline and d iazepam lower than t, at of cimctidme, the mter­ able for treatmg Zollmger-Ellison syn ­ (88). Lt has no antiandrogenic effect accion is of no clinical significance drome. anJ causes less prolacrm release than (64). Unlike c1met1dme, 1t does not FamonJine 20 or 40 mg bid or 40 mg cimctid ine (89). Nocturnal acid secre­ have antiandrogenic effects (65), docs at night produced healing rates at two, tion i:. Jecreased up co 90% with a

24 CAN J GA!>TROENTEROI VOi 5 No I j ANUARY/Fl:BRUARY 199 1 Pharmacolherapy of peptic ulcers

Currently, the histamine Hz recep­ relapse of duodenal ulcer has been reported ( 4 7). O meprazo le is highly tor antagonists are the cornerstone of shown to be superior to placebo and protein bound (95%); its plasma half­ prescription peptic ulcer therapy. Effec­ comparable to cimetidinc ( 102). In a life is about 1 h; and its pharmaco­ tive in healing and preventing relapse study comparing pirenzepine with kineric profile is not alrereJ in chronic of duodenal ulce r, this family of drugs placebo, pirenzepine 100 mg/clay for renal fa ilure or by hemodialys is. has revolutionized the treatment of one year had a duodenal ulcer relapse O meprazole 20 to 40 mg once a day peptic ulcer disease by decreasing the rate of 58%, versus 96% with placebo; inhibits gastric acid secretion for up to likelihood of complications and surgi­ this d ifference was statistically sig­ fi ve Jays, after which time it reaches a cal interventions. Compliance with H2 nificant ( I 03 ). Pirenzepine produces plateau (4 7 ). A J ose of 40 mg decreases receptor antagonists is easy: most are side effects at a therapeutic Jose of l 00 acid production by 99%; after the drug available as a once daily Jose leading to mg ( including dry mouth, constipation has been discontinued fo r one week, complete ulcer healing in four to six and urinary delay) in 7% of patients aci

CAN J GASTROENTEROL VOL 5 No I JANUARY/FEBRUARY 1991 25 MOLINA eta/

omeprazole al l wo weeks, but not at four (neutralizi ng capaciLy 162 mmol) tia lly to partially denatured or Jegraded weeks (77). Recurrence after discon­ prevented ulcer relapse about as effec­ proteins (positively charged) in Lhe tinuation of treatment is Lhe same as lively as cimetidine 400 mg at bedtime ulcer base, forming a protective bamer with Hz receptor antagonists (l 14). and better than placebo or Maalox TC against back diffusion of hydrogen ions It is likely that o meprazole will be al bedtime (1 18). AnLacids in liquid ( 127). Since the optimal pl I for bin

26 CAN JGASTROENTEROL VOL 5 Nol JANUARY/FEBRUARY 1991 Pharmacotherapy of peptic ulcers

has a marked ability co fix chloride ions, acid. They me rresent in the gastro­ drug is nm supcnor tn placcbo when a with the form;it ion of insoluble bismuth intestinal tract, especially the sromach, low annsecretory duse ( less than l 00 µg oxychloride, which prevents the J i(­ anse ol misopros­ Hea ling rates at four weeks of 50 to cretion by inhibiting adenylate cyclase tol was statistically supenor m the lower 89% (versus 8 co 42% for placebo) have via the 111h1hitnry CTP binding protein dllse oi misoprosttll and placeho ( l 59). been reported; al I studies showed stat 1:,­ Gt, which subsequently decreases eye! ic Another study reported rhat, after four ucal superiority in favour of bismuth AMP production ( 146). weeks, the ulcers of 64. 9lX, of patients compounds (36,129). Against rnn11i­ Proscaglandins have a t rophic act itlt1 taking misopmstol 100 µ g q1d and Jine, no statistical

CAN J GASTROENTEROL Vt1l 5 Nl) I jANUARY/FrnRuARY 1991 27 M OLINA et a/

younger than 40 years and had longer CIMETIDINE I I histories, frequent episodes of bleeding, - RANITIDINE : I --- 1 a fa mily history of peptic ulcer, previous MMOTIDINE I treatment with cimetidine, ulcer~ of - NIZATIDINE I ..____. I medium or large size, and moderate or - PIRENZEPINE 1- 1 severe duoden it is com pared w1th - OMEPRAZOLE I patients who responded tn cimcti

