REVIEW

Omeprazole: Inhibiting the final common pathway to acid secretion - The acid pump

A.B.R. T HOMSON. MD. Pl 10. FRCPC, FACP

ABSTRACT: Omepra:ole is the first agent in a new therapeutic ad\'ance class the proton or acid pump in hibitors which represents a significant therapeutic advance in the treatment of acid related disl',he, Omepra:olc reduces gastric acid secretion at its source - the acid pump of the parietal cell, thereby offering precise and consistent clinical effects. Omeprazole once daily has been shown to heal over 80°;, of duodenal ulcers within two weeks and over 950:, within four weeks In gastr'c ulcer, the healing rates are up to 80''o within four weeks ;rnd 96'\~ within eight weeks. More patients are free from symptoms earlier on omeprazole therapy than with rhe H2 receptor antagonises. Omeprazole is also effective in healing and symptom relief even where prolonged H2 receptor antagonist therapy has been unsuccessful. Omeprnzo le has been shown in clinical trials to be the first consis­tently effective treatment of erosive/ulcerative reflux esophagi tis. Complete heal ­ing is achieved in the maioricy of patients and symptom relief 1s rapid. In clinical trials with 20 mg once dai ly, over 70% of patients healed within four weeks and up to 85''o healed withm eight weeks. Also. patients with erosive/ulcerative reflux c~ophagitis resistant co three months or more of treatment with full therapeutic doses of H2 receptor antagonists have shown significant henefit, with healing rates of 49''., within four weeks and 73'n, within eight weeks of therapy with omcprazole. The rare Zoll inger-Ellison syndrome hns been difficult to treat in the past due to the massi"e hypersecretion of gastric acid Omcprazole ha!> proved highly effective in this syndrome, being well tolerated by patients who have received more than five years of continuous treatment with daily oral doses up to 160 mg. In ,ummary, in extensive clinical trials omeprazole has been shown co be highly effecnve in the treatment of duodenal and gastric ulcers, erosive/ulcerative reflux esophagitis and Zollinger-Ellison syndrome. Omepra:ole ,s well tolerated and is without any established side effects when used for short periods. It remains to be established whether Hz blockers still represent the best available therapy for acute treatment of pepnc disorders, and whether mamtenancc therapy 1s best achieved with Hz b lockers or with proton pump b locke rs. C a n J G astroente rol 1989;3(2) :61-71 < Pour resume. VOIT page 62)

Key Words: Acid pump, Duodenal ulcers. Gastric ulcers, Omeprazole

Dnrnon of Gmtroe11terulogy. U111wn11y uj Alber ILi, EJmonto11. Albcrw CorrcsponJcn.:e anJ rc/>nnt; Dr A BR Thom,on, On'ISlon uj Gusiroenterolu~y.

iJ9 Rubert Nctl'Wn Re.1cur.:h Bui/Jing. Ur11 veni1:v of Alberta. EJmunwn. Alberta T6G 2C2 Th11 p,1per I) to /,e prc,ented ttl ,he 1ympusium Ompcruzole ,rnJ pep11.: ulc.:er d1,ca.1c

m ToronlO. Onumu on May 12

c.~, J GASTRO~:-; r~ROL Vm 3 No Z Al'RIL I9tN

T HE KL Y TO Till PRl:C ISi:: CONTROL

of acid rela ted diseases lies in an understanding of the p roton pu mp o f the pam'tal cell ( I) G a!>tric acid 1s se­creted by the proton pu mp of the pari­l'tal cell located in thl' oxync,c glands of the gastric mucosa. A large concen tra­tion gradient of hydrogen ions 1s estab­lished across the secretory membrane in the pariecal cell and th is results in ;1 :,ub­sran w1l d ifference 111 p H between the cy tosol of the parietal ce ll ( pH 7 4) and th e lumen of the secretory canalicu la (approximately pH I ). T ht• parie tal ce ll has an extensive system of secretory can­aliculi and tubu lovesicles and is special-1:ed for acid s<.'cretion The w bulovesicles fu se with the membranes of the secre­to ry canaliculi to form an en larged secre­tor y surface when the parietal cell 1s stimulated

Hyd rogen ions arc secre ted across the su rface by the p ro ton pu m p and arc exchanged for potassiu m ions. T his p ump isan enzyme, H• ,K •-ATPase, that exchange:, hydrogen ions from the cyco­sol of the pn rietal cell with potassium ions from the secretory canalicu li. This e xch ange is p receded by the passive movement of hydrogen ions and ch lo­ride ions out of rhe cell cytoplasm into che secretory canaliculi upon stimulation of the parieta l cell. The net effect is thr1t hydrochloric acid b formed in the sccrc­tory canaliculi Thus, this enzyme, H•,K •­ATPase, the fina l common pathway for

61

THOMSON

L'omeprazole: Inhibiteur de la voie commune finale de la secretion acide - La pompe a acidc

RESUME: L'omcprazole est le premier agent d'un nouvelle classe de substances thcrapeutiques avancees - lcs inhibiteurs de la pompe .1 acide OU a proton - qui reprcscntent un progres important dans le trairement des affections assocics a l'ac1de gasrrique, L'omeprazole reduil la secretion d'acide gastrique a la source -la pompe a acide de la cellule pariccale gastrique a la s0urcc - la pompe a acide de la cellule pariecalc, procurant ainsi des cffets cliniques prccis ct consistants. Administrc unc fois par jour, l'omeprazole a fait ses preuves en guerissant 80% des ulcercs duodenaux en moins de dcux scmaincs ct plus de 95%, en moins de qua ere semaincs. Dans le cas des ulccres gastriques, lcs pourccntages de gucrison ~ont de 80'-Jo en moins de quatrc semaines ct de 96'\, en mains de huit scmaines. Traitcs a J'omcprazolc, un nombre p lus eleve de patients deviennent asymp­tomatiqucs plus rapidcmcnt qu'avec les antagonistcs du reccptcur H,. L'omcprazolc s'avere egalcment cfficacc clans la gucrison ct le soulagement d~s sympt6mcs, mcme a pres que le traitcment prolonge aux antagonistes du rcccpreur H, a cchoue. O'apres lcs etudes cl iniques, l'omepra:ole est k premier traitcmenr de l'~sophagite a reflux gastroesophagicn corrosif/ulcerat1f don e l'efficac1te est consistante. La guerison rornle e::,r obtcnue pour la majorite des patients er le soulagemenr des symptomes est rapidc. Au cours d'ctudcs cl iniqucs Oll 20 mg ont ete admmistrcs unc fois par jour, plus de 70°(, des sujcts ont etc gueris en q uacre scmaincs ou moins, e t le pourcentage attcint 85°0 en l'espace de huit semaincs. Les patients atteints d'esophagite a reflux corro~if/ulceratif. jusque-la resistants a un traitement de trois mois er plus aux antagonistes du receptcur Hi administres a pleine dose, ont cu aussi monrre des resu lLats significarifs avcc 49% de gucrisons en moins de q uatrc semaines et 73'';, en h uit ~emaines de traitemenr r'\. l'omeprazolc. Par le passe. l'hypersecretion d'acidc gastrique rendait le syndrome de Zollinger-Ellison difficile ii soigner. L'omeprazole a prouvc sa pleinc efficacite clans le traitcment de ce syndrome cc le medicament est bien rolerc par lcs patients ayant suivi un traitcme .t continu pendant plus de 5 ans avec une dose quotidienne orale atteignant 160 mg. En resume, au cours d'crudcs cliniqucs approfondics, l'omeprazole a demontre sa grande efficacitc clans le traitemenr d u syndrome de Zollinger-Ell ison. de l'esophagitc ii re flux corrosif/u lceratif, ct de l'ulcere gastrique ct duodenal. Utilise sur de courtes periods, l'omeprazole esc bien rolcrc er ne semble pas prod uirc d'effecs secondaires crnblis. II reste encore ii determine r si les an tagonisrcs d u recepteur HI rcprescn tent toujours la mcilleu re therapie pour le traitcment des affections pcptiqucs, ct si cc sonr cux ou les inh ibiteurs de la pompe a proton qui conviennen t le mieux a la thcrapie d 'entretien.

acid secretion, is known as the proton or acid pump. Evidence from monoclonal antibody studies suggests that this en­zyme is specific to the parietal cell (2).