28 CAN J GASTROENTEROL Vot 5 No I jANUARY/FEARUARY 1991 Pharmacotherapy of peptic ulcers

tive vagotomy to reduce the acid load class of antiulcerdrug, increase Lhe dose is based on individual preferences and permanently and thus reduce the risk or (in t h e ahsence of sid e effects) or other medical history of the patient, recurrent dut)Jemd ulceration, par­ prescrihe a drug with a different particularly smoking, concomitant ucularly if the patient is a young adult mechanism of action. medications, age and cost of the who might otherwise face years of drug In conclusion, there arc many effica­ medication, which can vary up to th ree therapy. A lso, the lesson co be learned cious drugs for the treatment of peptic to fo urfold for the treatment of is: if a patient docs not respond to one ulcer disease. The choice nf the drug(s) duodenal ulcers.

Gnstroenreml I 980;9:567-9 I. Clin Invest Med. l 987; 10:201-8. ACKNOWLEDGEMENTS: The authors 12. Samloff IM, Taggart RT. Pcpsinogcn,, 25. M,1lageh1da J-R, L:mich JR. Gastric aregrnteful to Mr Peter King for hi> cHutton D, Allen A, M, Thompson AB, Englert E. populations. Q J Med l 975;44:369-87. Gamer A. Gastnc and du,x.icnal Duodenal contraction w,ive pattern, 111 2. Rotter JI, Rimotn DL. Peptic ulcer surface mucus gel thickness 111 rat: patlcnts with and without ulcer. Am J disease - A hcterogcnous group of Effects of prostaglandins and damaging Gastroenterol l 976;65:52-6. disorders? Gastrol.'nterokigy agents. Am J Phys,ol 28. Pih,tn G, Gall c1gher GT, Szabo S. l 977; 73:604-7. l 983;245:0388-91. Biliary and p::mcrearic secretions }. Hamson AR, Elashoff JD, Grossman 15. Heatley NG. Mucosuhstance as a mfluence experimental du(xlcnal ulcer Ml. Peplic ulcer Jiseasc. In : Smoking barrier to diffusion. G;istmenterology without affecting gastric secretion in anJ Health: A Report of the Surgeon 1959; 37: 3 I 3- 7. the rat. Dig Dis Sci l 986;30:240-6. General. (DHEW Puhlicacion no. PHS 16. Pfeiffer CJ. Experimental ,malys1s of 29. l lazell SL, Lee A, Brady L, l lennessy 7950066.) Washington: Un ired Srntes hydrogen ion diffusion in W. Cam/)ylohacter pyloridi.~:i nd gastritis: Department of Health, Education, and gastrointestinal mucus glycoprotem. Association with interccllular ,paces Welfare, l 979:9.1-9.21. AmJ Phy,iol 1981;240:676-82. ,md adapt:-m on roan environment of 4. Doll R, ]lll1es AF, Pygott F. Effect of 17. Allen A. Structure and funcrnm of mucus as important factors tn smoking on the produl.tion ,rnd gastrointc~t inal mucus. In: John,on colonization of the gastric epithelium. main,enancc of gastric anJ duodenal LR, Christensen J, Grossman Ml, J Infect Dis 1986;153:658-63. ulcers. Lancet 1958;i:657-62. Jacobson ED, Schultz SG, eds. 30. Bartlett JG. Campylobacter /rylari: Fact 5. Shepherd AMM, Stewart WK, Physiology of the Gastrointestina: or fancy? Gastrocntcmlogy Wormsley KG. Pepric ulcerntinn in Traer. New York: Raven Press, l 988;94:229-12. (Edit) chronic renal foilure. Lancet 1981 :617-.39. 31. Slom, any BL, Bilski J, Muny VLN, I 973;i: 1357-9. l 8. Turnberg LA. Gastric mucus, ct al. Campylohacter pyloridis degrnylobacter /)ylori and and pyloric ulcers with low-Jose secrellt>n m ntmnal subjects and recurrence of duodenal ulcers - A antacid treatment. Gut duodenal ulcer pm1ents. Dig Db Sc, 12-month fo llow-up ~t ud y. Lancet 198 l ;22:97- l 02. 1985; 30: 381. (Abst) l987;ii:l 109-I I. 8. Tenenbaum J. Non-steroidal 20. Q uigley EM M, Tumberg LA. Ncurrnl l 3. Coughlan G, Gilligan D, l lumphries anti-inflammatory drug, (NSAll>..) m,cm-climarc lines human H, ct al. Campylobacter pylondis and cause gastrointestmal 111tolcrance and gastroduoJenal mucosa 111 viv1,. Gut relapse of duodenal ulcers. major hleeding-or Jo they? Clin 1985;26: I J 17. (Abst) Gastmcnterology 1987;92: 1355. (Abst) Invest Med 1987;10:246-50. 21. W illiams SE, T umberg LA. 34. Eberhardt R, Kasper G, Dettmer A, 9. Misiewicz JJ . Histamine Hz-receptl>r Demonstration of a pH gradient across I-fochtcr W, Hagena D. Effect of oral antagonist in short and long-term mucus adherent to rabbit gastric b1smuthsubsalicylatc on Cam/)ylolmcier treatment of ducxlenal ulcer. In: mucusa: Ev idence fo r .i />ylorrdis and on duodenal ulcer. Holtermuller KH, Malagelada JR, nb. 'mucus-bicarbonate' Gastroenterology 1987;92: 1379. (Ahst) Advances tn Ulcer Disease. harrier. Gut 1981 ;22:94-6. 15. Sturdevant RAL, Walsh JH. Duodenal Am,terdam: Excerpra Medica, I 980. 22. Lichtenberger LM . Membra nes and ulcer. In: Sle1senger Ml l, Fordtran JS, JO. Lam SK, Lai CL, Lee NW, et al. barriers: With a focus on the gastric eds. Gastromtcsunal Obeasc: Effective healing of duodenal ulcer mucosa! barrier. Clin Invest Med P,1thnphysiology, Diagnosis, with single night time dose nf 1987;10:181-8. Management, 2nd cdn. Philadelphi,1: oxmetidine -A double-hi ind 2 3. K1v1laakso E, Silen W. Pathogenesis of WB Saunders Company, 1978:840-60. controlled study. Gasrmenterulogy cxpcrnncntal ga,tric mucosal mjury. 16. S:-1lcna BJ , Hunt RI I. The lim1tanon, 1983;84: l 221. (Abst) N Engl J Med I 979;301:364-9. of current therapy in peptic ulcer I I. Walsh JH, Lam SK. Physioloi.,,y and 24. Chcung LY, Ashley SW. Gastric bkx,d disease. C lin In vest Med pathology of gamm. C l111 flow and muco,al defense mcch,m isms. 1987;10:17 1-7.

(AN J GASTROENTEROL VOL 5 No l JANUARY/FEBRUARY l 99 l 29 MOLINA et al

37. Thomp~on ABR, Mahachai V. high-dose antacid. Gastrocnterology 67. Colin-Jones DG. Medical treatment of Pharmacological management of 1981 ;80: 1451 -3. peptic ulcer. In: Misiewicz JJ , Pounder patient~ with pepuc ulcer Jisease: 52. Gugler T, Rohner H-G, Kratochvil P, RE, Venables CW, eds. Diseases of the Prospects for the late 1980\. Clin Brandstatter G, Schmitz H. Effect of G ut and Pancreas. Oxford: Blackwell Invest Med 1987; I 0: 15 2-70. smoking on duodenal ulcer healing Scientific Publications, l 987:288-31 5. .38. Lam S-K, Koo J. Accurate prediction with c11netidine and oxmctidine. Gut 68. Peden NR, Boyd EJS, Saunders JI IB, of duodenal-ulcer he.1ling rate by l 982;23:866-71. Wormslcy KG. Rnnmdine 111 the discriminant analysis. 53. Bardhan KO. Long term manage1nent treatment of duodenal ulcernrion. Gastroenrerology ! 983;85:403-12. of duodenal ulcer. A physician's view. Scand J Gastrocnrcrol 1981; 16:325-9. 39. Piper OW, McIntosh JH, Anmti DE, In: Baron JH, ed. C imctidine in the 69. MacKay C, Mohammed R, Lee Fl, Fenton BH, Maclennan R. Analgesic 80s. Edinburgh: C hurchill-Livingstone, Fielding JD, I lolmes GKT, Hine K. ingestion and chronic peptic ulcer. 1981. The effect of ranitidine, a new Gastrocnrerology 1981 ;80:427-32. 54. Walan A, Porro GB, Hentschel E. h1stammc 112 receptor antagonist on 40. Soll AH, Grossman Ml. Cellular Maintenance cirnctidinc fo r up to che healing rate of duodenal mechanisms in acid secretion . Annu three years. Lancet l 985;i: 11 5-6. ulceration. Gastroenrenllogy Rev Med I 978;29:495-507. 55. Sontag S, Graham DY, Bclsiro A, ct al. 198 l ;80: 1219. (Alm) 41 . De Garn CJ, Jones DB, Hunt RH. A C imetidine, cigarette smoking, and 70. Dobrilh1 G, Granata F, Fclelcr M, physiological basis for the rational recurrence of duodenal ulcer. N Engl J Piazzi L, Castelli G. A smgle nocwrnal therapy of peptic ulcer. Mod Concepts Med l 984; 311 :689-93. JlJSe of ranitidirie for the shon -tcrm Gastrocnterol l986;l:l-32. 56. Thomas JM , Misiewicz G. Histamine treatment of Juodenal ulcer: lntcnm 42. Saccomani G, Helander I IF, Crago S, I Ii receptor antagonists in the results of an Italian multicentre stud)'· Chang HH, Dailey OW, Sachs C. shortand long-rerm treatment of In: Misiewicz JJ, Wmxl JR, eds. Characterization of gastric mucosa I duodenal ulcer. C lin Gastroenterol Ranitidine: Thernpcuric Advances. membranes. X. Immunological studies 1984; 13:50 l-4 l. Amsterdam: Excerp rn Metlirn, of gastric (H+ K+) ATPase. J Cell Biol 57. DclitalaG, Stubbs WA, Wa~JAH, 1984: 154-67. 1979;83:27 l -83. Jones A, William S, Besser GM. Effects 71. Boyd EJS, Wibon JA, Wormslcy KG. 43. Sachs G, Chang 11 , Rabon E, of the 112 receptor ,mtagon ist Safety of ranitidinc mamtcnance Shackm:rnn R, Sar::iu HM, Saccomani cimctidinc on pituitary hormones in rreatmenr of duodenal ulcer. Scanc!J G. man. C lin Endocrinol l 979; 11: 161-7. Gascroenrerol 1984; 19: 394-400. Metabolic and membrane aspects of 58. Jensen RT, Collen MJ, Pando! SJ, 72. Korman MG, H ansky J, Merren AC, gastric 1-l + transport. Gastroentcrology et al. C imetidine-induccd impotence Schmidt GT. Ranitidine in duodenal l 977;73:93 l-40. and breast changes in patients with ulcer: Healing rate anti effect of 44. Branski D, Sharon P, Karmcli F, gastric hypcrsccrcrory states. N Engl J smoking. Gastrocntcrology Rachmilewicz D. Effect of cimetidinc Med 1983; 308:883-7. 