The phases of acid production include cephalic, gastric, intestinal and interdi­gestivc stages. The cephalic phase is acti­vated by way of the vagal nerve; the gas­tric p h ase is stimulated by peptides. amino acids and gastrin; the intestinal phase is influenced by absorbed amino acids; and the in te rdigcstive phase b influenced by vagal nerves, mast cells and histamine. The parietal cell i;; stim­ulated to secrete acid by activation of receptors on irs basolatcral membrane (3). Following activation of the histamine, gascrin or accrylcholinc receptors, intra­cellular second messengers (such as cyclic

62

AMP and calcium) transmit the stimu­lus to the secretory membrane o f the parietal cell where acid secretion begins ( 4 ). Additional activators include factors such as epidermal growth factor, somato­statin and prostaglandins. The acerylcho­line receptor is calcium dependent but the gastrin reccpror appears to be cal­cium independent.

Gastrin released in response to food stimulates gastric acid secretion by the parietal cell. When the acid concentra­tion in the stomach is high and t h e in tragastric pH is low, gastrin secretion falls and further acid secretion is pre­vented. Thus, the gastrin mechanism is a naturally occurring feedback system which operates in response to variations in intragastric luminal pH.

WHAT IS OMEPRAZOLE? T he bindingofome prazolc to H+,K•­

ATPasc, the proton pump. is activated in the acidic environment of the enzyme in the parietal cell. Omcprazolc infl u­ences acid secretion at the final common pathway rathe r than at the surface recep­tor or at the intracellular cyclic AMP. pro­tein kinase or calcium level. Omcprazolc is a sulphoxidc compound containing two ring structure:,, pyridine and benz­imidazole (Figure l A). This lipoph1hc compound of molecular weight 345 .42 penetrates membranes rapidly, is a weak base (owing to the presence of the pyri­dine ring) and is activated in the acidic e nvironment of the parietal cell close tc, the target enzyme, the proton pump. The o ral formu lation is supplied in hard gel­atin capsules containing enteric coated granules. The capsule disso lves in the stomach, but the enteric coating ensures that omeprazolc is protected until it reaches the small intes tine where it 1s

absorbed. An intravenous formu lation is available, supplied as a vial and an ampoule.

Omeprazole shows H +,K+-ATPase inhibitory activi ty below pH 4. with omcpra:ole gaining protons; this 'pro· tonatcd ' omcprazole is transformed into rhc active inhibitor of the proton pump, a sulphenamidc (Figure l B) . The sul­phenamide reacts with a mercapto (SHJ group of the H• ,K•-ATPase, which 1~

accessible from the luminal side of the secretory canalicular membrane. A di­sulphide (-SS-) link is formed between the active inhibitor and the enzyme (51 and this inactivates rhc enzyme (6).

ANIMAL STUDIES The acute toxicity of o meprawle in

animals is low: rhe LO s,> (the lethal dme in 50":. of the animab tested ) for acute oral administration in mice and rats can­nor be obtained with precision , since the highest dosage that could be given prac­tically (4 g/kg) did not cause death 1t1

e ither species (7). The highest intrave­nous dose ( 50 mg/kg) that could be given in the rat was also nonlethal. In mice, the acute intravenous L050 was estimated to be 82.8 mg/kg, the dosage at the top o f th e range that could be physically given.

The gastrin response to acid inhib1-

CAN J GASTROE:S:TEROL V Oi 3 No Z APRIi. 1989

A Substituted pyridine

ring Substituted benzimidazole ring

Sulphoxide chain

I H

B Omeprazole (schema1,c chem,cal structure)

Omeprazole (s1erically ad1us1ed chem,cal slructure)

Att,ve 1nh1b1tor (sulphenam,de)

D Step t

(H')

D D

Step 2

OCH,

CH1t $:(H' II N :@JOCH'

N CH -S II 0 . -'I,,_ N

I H

OCH,

CH,:~N rfffi CH, CH ·S I

~ H 0

Enzyme · 1nh1b1lor complex

(En~ SH)

Figure 1) A Omc/>rn,olc conmrs of chrcc 11arr.1. all oj H h1ch are e.1.<cnual for 11, /,wlo)!icul acr1on. a iuhsr1111rec.l pyml111c rmR. a mbsrrr11rd /,e11t11niduzolc r111R and a ..:onnccr111R ~11/phox1Jc conwinm!( chain. B In rite acidic .1crrcror;1 rnnalirn/1 of chc pancwl cell clo.,c write /miron pum/J, omeprazolc gum, prorons and rh1.1 ·p,ownateJ' omcpra,ole 1.1 rnpidly rrnm/ormcJ 111ro u ,11lphc11,11111dc. rite acr1w mlt,/,,. ror of the proron /nrn1/1 The , 11/phc11,.rn11Jc rcucrs rap1JI:,, u·11h a mcrca/JCO r -SH I )!TOII/J of the H\K+-ATPasc, wluch 1s accc.rnble from chc l11m111u/ s1Jc of chc wcrccor-v canalu:11/ar membrane A cl,mlphide ( -SS- J lrnk i.1 formed beru•ccn rite acuw inhtb1tor ,md 1/tc enzyme und 1h11 cjfcc[lw/y marn mres r/l(' enzyme r ~61

tion is a n0rmal physiological event: when gastric ac,d secretion is inh ibited. the intragastric pH rises and there is a feedback increase in the release of gas­

trin from the antral G cel ls of the stom­ach. Thus. the greater the acid inhibi­tion, the greater the rise in gastrin. In

CAN J 01\STROE~Trnm Vol j N,) 1 ArRll 1989

l0ng term toll.icnlogy srudtl'S of omepra­zole in the rat ( 7,8 ). a dose dependent and reversible hypertrophy of chc gas­tric mucosa was reported, including gas­

me enterochromaffin-l ike (ECL) cell hyperplasia secondary to prnfound and long standing acid inhibition. It 1s of nme

Omeprazole and inhib ition of the proton pump

that in short and long term clinical use of omcprazolc, no changes in mucosa! histology have been rcpmted.

In a cwo yea r toxicity study in the rat , gasrric ECL cel l hyperpla:-.ia anJ rnrci­noids were found (7) ECL cclb arc the dominant endocrine cell rypc in the rm gastric mucosa and gastric ECL cell rnr­cin0 ids were found in some animal:, (8),

developing towards the end 0f the ani­mal's natural life span. The carlie~t occur­rence of a carcinoid was after 19 months of con tinuous and profound acid inhi­bition for almost the entire natural life­time of the animal. This £CL cell hyper­plasia/carcinoids was found t0 be due m hypergastrincmia, the natural feed­back response to profound acid inhibi­

tion . The proliferation was not a direct effect of omcprazole. Such proliferation is also seen following the administration of the gastrin analogue penmgastrin and also experimentally following surgical exclusion of the antrum (9). High dose ranitidine abo cnuscs hypergastrinemia and has been shown to increase gastric £CL cell density in female rats ( 10).