198 l ;80: 1197. (Alm) on human gastric and duodenal 59. McMillen MA, Ambis D, Sicgcl JH. 73. Boyd EJ, Wilson JA, Wormslcy KG. prostanoid synthesis. Scaml J C1metidine and mental confusion. Review of ulcer treatment: Role of Gastrocnterol 1984; 19:45 7-60. N Engl J Med l 978;298:284-5. ranitidinc. J C lin Gasrrocntcrol 45. Wollin A. Regulation of gastric acid 60. McGuigan JE. A consideration of the I 983;5(Suppl I): 13 3-4 J. secretion at the cellular level. C lin adverse effects of cimecitlinc. 74. Gough KR, Konnan MG , Bardhan Invest Med 1987; I 0:209-1 4. Gasrroenterology 198 1;80: 181-92. KD, ct al. Ranitidinc and cimetidmc in 46. Dcbas HT, Mulholland MW. New 61. Smith JR, C leverley MT, Gancllin prevention of duodenal ulcer relapse: 3 horizons in the pharmacologic CR, Metters KM. Binding of 1 H] A double-blind, ra ndomised, management of peptic ulceration. A m cimctidinc to rat brain tissue. Agents mulciccntre, comparative trial. Lancet J Surg 1986; 151:422-30. Actions 1980; I 0:422-6. I 984;ii:659-62. 47. Weir DG. Peptic ulceration. Br Med J 62. Lakoski JM, Aghl1janian GK, Gallager 75. Silvis SE. Final report on the United 1988;296: 195-200. OW. Interaction of histamine H2 States multicentcr trial comparing 48. Thompson ABR, Mahachai V. receptor antagonists with GABA and ran itidine to cimeridinc as Medical management of bcnzodiazcpine binding sites in the maintenance therapy following healing uncomplicated peptic ulcer disease. In: CNS. Eur J Pharmacol l 983;88:241 -5. of duodem1l ulcer. J C lin Gastrocmercil Berk JE, ed. Bockus Gamocnterology, 63. Peden NR, SaundersJHB, Wom1sley 1985;7:482-7. 4th edn. Philadelphia: WB Saunders, KG. Inhibition of 76. Gledhill T, Howard OM, Buck M, 1985: 111 6-54. pcnragastrin-stimularcd and nocturnal Paul A, Hunt RH. Single nocturnal 49. Navert 1-l, Archambault AP, C learor gastrin secretion by ranitidine: A new dose of an H2 receptor anragonisr for IGM, ct al. The efficacy of two H2 receptor antagonist. Lancer the treatment of duodenal ulcer. Gur therapeutic regimens of cimetitlinc in 1979;i:690-2. I 983;24:904-8. the treatment of duodenal ulcer disease 64. Rcndic S, Alebic-Kolbah T, Kajfez F, 77. Archambault AP, Pare P, Bailey RJ, - A Canadian multicentcr tria l. Annu Ruf H -H. Interaction of ranitidinc ct al. Omeprazole (20 mg daily) vcrsu, Rev Coll Phys Surg Canada with liver m1crosomes. Xcnobiorica cimetitlinc ( 1200 mg daily) in 1983; 16:332. (Abst) 1982;12:9-l 7. duodenal ulcer healing and pain relief. 50. Kildebo S, Aronscn 0, Bcmcrscn B, 65. Pearce P, Funder JW. Histamine H 2 Gastroentcrology 1988;94: 11 30-4. ct al. Cimetidinc, 800 mg at night, in receptor antagonist: Radioreceptor 78. Muller P, Dammann HG, the treatment of duodena I u leers. assay for antiandrogenic side effects. Schmitlc-Gayk H , LichtwalJ K, Stmg~r Scand J Gastmcntcrol C lin Exp Phanm1col Physiol C, Simon B. Famotidinc (MK-208): 1985;20:] 147-50. 1980;7:442. (Abst) Duration of action, 24-hour 51. Korman MG , Shaw RG, Hansky J, 66. Nelis GF, van de Mcenc JGC. inrragastric tic idity, antipyrinc kincncs Schmidt GT, Stem Al. Influence of Comparative effect of cimetidine and and basal honnonc levels in man. smoking on healing rate of Juodcnal ranitidine on prolactin secretion. Gastroenterology 1984;86: 1190. (Ab~t) ulcer in response to cimetiJine or Postgrad Med J 1980;56:478-80. 79. Smi th JL, Camal MA, Chrcmos AN,