What is the relevance of rhcse studies to man ? Gastric carcinoids arc rare in man ( 11 .12) and arc relatively benign and slow growing ( 13, 14 ). Gastric ECL cell carcino ids have been associated with atrophy 0f the gastric body with or with-0u t pern1c1ous anemia ( 13.15. 16) and wi th the Zollinger-Ellison syndrome ( 17). The dependence of gastric carcinoids on the trophic stimulation of gastrin is sup­por red hy the foct that gastric carcinoids have not been reported after Billroth l and II gastric resections (which involves the rcm0val of the an tral gastrin con­tainmg G cells), and that partia l gastrec­tomy with antrectomy in patients with nonantral atrophic gastritis has resulted in regressi0n of gastric carcinoiJs ( 18.19).

HUMAN PHARMACOLOGY The pharmacological effects of 0me­

prazolc have been extensively studied in healthy subjects and in duodenal ulcer

rauents in remission. Acid 1nhihition wnh omeprazole 20 mg once daily, in­hibits acid secretion over 24 h. This effect is rapid in onset, dose dependent and increases during the first few days of treat­

ment after which time it srabili:cs. Acid control is maintained in chronic use and

61

THOMSON

Ac,d output (mmol/15 m,nu1es)

10 , v Pen1agas1rin 30 1,<g1hour

5

~ • • • • .. • • • • • 0 -1 0 2 3 4

a Placebo O 20mg • 40 mg T,me (hours)

+ 60 mg a80 mg

Figure 2) Snmt1lutcd ,.icid sccre11on t1·w ,1chiet•ed 111 s,x hcalchy l'Olt1nrcen by che admmisrrcwm1 c1/ mrw1·cnc11L1 /Jcnll!,l(astrm. and oral umc/m1zo/c w,11 ,l(it•en 111 doses of 20 co 80 ml{< 201 Ome/Jra~olc ,lwtced a dose dependenr mluh,cwn uJ l1.:1cl <ccrecwn A .1mglc 2l1 mg dose n'd1tced mean srim 11/wed acid uucpw I,:,· 36'\, I co .J h a(ce1 adm1111.1rrarwn

Acid output (mmol/15 minutes)

10 - -----""?"------91Placebo

8

6

4

2

0

i Omeprazole

...o------y20 mg

40 mg

2 3 14

T,me(days)

Figure 3) The omc/1rn~o/e mcluced inh1h1ric111 of am/ sccretwn 1.1 rct•crnble, ma! a{cer a smg/c dme of omeprazole. ,wd 111/11b1C1on rewrm co nonnul m cu o ro chree duy.1 < 201

acid secretion smooth ly return~ to nor­mal within three to four days of stop­ping omepra20lc treatment. Omepramle causes ;i dose dependent inhibi tion of pentagasrrin stimulated acid ~ecrerion in healthy subjec1~ (Figure 2) There is a rapid increase and then decline in the plasma conccnt rati(,n of omepra:ole (half-life 40 mins) after a single oral 20 or 40 mg dose (20). The peak plasma concentration of omeprazole is reached after I to 3 h when it is given as rhe enreric coated formulation.

64

The degree of acid inhibition is corre­lated to the area unJer th e plasma ome­prazole concentration-time curve and the given dose of omcprazole. However, the degree of acid inhibition at any given point in time is nor correlated with the plasma concentration at that point in time, since the du ration of acid control is long, inhibiting acid secretion long after the plasma levels of the drug are unde­tectable. Thus. once Jai ly omeprazole provides effective acid inhibition d uring a 24 h period. even rhough omeprazolc

or Its mcrab0l1tes have disappeared from Lhe blood. Omepra:ole induceJ inh1h1 tion of acid secretion 1s reversible and after a sing le dose returns to normal wi thm two m three days (Figure 3).

With rq.,eated do;.ing. the anrbecrc· cory effect of this proton pump inh1b1-tor increases and Lhcn srnbilizes(20-22J This increasing effect of omepramle i, thought to be due to :rn enhanced syv tcmic availabi lity and l(ing durntiC1n of action (23). With repeated admmistra· uon of cnteric coated omcprnzolc at a dose of 20 mg once daily, the mean mhi­bition of peak acid output b approxi· mately 60'';, m heal thy volunteers (22 ,

24.26) ,rnd about 70''., in pritienn, with duodenal ulcer disease ( 27.28) when measured 24 h after dosing.

Another method to assl'ss the effect of a d rug on in rragastric acidny ism per­form repeated measurements over a 24 h pl'rioJ. After repl'ated dosing with varv­ing doses of omcprazole, acid secretion is inhibited dose dependently (Figure 4). with 20 mg giving an average decrease in 24 h intragastric acidity of approxi­mately 80"{,. Omcprnzole taken in the morning or in the early evening produces similar control of acid secretion (29) Duodenal ulcer healing wi th acid inhib­icors is best correlated wi th the degree of suppression of 24 h intragastric acid­ity (rather than suppression o( nonur· nal acidity) ( 30).

It is important to know that the rcduc· tion in 24 h inrragastric acidity is lc•ss using standard doses of H1 receptor an­tagonists ( 3 I-3 3 ). For example, mean re­duction in 24 h in tragnsrric acidi ty with cimeridinc 200 mg bid has been reported to be 5 5°/,. ranitid ine 150 mg hid is 69°;, and famoridi nc 40 mg ncic te b 70°11.

Fasting plasma gastrin ccincentratinns remains normal until there is greater than an 80"o inhibition of stimulated acid out­put after omeprazole. There was little or no change 24 h after a single dose ( 34) T hl' dbease induced hypergastrinemia in patients with Zollinger-Ell ison syn· drome has not been altered by up to 120 mg of omeprawle during five years of rhernpy (35,36). In patients with raniti­dine resista n t peptic ulcer and reflux esophagi tis who received omeprazole at

a dose of 40 mg daily, the basal plasma gastrin concentration increased a further

H ... act1v1ty (mmol/1)

Mean hourly 1ntragastnc ac1d1ty

80

60

40

20

0 09 12 15 18 21 24 03 06 09

Time of day -- Pre-treatment ~ 20 mg (hours)

~ 10 mg _._ 30 mg

Figure 4) Tu·cncy /c110 lwm 11111aga,tr1, <1c1</11v 1.s red1Cccd 111 J,wden,1/ 1Cb:r pa11e111., 111 rcm1,11c111 a/cer dosrn.~ 1n1h 0111cprn,olc Jor ,rwn d,,,s I~ ,i A/cer ,ctcn Ja~, of mnc/m1,11/c cher,· 1., un Ill.''., red1wl()n of 2~ h 111crngu.<inc ,rc1drr~ The <ame (cmrro/ 1, a.:h1c1 d u·hcr/1,·r omcpra,o/c i, ~11.:11 111 rhc mornmi: or 111 che eurly c1·cnrn1; 121>1

89 pg/ml and 1hcn rcm:11nL·d un ­changea for periods ot up to four years (37). Repeat endoscopic biopsies in these patients have demonstrated no treatment rel med h 1stological ahnormali tics. The

,mall rcducuon 111 rentagasmn stimu­lated pepsin output observed with high doses of omepra:ole ( 20, 38) is likely due co the reduced volume of secretion from

the oxynt1c glands. lntnns1c factor secre­tion is unchanged after single or repeated dosmg with omepra:ole ( 39 ).

Omepra:ole has no effect on plasma concentrations of somatostatin, insulin

2 weeks lherapeullc gain

Omeprazole Ran11,d1no Omepra;zole

Relerence Dose belier belier

61 20 mg

63 20 mg

69 30 mg

61 40 mg

or gluc::igon and the slight decline 111 the postprandial levels of ,ecrettn 1s an expected result of the reduced acid load on the duodenum iollo\\'mg gastric .ic1d inhibition (40:fl ). Omeprazole has no effect on plasma levels of C-repude. parathyroid hormones. thyroid hor­mones, sex hormones rnch as prolacun. testosterone or estrndiol, or basal levels

of cortisol (20.22,41-45 ). Gastric empty­ing rate is unchanged after a single dose of omcprazole (4(1) and the lower eso­

phageal sphmcter pressure is unaffected ( 47) The mcreases in wncentrarion 1,f

4 weeks lherapeu11c ga,n

Rar,11d1ne Omepra,ole bell er better

lO O 10 20 30 40 50 60 Ga,n (%)

10 0 10 20 30 40 Gain(%)

Figure 5) In a/1.:ompt.mmt·r ,cud1cs of umepra,olc and ra11111d111e m duodenal uh'f hea/1111; ( 61.68.69!. cherc tm~ a cherapctte1c g,1111 of omeprazolc ac ru·o and four u eeks The rhcra/1eu11c gam rcpre.1enc1 clie /)t.'fCCnUJRC Jijfcrenc,• fahwluce) m healmi: rnrc l>cru·cen omeJ>ra,ole and ra111tul111e 1mh ()~''<, ccm~­Jcnce 111 rerm h

Omeprozole and inhibition of the proton pump

,·,able hactcn,1, nitrite and N-rltlroso

compounds ohserved in 10 suhjccu,

given omcpra:olc. 30 mg daily for rwo weeb ( 48) arc not thought to he of cl1111-cal s1gnific;111ce ( 49) Thus, gasmc carci­noma certainly will nor develop with

shon term use of omepra:ok', but via­ble baccern1, nitme and N-n1troso com­

pounds arc seen after omeprazole ther­apy. and 1f this b rrolongeJ for several years, rhl.' pt1ss1hilny of devclopmt'nl of g;1str1c cancer is enhanced.

AhS11rpul1n t1f omcpra:ole from cntenc coated formulauon 111 a gelaun capsule 11ccur, 111 dw sm.dl 1ntest1ne usually \\'ithm l ll' (1 h Pl'ak pl.isma concentra­tions arc reached wi1h111 I to 1 h of a

single dose and ,1hsorption of omepra:ole 1s unaffected hy 111rake of food or ant­acids T he small volume of distrihu11on

of omeprnmle (0 3 ro 0.4 I/kg) ( 50) cor­rc,ponds 10 the volume of the exlraccl­lular fluid OmL'pra:ole 1~ 95'',, bound to plasma protein and i:. extensively meta­

boli:l'd on first pa~s through lhe liver. The ws1em1c h1oavailahility of a smglc dmc of omepra:olc ( 20 mg cnteric coat­ed) is 35''.,comparcd with the same dose .1dm1111stered 1111ravcnously. This bio­availability increases to approximately 60"., after rq1cawd, once daily admini­stration ( 50-52)

The b1oavadabdiry of omcprazolc 111 duodenal ulcer patients is similar to that 111 young, healthy volunteers (51-55). This may increase m 79"~ of a single oral 20 mg dose when given in buffered solu­tion to elderly individuals ( 56 ), possibly

as a result of the age related decrt•ase in first pass metabolism of omcpra:ole Bioavadahility may mcrcase slightly to

70'\, 111 patients with impaired renal f unc­t1on ( 57). In patients wi th chronic c1r­rhos1s of the liver. omepra:ole ha;.. a bioavailabiliry of approximately 98"{, due to impaired hepmic first pass metabo­lism effects (58). The plasma clearance differs bet\\'een 111div1duals. possibly due to variations in li ver blood flow and the degree of first pass metabolism (50)

Despite the relatively shon plasma h.il(­life l'f omepra:ole in man (about 40 mins) ( 59) once daily dosing leads to acid

control over a 24 h interval This dura­tion of action of omeprazolc far exceeds the short plasma half-life of nmepra:olc,

likely due to the prolonged inhib1t1on of actton of the proton pump.

65

THOMSON

CLINICAL STUDIES Duodenal ulcer: Over 2000 parienn, have participated in clinical trials examin­ing rhe therapeutic benefits of using omeprazole in duodenal ulcer. In dose ranging. double-blind studies evaluat­ing the effects of omcprazolc in doses from IO to 60 mg once daily in a total of 405 patients (60.61). the 20 mg daily dose was found to be highly effective. with a mean of78%of ulcers healing within rwo weeks and mean of 97"(, healing within four weeks. Daily dose~ of 30 tC'I 60 mg were found to be similarly effective. A loading dose has been found to have nn influence ondundenal ulcer hea ling with omeprazole ( 62 ).

Therapeutic gains in healing have been achieved with omepra:olc in com­parison with H? receptor :rnragonisrs ( Figure 5 ). Double-blind comparisons of omeprazole with H 2 receptor antagonists in duodenal ulcer have included over 1400 patients. The comparison drugs were cimetidine in five triab nnd ranit1-dine in three trials (61,63-69). Consis­tently higher healing rates were obtained m omeprazole treated patients th:rn those treated wi•1 cimeridine in the compara­tive trials, both at two weeb and at four weeb At rwo weeks the heal ing rnte for patients who received omeprn:ole, 20 to 40 mg Jaily, was 111 the range 58 rn 82'';, The corresponding figures for those receiving standard doses of cimetidine were 44 to 49"o. At four weeks the fig­ures were 84 to 100''., for omeprazole anJ 74 to 84";, for cimetidinc. Omepra:ole 20 to 40 mg once daily also produced higher healing rates than ranit1dine. 150 mg bid, both at two weeks and at four weeks. Omcpra:olc healed 71 to 8 3"i, of duo<lenal ulcers after two weeks and 92 to 100°0 of ulccn, after four weeks. Rani­ndine healed 53 to 60'~, after two weeks and 82 to 91 °,, ;ifter four weeks The rec­

ommended standard dose, 20 mg, of omeprazole rroduced significantly higher healing rates than ~randard dose rani­cidine (61).

Large duodenal ulcers usually take longer to heal than small ones. but 52°0 of ulcers greater than IO mm di;imeter arc healed at rwo weeks with omeprazole versus 35°(, with H2 antagonists (61,63-65,68). Healing rates with omeprazole in smokers are superior to healing rates

66

4 weeks 1nerapeu1,c ga,n 8 weeks theraoeutLc gain Omepra, ole

Ran111d1ne Omeprazo1e Ranlt,01ne Omep,azOle Reference Dose belier belier bener belier

77 20 mg - -"" -78 20 mg

75 20mg - ---75 40 mg

10 0 10 20 30 10 0 10 20 Ga,nf%) Ga,n(%)

Figure 6) Omepra;;ole 20 mg once daily hm heen compared wuh ran111dnw l.'iO mg Ind rn ihrce srud1e.d 75.7i;78J Omcpra;;ole hcabl more ulcers moreqi.uckly ell week.s 4and 8. sliotW\~ a 'rherapcuuc .{(t1111 m heal mg rangm!l'from 210 21'';, aijo1tr u·eeks and from 3 to J/0:, ar eighr weeks Therapcuuc gam re/>re,enLs ihe absol111e J1crcenu1ge difference in healmg race be1ween omepra;;olc und rcrnwdmc m paucn1~ u•11/i ga11nc 11/ccr 11·rch 9.~'~, wnfidcnce lrm1t,

in pati.:-nrs receiving H1 receptor anrag­onisl!> and rhe patient's age, ex and alco­hol consumption has not been found to

be influential on ulcer healing rates with omeprazole. The speed and degree of symptom relief with omeprazole is supe­rior to that achieved with cimeridine and ranit1dine (61,62.70-72). For example. in comparison with ranindi ne, omepra:ole treated patients experienced fewer days of pain ( median one to two days) than ranitidine treated patients (median seven days). However, borh drugs provide rapid and effective relief of nocturnal pain (61 ).