30 CAN J GASTROENTEROL VOL 5 No I JANUARY/FEBRUARY 1991 Pharmacotherapy of peptic ulcers

Graham DY. FammiJme, ,1 new I lz ScanJJ Gascrocnrerol l987;136:79-83. inhibit gastnc acid secretion by receptor antagonist: Effect on parietal, 94. I lcntschcl E, Schiitzc K, Reichel W, hlocking (11• + K+)ATPasc. Naturl' nonpariernl, anJ pepsm ,;ccrction in ct al. Nizatidinc versus rnnicidine in 1981;290: 159-61. man. Dig Dis Sci 1985;30: 308-12. the prevention of duodena I ulcer 107. Londong W, Londong V, Cederberg 80. Ryan R. Clinical pharmacology of relapse: Six-month interim results of a C, Steffen 11. Dosc-rcspon,c study of famotidinc: Summary of J arn from the European multiccntrc stuf The effect of an oral evening Jose of in the management of duodcm1l ulccr. duodenal ulcer with antac1J anc.l nizatidinc on nocturnal rmd Curr Ther Res l 983;34:853-6. sulpiridc: A double-hlinJ controlled pcpwncstimulated gastric acid and 103. Dal Monce PR, Bianchi Porro G, study. Gastrocnccrology gastrin secretion. Sc;md J Petrillo M, Giuliani-Piccari G, l 979;76:315-22. Gastrocncerol 1987; 136:41-6. D'lmpcrio N, Daniom S. Long-term 117. Kumar N. ViJ JC, Karol A, AnanJ BS. 91. Dyck WP, Cloud ML, Offen WW, treatment of duodenal ulcer with Cnncrollcc.l therapeutic trial rn Matsumoco C, C hern1sh SM. p1renzcpme: A double-blind, detcrmmc the optimum dose of Treatment of Juodcnal ulceration m placebo-controlled trial. Scand J antacids in duodenal ulcer. Gut the United States. Scand J Gamocmcrol l 982;72:225-8. 1984;25:1199-202. Gastroentcrol 1987;136:47-55. 104. Walan A. Antacids and 118. Bardhan KD. Arc antacids as effective 92. Simon B, Cremer M, Damm,mn HG, anticholinergics in the trcai mcnt of as cirnetidinc in preventing duodenal ct al. 300 mg nizaciJinc at night versus duodenal ulcer. Clin Gastroenterol ulcer relapse? A multicenter study. JOO mg ranitidine at night in patients i 984;13:473-99. Gastroentcrology 1986;90: 13 36. (Ab~t) with c.luodenal ulcer: A mult1ccntrc 105. Barhara L, Bclsasso E, Bianchi Porro 119. Barnett CC. Richardson CT. In vivo trial in Europe. Scand J Gasrrocnccml G, ct al. Pirenzcpinc m duodenal ulcer: and in vitro cvaluauon of 1987;136:61-70. A mulriccntre double-blinJ ClmtrolleJ magnes1um-alum111um hydroxide 93. Cerulli MA, Cloud ML. Offen WW, clinical trial: Second of rwo pares. antacid tablets and liquid. Dig Dis Sci Chem1sh SM, Matsumoto C. Scand J Gastrocnterol 1979; 5 7: l 7-9. 1985;30: 1049-52. Nizatidine as maintenance therapy of 106. Fcllenius E, Bcrglindh T, Sachs C, 120. lppoliti AF. Antacid therapy for duodenal ulcer disease m rem1ss1on. cc al. Suhsmured henzim1dazoles duodenal anc.l gastric ulcer; The