Dundenal u lcer patients healed with omepra:ole have been followed-up in periods ranging from six to 12 month:. 128.60-63.73). ln the fi.rstsix months after healing, without further treatment. 34"~ of patients developed symptomatic ulcer­ation . No difference in relapse rates was detected in patients originally healed after rwo weeks' therapy compared with those healed after fou r weeks' therapy (73). ln a l2 month follow-up study, the incidence of ulcer relapse was 56% (60). Symptomatic ulcer recurrence in the first six months after healing with omcprazole occurred in 48°~ of uch individuals as compare<l with 60'1 of patients healed with c1metidine (63). a difference which was not statistica lly significant. Six­month relapse rate~ following healing with ranitidine or omeprazole were com­parable (61 ). Gastric ulcer: Omeprazole has shown therapeu tic gain~ over cimetidine and ranitidinc, both in terms of healing rare and symptom relief in clinical trials in­volving approximately 1200 patients with gastric ulcers. Healing in gastric ulcer is

generally slower than m duodenal ulcer Four and eight week healing rares arr higher with 40 mg versus 20 mg (80''., versus 69":, at four weeks and 96""o ver~us 89°,, at eight weeks. respectively) com­pared to raniridine (59'\, and 85°,,. re­spectively) ( 74 ). Healing rare~ were al,o higher with omeprazole than with cirnen­dinc in pre pyloric gastric ulcer (75). Stud­ie~ comparing gastric ulcer hcaling wtth omeprazole 20 mg versus raniridinc ISO mg bid showed that ulcers healed more quickly with omcprazole than with rani­ridine, showing a therapeutic gain rang­ing from 2 to 2l't at four weeks and 3 to ll "'oat eight weeks ( Figu re 6). Omcpra­:ole healing races at eight weeks were sim­ilar in smokers and nonsmokers and healing rares were unaffected by age, sex and alcohol consumption .

The healing rate with omeprazole 20 and 40 mg daily. was substantially higher than with ranitidinc 150 mg bid in pa­t ie nrs with gastric ulcer receiv ing NSAIDs (74). There is a statistically sig­nifican t d ifference in favour of omepra­zole in relief of daytime pain compared with ranirid ine (Figure 7) (74,76,77).

Six month untreated follow-up <lata in gastric ulcer patients has demonstrated no difference in recurrence rate follow­ing either omeprazole or ran itidine 174). Resistant ulcers: A small proportion of patients treated with H 2 receptor antagonists will fai l to heal their ulcers. ln patients with endoscopically con­firmed duodenal, gastric or anastomotic ulcer unhealed after long term therapy with H2 receptor antagonists. omeprazole was found to be very effective: duode­nal ulcer patients had been treated for

CA:,.; I G,ISTRllE:s!TfRlll VOL 3 No 2 APRIL 198Q

Healtng rate (%)

100

75

50

Omeprozole and inhibition of the proton pump

Healtng rate (%)

100

80

60

40

25 Omeprazole 40 mg o m

Omeprazole 20 mg o m

- Ranit,d,ne 150 mg b , d

20

0

_._ Duodenal ulcer (n = 30) - Anastomot,c ulcer(n = 11) - Gastric ulcer (n = 51)

0 4 8

T,rne (weeks)

0 2 4 8 T,me (weeks)

Figure 7) In ,1 cwn/1t1ra1i1·e 1riC1l oj /J£lliem1 u iih nom1ero1Jal anri m/!ammarory Jrng ussocw1cJ gmcnc crowm t1nJ ulccrarwn ( 7'iJ. rl1c four U'eek heal mg raies were /11ghcr Jor omeJm1zole 20 w ·IO mg once dwl:, than {or ranmdme J'iO mg /ml

Figure 8 ) The cjjccc oj omcpwzolc on rcmurnt ulcers u·us exammcJ ( 70/. After trc?ating />a1ic1111 mLh cimeiiJinc or ra11iridi11efor a mean of 32 1t·ceb Jor duodcnu I ulcer. 29 weeks Jor gasmc ulcer and 46 weeks for ana1tummic ulcer. oral omc(>m~olc -#J mg once daily was given for two to e1gh1 u·eeh 01,er BO"o of the ulcer., then healed wa/1111 eight weeks

an average of 32 weeks wi th H 1 recepto r antagonists; those wi th gastric ulce r had been treated for a mean of 29 weeks; and those with ana~comic u lcer had been treated for a mean of 46 weeks with either cimetidinc or ranitidine. Oral omeprazolc 40 mg once daily was given for cwo to eight weeks and approximately 80°/., of rhe duodenal ulcers healed in four weeks as did gastric ulcer~; ;rnastomotic ulcers healed afte r e igh t weeb of omeprazole therapy (Figure 8) t 78J. Reflux esophagitis: Symptomatic relic( and endoscopica lly confirmed complete hea ling of reflux esophagitis has been found to be effective with o me p razule . Omeprnzole h as been compared with ranirid ine in th ree double-blind studies in erosive/ulcerative re fl ux esophagitis (79-81). Omeprazole was given in doses of 20, 40 or 60 mg daily and ranitidine given in the standard dai ly dose of 150 mg bid. In these studies omeprazole pro­duced significan tly better healing rates than ran itid ine , both ar fou r weeks and at eight weeks, with abo ut twice as many patien ts healed with omcprarole as with ranitidine (Figure 9 ). At four weeks the healing rates were 6 7°0 with o meprazole 20 mg once dai ly versus 31 'l(, for raniti­dine 150 mg b id, whe reas at eight weeks

CAN) GASlliOENHROl VOL 3 Nol ArRll 1989

the healmg races were 85°(, and 50'\,, respective ly (80). T hose patients :;till un healed after eigh t weeks of ranitidine were then switched co omcprazole a nd I, o( rhese 15 patients (87''o) were hea led after eight weeks of omeprazole, whereas only one of th ree patients u nhealed after eigh t weeks of omeprazole therapy was healed afte r a furth er e ight weeks o f ranicid inc the rapy. The h ighest healing rates with omepra:ole were seen in mild cases and a ny healing benefits o f omc­prazole over ranitidine were most pro­nounced in those patients with ~everc di~ease (80-82), wi th healing races unaf-

4 weeks therapeutic gain

Omeprazole Rarnltdme Omeprazole

Reterence Dose belier belier

82. 20 mg

83 40mg

81 60mg

fccted by age, sex, smoking or alcohol. A fcer a four week course o( treatment, a significan tly larger proportion of ome­prazole treated patients (80'\,) were free from heartburn compared with chose on ranitidine ( 30'\,J (79-81 ). Overall , symp­tom relief was more rapid and more pro­nnu nccd with cimeprazole than wi t h ran itidine (80), wi.th 65"-'oof omeprazole treated patten ts being symptom-free after two weeks, compared with 25";, of rani­tidine created patients.