CAN J GASTROENTEROL VOL 5 No I JANUARY/FEBRUARY 199 l 3 l MOLINA eta/

experience in the United Scates. Scam! et al. Effect of sucralfate on peptic 148. Kauffman GL, Grossman Ml. Gastric J Gasrrocnterol I 982;75:82-5. ulcer recurrence: A controlleJ alkal inc secretion: Effect of topical and 121. Herzog P, HoltcrmLillcr K-1-1. Antacid double-blind multicenter study. Scand intravenous 16-16 dime1 hyl therapy -Changes in mineral J Gascroentcml l 983;81:61-8. prostaglandin Ei. Gastrocnccwlogy metabolism. Scnnd J Gastroentcrol 136. Brogden RN, Pinder RM, Sawyer PR, 1979;76: 1165. (Abst) I 982;75:56-62. Speight TM, Avery GS. T ri -potassium 149. HclanJcr I IF, Johansson C, Blom 11, 122. Walan A. Metabolic sidc-effe m and di-citrato bismuthate; a repon on its Uribe A.Trophic actions of E2 interactions. Scand J Gasrrocntcrol pharmacological properties anc..l pmstaglimdins in the rat 1982;75:6 3-8. therapeutic efficacy in peptic ulcer. gastmintestinal mucosa: A 123. Barreras RF. Acid secretion after Drugs 1976; 12:401-11. quantitative morphologic study. calcium ca rbonate in patients with 137. Baron JH, Barr J, Batten J, SiJebotham Gastrocncerology 1985;89: 1393-9. duodenal ulcer. N Engl J Med R, Spencer J. Acid, pepsin and mucus 150. Bolton JP, Palmer D, Cohen MM. 1970;282: 1402-5. secretion in patients with gastric and St11nulation of mucus and nonparicrnl 124. Fordtran JS. Acid rebound. N Engl J duodenal ulcer before and after cell secretion by the E2 prostaglandin,. Med I 968;279;900-5. colloidal bismuth subcitratc (De-Nol). Am J Dig Dis J 978;23: 359-64. 125. Brogden RN, Hee l RC, Speight TM, Gut l 986;2 7: 486-90. IS I. Leung FW, Robert A, Guth PI I. Avery GS. Sucralfote: A review of its 118. Bekker J, Pinatsis A. Information G;iscric rnucos;il blood fl ow in rats after pharmacodynamic properties and about De-Nol chewing tablets. J Drug ac..lmi nistration of 16, J 6-dimethyl therapeutic u;,e in peptic ulcer c..liseasc. Res 1982;7: 1541 -5. prostaglnndin Ez at a cy1oprotcctive Drugs 1984;27: 194-209. 139. Lee SP. A potential mechanism of dose. Gastroentemlogy 126. Naga~hima R, Yoshida N. Sucralfate, ;1 action of colloidal bismuth subcitratc: 1985;88: 1948-53. basic aluminum salt of sucrose , ul fatc. Diffusion barrier to hydrochloric acic..l. 152. Ahlquist DA, Dozois RR, Zinsmeister I. Behaviors in gastroduodenal pl-I. Scand J Gastroencerol 1982;80: 17-2 1. AR, Malagelada J -R. Duodenal Arzneimittelforschung 140. Wilson TR. The phannacology of prostaglandin synthe~is and acid load 1979;29:1 668-76. tri-potassium di-citraro bismuthate in health and in duodenal ulcer 127. Nagashima R. Mech,misms of acnon of (TDB). Postgrad Med J J 975;5 I (Suppl disease. Gastroentcrology sucralfate. J Clin Gastroenterol 5):18-21. I 983;85:522-8. 