In patients with re flux esophagitis unhealed after at least th ree months of treatment with at least 1200 mgofcime-

8 weeks' lherapeulic gain

Aan111d1ne Omeprazole better belier

,o 0 10 20 30 40 50 60 70 80 10 0 10 20 30 40 50 60 70

Ga,n (%) Ga,n(%)

Figure 9) Three double-blmd studies haw compared orneprazofo umh ranwdme rn erum1e/11/cerw11·e reflux eso/>hugitis (80-82) Oral omc/mizole «•as gi1•en at 20. 4() or 60 mg daily cmd ran111di11e was gi1•en ar 150 mg bid. For the three doses of omeprazole, a 'rhcrape,ttic gam' in healmg was observed at weeks 4 and ll. Thera(>eunc gam represents tlw ahsolure (>ercentage difference in healing rate /,ec11'een omepraz:olc and raniridine w,ih 95"o confidence l1mi1.1

67

THOMSON

cidine daily, or ac least 300 mg of raniti­

dinc daily, 49''., were healed after four weeks of omepra:ole 40 mg daily, 7 3''., after eight weeks and 81 ";, after 12 weeb (83). Zollinger-Ellison syndrome: Approx­i mate!y 20() patients with Zollinger­Ellison syndrome have been treaced with omeprazolc in clinical trials, some for up to five year~ (35,36,42). The long cerm mean daily dose varied between 60 and 70 mg daily in order to achieve rhe 1ar­get reduction in acid output nfles~ than

10 mmol/h before the morning dose. Approximately 80°0 of patients were con­trolled within one week and more than 90''{, were maintained on daily oral doses of between 2() and 120 mg. No tachy­

phylaxis was ob~crvcd in up co fiw years' continuous treatment with omepramle. There was a pronou need ca rl y improve­ment in acid related symptoms, with the

therapy being well tolerated and no treat­ment rela ted mucosa! abnormalities

found on histological evaluation of biop­sy samples ( 36,84).

SAFETY A lack of ~ystcmic side dtccts ot ome­

prazole b perhaps to be expected since

the drug targets precisely the acid pump. Furthermore, it is b1ological ly inactive at the physiological pH prevailing in tis­sues and o rgans ocher than the secretory canaliculi cif the parietal cell. Nonseriou~. mild and tran~ient adverse events which

have been reported most often arc gas­crointesrinal in nature and include cpi­gastric pain, nausea. diarrhea, constipa­tion, flatulence. headache and a few cases

of skin rash . No difference in adverse events could be detected between ome­prazole and placebo (85) or between omeprazole 20 ro 60 mg daily and raniti­dine 300 mg daily ("fable l ). Significantly fewer gastrointestinal adverse events

were reported in two comparmive tricils with omeprazole than with either cime­tidine in prcpyloric ulcer (75) or ranici­dine in reflux csophagitis (80). There were no reports of gynccomastia, i m po­tcnce, confusion in the e lderly or in­creases in scrum creatinine concentra­tion with omeprazole. T he pooled inci­dence of serious adverse events has been

similar in comparative trials for time­prazolc, cimctidinc and ranicidinc, and

68

TABLE 1

Most frequent adverse events reported in clinical trials of omeprazole versus raniti­dine in duodenal ulcer, gastric ulcer and reflux exophagitis

Omeprazole Ranitidine Number of Number of

Adverse effect patients % patients %

Epigastric pain (aggravated) Headache Nausea Diarrhea Flatulence Dyspepsia Abdominal pain Vomiting Fatigue. asthenia Diwness Skin rash urticaria

less than the incidence of serious adverse

events during placebo therapy (4.7''/,), probably resu lting from the untreated disease.

o histo logical changes in oxyntic endocrine cells of the gastric mucosa have

been found after short term healing cour~e~ of omeprazolc or H 2 receptor antagonist~ in peptic ulcer disease pa­tients (84-86,87). No treatment related histological abnormalities of these cclb have been found in up ro five years of cominuous high do c omeprazole ther­

apy in patiems \\'ith Zollinger-Ellison syn­drome (86,88). Once daily oralomcpra­zolc at a dose of 40 mg daily has been without histological sequelae over the past three years, in a trial still in pro­gress, in peptic ulcer and reflux esopha­

gi tis patients resistant to cimetidine or ranitidine and created with omeprazole (90). Omepra:ole has not been shown to have any significant clinical effect on laboratory ,·ariablcs (85), and provoca­tion testing in subjects in whom an

increase in the liver en:ymes aspanate and alan ine aminotransferascs and alka­line phosphatase have been reported,

have not confirmed a further and subse­quent change in those individuals (91,92).

Omcpra:ole is metaboli:ed by che cytochrome P-450 system in the liver. Studies have shown that omepra:ole does not interfere with the pharmacoki­necics of oral or intravenous thcophylline or oral propranolol (93,94) but interac­tions with diazepam (95,96) and pheny­

toin (95,97) have been described. Small changes in che low potency R-isomer of warfarin but not with the potent S-

59 33 29 28 28 25 24 18 12 10

5

5.7 39 5.0 3.2 18 2.3 2.8 24 30 2.7 13 1 7 2 7 18 2.3 2.4 33 4 2 2.3 13 1 7 1 7 18 2.3 1.2 14 1 8 10 10 1 3 0.5 4 05

isomer have been described with ome­prazole 20 mg daily (98). Monitoring of omeprazole patients also receiving phc­nytoin or warfarin is recommended

SUMMARY ln extensive clincial triab omeprazolc

ha~ been ~hown to be highly effective in

the treatment of duodenal and gastric ulcers, reflux esophagi tis and Zollinger­

Ellison ~yndromc, with fost and pro­nounced symptom relief both during the

day nnd nt night. Omeprazole h.1s been well tolerated and ha~ been without anv established side effects. Time and expe­rience will be needed ro establish whe­

ther H ! blocker~ stil l represcn t the be,t avai lable cherapy for acute treatment of peptic d1s(1rders and whether mainte­nance therapy is bes1 achieved with H blockers or with proton pump blockers·

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Oxford Clinical Commun1ca11om, 198tU.

2 Sml>lka A, Helander HF. Sachs G Monoclonal antibodic, against ga,1ric H• .K+-ATPasc AmJ Physiol 1983:245:0589-%.

>. Berglindh T, Sach, G Emcrgmg strategie, in ulcer therapy, Pump, and reccpmrs. Scand J Ga,1rocnrcrol 1985,20 (Suppl 108) 7-14.

4. Sachs G. The parietal cell as a therapeutic target. Scand J Gastrnemerol 1986;21 tSuppl II 1:1-10.

5. Lindberg P. Nordberg P. Almingcr T, Brandstrom A. Wallmark B. The mechanism of action of the gastric acid sccrcnon 111hib1tor omepra:olc. J Med Chem 1986:29· 1.127-9

6 Wallmark B. Carl"('l1 I::, Lir",>n H. BranJ,tmm A, L111dherg P Ne\\ mhibuor, of gasmc ac,J secreuon Propcmc, and design of H • .K •-ATPa~· blocker,. In Lambert R W, cd Third SCI-RSC Medical Chemistry Sympo,1um Lomkin \Vhn,1ahk L11ho. 1986 293 rn.