198l;3(Suppl 2): 17- 127. 141. Lee Fl, Samloff IM, Hardmarn M. 153. HowJen CW, Burget DW, van Ecdcn 128. Konturek SJ, Kwiecien N, Obrulowicz Comparison of tri-porassium di-citraco A, Hunt RH. Enisoprost: Marked W, Kopp B, Olesky J. Double blinc..l bismuthatc tablets with ranitidinc in inhibition ofhistamine-stimulateJ <1c1J controlled swc..ly on the effect of healing and relapse of duodenal ulcer. and pepsin secretion in man. sucralfate on ga~1ri c prosraglandin Lancet 198S;i:1299-302. Gasuoenterology 1986;90: 1466. (Abst) formation and microbleeding in 142. Martin DF, Hollanders D, May SJ, 154. Bauer RF. Misoprostol: Preclinical normal and aspirin treated man. Gur Ravenscroft MM , Tweedle DEF, Miller phnrmncology. Dig Dis Sci 1986;27: 1450-6. JP. Difference in relapse rates of 1985;30: l 18S-25S. 129. Tytgat u'NJ, Hameeteman W, V,111 dutxlenal ulcer after healing with 155. McGuit,ian JE, Chang Y, Dajani EZ. O lffen O H. Sucralfatc, bismuth cimetidine or tripotassium dicitrnto Effect of misoproscol, an ,1 ntiulccr compounds, substituted bismuthatc. Lancet 1981;i:7- l0. prostaglandin, on scrum gasrrin in benzimidazoles, trimipraminc and 143. Vantrnppen C, Schuunnans P, patients with du(xlcnal ulcer. Dig Dis pirenzepine in the short and long-term Rutgeerts P,JanssensJ. A comparati ve Sci 1986;3 I: 120S-5S. treatment of duodenal ulcer. Clin study of colloidal bismuth subcitrate 156. Steiner JA. Misoprostol clinical Gastroenterol 1984;1 3:543-68. and cimetic..line on the healing :mWright JP, Lucke W, triphosphate-binding protein of 160. Sontng SJ, Mazurc PA, Pontes JF, G irdwood JH. Relapse rntcs after adcnylate cyclase. Gasrroencerology Beker SC, Dajani EZ. Mboprostol in initial ulcer healing with sucrn lfatc and 1988;94:11 21-9. the treatment of c..luodenal ulcer: A ci metidine. Scand J Gastrocntcrol 147. Garner A, HeylingsJR. Stimulation of multiccntcr double-bl ind 1982; 17:429-32. alkaline secretion in placebo-controlled study. Dig Dis Sc, 134. Mosha[ MG, Spitacls J-M, Mnnion amphibian-isolated gastric mucosa by 1985;30: I 59S-63S. CL. Double-blind placebo-controlled 16, 16-dimcthyl PGE2, anJ PGF2a: A 161. Bright-Asare P, Sontag SJ, Gould RJ, evaluation of one year therapy with proposed explanation for some of the ct al. Efficacy of misoprostol (twice sucralfo te in healed duodenal ulcer. cywprotecrivc actions of daily dosage) in acute healing of Scand J Gascrocnterol 1983;83:57-60. prostagland ins. Gastroenterology duodenal ulcer: A multiccnter 135. C lassen M, Bethge H, Brunner G, l 979;76:497-503. double-hlind controlled trial. Dig Dis