7 Ekman l , Hanss(ln I-, Ila vu N. Carls,on E. Lundberg C. To:-.1colog1cal ,ll1d1cs on omepra:ok Scand J Ga,mK'11tcn1l 1985.ZO !Suppl 10hl 'i 1-69

R Carl,s(,n L. Larsson H. Mattsson H, Ryber~ B. Sunddl l, Pharma,ologv and mx1c(>logv of (>nwpra:11k• with special r,•(crence to the effect, on the• gasmc muco,a. Sca11J J Ga,troentcrol 1986,2 1 (Suppl IIHUl -h

9 Hakan'><lll R. O,car"nnJ, Sundler F. Gasmn and the trophic control ol ga,tric muco,a Scand J Ga,mwn1crol 1986.21 (Suppl IIH) IH· 30

10 Sundb !', Carls~on I::. Hak,111'><>11 R, Lar,,on H, M:i1ts,nn H . lnh1h1mrn of gastric aud secre11<1n hy omepra:ole :ind raniud,ne Effects (,n pla,ma ga,mn .ind ga,mc lw,tamme. h1,11J111c decarbox,l­,1se acuv11y .ind ECL cell d,•ri-ny 111 normal and antrectnm1zed ra1s Scand J Gastroentc'rol 19t,(),21 (Suppl 111'} W-45

11 MacDonald RA A study nf 35{) carc1no1ds nf the gastrointestrnal rrnc1. Repurt of four new ca,e, of chc carcinnrd ,ynJronw Am J 1--1,•d 195 ,.21 h67-78

12 Goodwrn JD II CarcrnorJ tumors An analy,r, ,if 2.1' 17 c,1sc•s Cancer 197 5. 36 56l~-9

I l H~rwy RI·. BrnJ,ha"' 1' !I, D,l\ 1d,on CM. \\'1lk11wm SP 1'1ulnfocal g.1stnc camnord 1umour,. ,Khlorhvdna ,ind hyperga,1nnaem1.1 Lmcct 19ti5.195 l -4

14 Borch K l::pidcm1ol()g1c. dm1rnpathn­l()g1t, and ,',(>nom1c .1,pect, (>I gasrro,cnpK scrcemng oi pau,'nt, wirh pern1c1nus anemia S,and J G.istm· cmeml 1986,21 21- >l~

15 \\'iland,•r E. Nmdgren H. Olx·rg K Nonantral gascric c.1r,rno1d cumour~ associa ted wnh h)'!wrgasmnacm1a Acta Med Scand 1986,219 W,-7.

lb. Burch K. Renvall H L1edherg G Ga,mc endocrine cell hyp,·rpla,ia and carcrno1d rumors in perl11Cll>U:, anemia. Gastrot•nterc>logy 1%5;88.c, 3h-4h

Ii Solcia E, Capella C. Buffa R. Fngcno B, Fiocca R Pacholngy of the ZollinJler-Ellison syndrome Prug Surg Pacho! 1%0.1 119->l Lattes R. Grossi C. CarcrnrnJ 1umors of the stomach Cancer 1956;9 .691'-711.

19. Richards AT. Hinda RA. Harrison AC Gastric carcrno1d tumours a"oc1atcd with hyperga,mnaem1a and pt'rn1c1ou, anemia Regres.ion of tumours hy amrcctomy A case report . S A fr Med J 1%i.7Z51-,

20 Lmd T. Cederberg C. Ekenved G.

C~~ J GAsTROl\ rl ROI \ ()I > N,, ! APRIL 191N

H.tglund U. O lbe L. l::fft-rt of omeprmolc a gasll ll protlln pump rnh1h1tor on pcntaga,tr111 ,umul.ncd ac1d ,ecrcta>n 111 man Gui 198 l.24.270·6

21 Cedcrgerg C Ekenved <.,. Lrnd T. Olhe L. Acrd 111hih1tory charal!emtlr'> of omepra:nle rn man Scand .I Ga,1rocnterc,I 1985.20 !Suppl 1081 IC15-12.

22 vnn Muller P. Seit: HK. Srmnn H. Dammann I {G Saure,t•krenonsn·r· haltcn und Plasma,p1egel unter euwr mehrtagrgen Omepra:1>!-gahe Ar:nt·1-mr1tclfor,ch 1% 3, 3 > l(,S5-6.

2 3 Brandsm>m A, Lmdherg P. Junggrl'n U S1rucrure ac11,·i1y relauon,h1p, of ,uh,muted bt·n:rm1da:ok',. Scand J Ga,trocnteml 1%5,ZO (Suppl IC'h}. I 'i-12

24 ,·on Muller P, Seitz HK , Simon B. l'I al Vierwnchrge omepra:(>l-gahe hniluss ,tuf s.1ure,·erhalten und b,h::tle H(1rmon,p1egt·l Z Ga,1roen!l·rol 1984,22.2 3()-f(l

15 Sharm,1 B. A ,el son t-.t. P1,unckr RI::, ,·t al Acrd st•crcmrv capacity and rl,1,m.1 gastnn concl'nrrauon ,1ftcr adm1111s[ra· uon of onwprn:ole lo normal suhJc'c1s Alrmcnt Pharm.icol Thl'r 1987 .ln7- 76.

26 Cederberg C. Lmd T. Axelson M, Olhe I I ong 1errn acid inhrhnory effect l>f cl1ffere111 daily doses of orncpra:ole 24 hl>ur, after dosing Ga,m1enter1,lng\ 1%4;t!6.104 3 !Ab,tl

17 Karvonen AL. Keynlamen 0. lJl1S1tillo A. ,·c ,ii Effecc, of omepra:ole 111 duodenal ulcer pa11e111, Scand J G.1s1roentl'ml 19S'i.2 1 449-54

28 Mcyrrck-Thom,nn J, M i:,1e,1'1c: JI. Tm1man 11 . et ,ii Omcpra:olc rn duodenal ulccranon A,rd 111h1brrnm. ,ympwm relid. endo"oprc healrng. and recurrence C:ooperauve study BrMedJ 1%4.21'9 5L'i-K

29 Pmchard PJ Yeoman,:,..;[), Jon,•, DB. McNeilJJ, Lou1d WJ, Smallwood RA. Effe, r of morning or ev,•nrng dosage• wuh 10 mg (>mepra:c>le 1,n 14 h ga,mc pH 111 duodenal ulcer paucncs rn rem1s,ion. Ga,1rocntl'rulogy 1984,86 1213 (Abtl

3l1 J11nes DB. Howden C\\' Burget D\\. f.:err GE. Hunt RH Acrd ,uppress11,r1 of duodenal ulci:r A rnew·ana ly,is ll> define optimal dosing ,1·1th anu,ecremn• drug, Gut 1%7,2h.1120-7

31 Pounder RE. Md1on-Thompson Gj, Williams JG. M1siew1c~JJ. 24-ht>ur cuntml of intragastri~ add1ty by rnnendmc rn duodenal ulcer paucnts Lancl't 1985.ii 1069-72

32 Walt RP. Male PJ , Rawlrng,J. Hunt RH. Mdrnn-Thmmpon GJ. Mt~iew1c:JJ Comparison of the effects of ranr11dine, omctidrnc and placebo on the 24 hour 111tragastnc acidrcy and nocturnal acid ,ecrcnon 111 pa11e111, ,nth duodenal uker Gut 1981.22:49-54

Omeprozole and 1nh1bllion o f the proton pump

3 3 Mulkr P, Simon H. D,1111111,11111 HG. l·ul·rler G, Lrch1wald K. "d1m1dt-Ciayh· H Effect ot ,rngle d.111) do,1•, of HZ-blockers on .1C1d ,ecr,·uon rn m.111 Schwerz Med Wochcn,chr 1984.114 667-71

H Lrnd T. Axcl,on M. Olhc 1 Do,e-respon,e relmronshrp (lf gaslrl( ,mJ 111h1h1uon 111 clderlv pauent, ,iftL't repeated adm1111strat1on of omcpra:oll' D1g Dis Sc, 19Ho, 31 (Suppl I >52S (Ab,t)

35 Lloyd -Dav1es KA. Rutger,,on K. Solvcll L Omepra:nk rn Zoll mg,·r-Ellison syndrome Four·,<'ar internauonal scudy Gastroenierology 1986;90: 152 3 (Ahst)

36 Maton P. McArthur K. Wank S.1·1 al Long term effrcacy and safery of omeprnzok 111 pa11c111s wnh /ollrngcr-Ell1son ,yndrome (!ES) G,Nmenterology 1985;90: 1537 (Ab,1)

37 BrunnerG. Creudcldt W Harke U. I ambcrt R. Therapy with omcprazt,lc in pau1•nt, wuh peptic ulcer,111011> resi,wnt 10 ,·,tendcd high-Jose raniudmc 1rc,1111wnc D1gc,uon 1988, 39:80-90.