32 CAN J 0ASTROENTEROL VOL 5 NO I JANUARY/FEBRUARY 1991 Pharmacotherapy of peptic ulcers

Sci 1986; 31:63S-7S. Ulcer D1sca,c anJ NSAI[) lnJuccJ RFC. Cimcudmc or vagmomy? fir J 162. Nicholson PA. A muluccntcr Gastropmhy. Chicago: GD Searle and Surg 1984;7 I :402-3. (Leu) mtemariona I conrrollcd companson of Co, 1987. 171. Savanno V, Mela GS, Scalahrm1 P, two dosage regime, of ml'oprostol anJ 166. Van devcnter GM, Schneidman D, Celk G. J lz receptor ,tntagom,1 c1metidine in the trefltment of Walsh JI 1. Sucralfote and c1mctidine as nonrespomlers. Lann't 1987;11: 1281. duodenal ulcer 111 ouc-pauenr,. Dig D1, ,111gle agents and 111 combination for (Leu) Sc1 1985; 30: 171 S-7S. treatment of ;"tCttvc JuoLau WY, Choi TT, ct al. Joublc-blind, placebo-cont rolled trial. anrngonbt non-responders. L1m:et Prostagl.111d111 Et (misopn>stol) AmJ Med 1985;79(Suppl 2C):39-44. I 988;i: 127-8. overcome, the .,dverse effect nf 167. flardhan Kl), Thomp,on M, flose K, ct 171. Lam SK, Lee NW, Ko,iJ, Hui WM, chrome cigarette smokmg on Jundenal al. Combmcd anrt-muscminic anJ 112 Fok Kl 1, Ng M. Randomised crossover ulcer healing. Dig Dis Sci receptor hlockade 111 the healing of mal of tnpotas,ium d1C1trnro 1986;3 I :68S-74S. refr.1ctory duodenal ulcer: A double bismuthate versus high do5e c11nct1Jinc 164. Bimlhan KD, Bose K, l linchliffe RFC, blind study. Out 1987;28: 1505-9. for duodenal ulcers res1'tant to ct al. Enprostil (E) ver<,tts ran1t1dinc 168. Bardhan KD. Refracrory drn xlcna I standard dose of c1meud111c. Gur (R) Ill duodenal ulcer (DU). Gut ulcer. Gut 1984;25:711-7. 1984;25:703-6. 1985;26:1149. (Ahsr) 169. Gledhill T, Fluck M. Hum RI I. Eff~ct 174. Gitl in N. Tlw role of misoprrn.tol in 165. Nicholson P. Swahh E, Clay G, of no treatment, c1meuJinc I g/day, the management of pcpuc ulcl·r Souched. J. Duodenal ulcer rcl.tpsc umcndme 2 g/day and c11nettdmc d1~e.i,e. Sympo'1um ofCltn1l.,tl followmg acute heal mg hy misoprrn,col comhincd with atropmc on nocturnal Dcvdopmems on Mboprmtnl: Peptic or Hz antagonist: A global amily,1., of g,Mric ,cul'lilln 111 cimctidme Ulcer Disc,1se and NSAlll lndun·J 49 trials. In: Symposium on Cl1111c.1l non-responders. Gut 1984;2 5: 1211-6. Gascropachy. Chicago: GD Searle and Dcvclopmcnt1, nn MtM)prostol: Peptic 170. flardh.in KD. Kapur B, Hinchliffe Co, 1987.

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

The Scientific Gastroenterology Journal of Research and Practice Diabetes Research Disease Markers World Journal Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of International Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Submit your manuscripts at http://www.hindawi.com

BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of Obesity

Evidence-Based Journal of Stem Cells Complementary and Journal of Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Parkinson’s Disease

Computational and Mathematical Methods Behavioural AIDS Oxidative Medicine and in Medicine Neurology Research and Treatment Cellular Longevity Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014