)H Lincl T. Cedcrhcrg C. Ekenvt·d G, Olht· L Inhrh111cm of basal and heta.:ole- and ,ham ft·cdmg mduccd acrd secrenon by omt·prazole 111 man Scand J Gastmc·nteml 1986.21 · !004 10

N Kmang E. Aadland E. Schion,by H Effc•ct ni omeprazok on the '-t'Cretion of intnns1c factor, gastrrc acrJ and pepsm 111 man Gut ILJ85,Z6-594·h

40 Allen JM. AJrran TE. \\'ehstcr J. Ht>we A. Bloom SR Effect of a single dose of omcpra:ole on the gastrointcsunal peplldL· re,pon,e to food Hcpatogastro· enterology 1984. 31.44-6.

41 Bluom SR. Daly MJ. Cederberg C. The cffe.:1 of omepra:ule on meal-stimulated g.1,tm1mcst111,1I hormone, rn hcahhy suh1cc1, AB Hassle Internal Report, 1%5

42 Lam,·r, CBHW, Jansen JBMJ lnh1b1t1on of gastrrc acid st•crc·uon 111 Zollmger-Elh,on syndrome by omL·prazole. a potent and long-acting anusccremry drug Gut 1982,23 A907 IAbstl

4 3 EkcnveJ G. Heggclund A, Lundborg P The effect of omcprazole on circulating levels of thyroid hormones in healthy ,ubiccis. AB Hassle , Internal Report, 1983.

44. Lundborg P. HeJ,Jgelund A,Jc,hnsson G Tt,lerability study of H 168/68 111 healthy subjects. AB Hassle, Internal Report, 1981.

45 Howden CW. Reid JL. Omcprazol;:, a ga~mc proton pump inh,bnor'. Lack of effect on renal handling of electrolytes and Llrin ary acidification. Eur J Clin Pharmacol 1984,26:639-40.

46 Horowm M. Hetzel DJ. Buckle PJ , Chntwrton BE, Shearman DJC. The

69

THOMSON

effect o( omcrra:ole on gastric emptying in patients with dut>dcnal ulcer di>ca,c. Br J C li n Pharmacol 1984: 18: 791-4.

-+ 7 Dem J. Downton J. Buckle P. Cl al Omeprawle heals peptic esophagi tis by elevation of mtrag.i,tric pH Gasrmcnrcmlogy 198'i;88 1363 !Ab,tl

-+8 Sharm.i BK. Santana IA . Wood EC. ct al. lntragastric bacterial activity ;md nitrosation before. during and after treatment with omt'p razole Br Med J 1984.289:717-9

49 Colin Jone, DG. Langman MJS, Lawson DH. Vessey MP Review: Post-m arke ting surveillance of thr safety of c1111ettd111c

the problem, of data interpretation . Aliment Pharmacol Ther 1987, I 16 7-77.

5(' Rcgardh CG. Gabrieb,on M. Hoffman KJ . lciberg I. Skanbcrg l. Pharmarnk111et1cs and mctaholhm of omep rnmlc in an1mab .me! man An overview. Scand J Gas1men1erol 1985,20 (Suppl 108) 79.94

51. Andren K. Andcmon T, Cederberg C. Sknnberg I. Rt'gardh CG Omeprawle pharmacok111et1c, during repeated oral adminis1rnmm Annual Pharmaceutical Congress. Stockholm 1985· 112 (Abst)

52. Rbh5S K. Andren K. Hcggclund A. Lagerstriim PO. Lundborg P, Bioavrnlahdi1y nf t>meprn:nlt' given 111 cnniuncuon with food Ana Pharmacol Tox1col 1986:59 (Suppl 5 ):85 iAb,tl

5 3 Sharma aK. Walt RP. Pounder RE. Goml'!s MdcFA, Wood EC. Lt1gan LH Opumal dose of oral omcprn:ole for max imal 24 hour decrea,c of 1111ragas1ric ac,dnv Gut 19H4.25·9'i7-64

54 Nae,dal J. Bodcmar G. Walan A Effect of omeprazole. a ,ubstitu tcd ben :1m1da:olc, on 24-h 111 traga,1r1c ac1d1ry in p:1ticnt, with peptic ulcer d,~ease Scand J Gastroenterol 1984. 19:9 16-22.

55. Lundborg P, Heggelund A, Pilhrant A. B,ovailabrlny nf omcprawle. Compari· ,on bet\\'Cl·n the cntenc·coatcd formulation used in rhasc Ill clrn1cal stud il'!, and I he intended ma rke t formulation AB Hassle. Internal Rcron. 1986.

56. Bianchi A, Rotenberg A. Soule JC, ct al Tranement de l\1 lcerc duodenal en poussc par l'omeprnzolc Rcsultats d'unc cwdc non cuntrolce multiccntriquc G astroenrerol Clm Biol 1984:8·94 3-6.

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58. Andersson T. O lsson R. Skanberg I. ct al. Pharmacokineucs of omeprazole in patients wnh liver cirrho rs Acta Pharmacol Toxicol 1986;59 (Suppl 5) 203. (Abs1)

59 Lundborg P, Ekenved G. Heggelu nd A, Pilbrant A . Bioavailabdi1 y of

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60. Pri tchard Pl. Rubinstein D , Jones DB, ct al. Double blmd comparau ve stud y of omcpra:olc 10 mg and 30 mg d.iily for healing duodenal ulcers. Br Med J 19HS,290:601 • 3

6 1 Bardhan KO, Bianchi Porro G, Bose K. c t al A comparison o f two different doses of omcprazole versus ran1tidine 111

treatmem of duodenal ulcers. J Clm Gasrroenterol 1986;8:408-13

62 Walan A. Bergsaker·A,p6y J. Farur P. ct ,ii Four week study of the rate of duodenal ulcer heal mg with omepraznle Gut 1983;24:A972. (Abst)

ed. Lauritsen K, Rune SJ, Bytzcr P. c t ~I Effect of l>mcpramle and c1me11dinc on duodenal ulcer. A double-blind comparative stud y. N Engl J Med 1985,312:958-61.

64 Bader JP Etud c de l'effcct de l'omerrazole sur la c1catrisation des ulcere, d uodena ux. comparaison a\·cc la cimetidinc Oastroenterol Clm Biol 1986.10·191A (Abstl

65 Archambault AP, Navcrt H. Pare P, et al. Omeprawlc ( 20 mg daily I versus omcuJ111e ( 1200 mg datly) m dul,denal ulcer hcalrng and pain relief Ga,cmentcrology 1988:94. 1130-4.

66 Het:cl DJ. Korman MG. Hansky J. et al A dl,uhle blrnd multicentre compa rison of omeprazolc ,md cimetidine in the 1rt'atmen1 of duodenal ulcer. Aust NZ J M,·d 1986: 16 (Suppl 3):595 (Abst)

67 Dahlgren S. Hrnd sky M, Norryd C, e t al The effect oi omeprnzole anJ cimcudine on ulccr hcalmg 111 treatment of duodenal ulcer patients. A Swedish mul1iccn1rc study. Dig Dis Sci 1986. 3 I (Surrll:44S. (AbstJ

68. C lassen M. Dammann HO, Domschkc \V. t't al Kumeit-Therap1c des Ulcus duodeni mit O meprazol und Ranitidin. Ergebnrsse etncr deutschcn Multi· zengerstudie. Dtsch med Wochcnschr 1985: 110:Z L0-5

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75 Laumsen K. Rune SJ. Wulff HR. ctal Effect nf (1mepra:ok and cimetidme on prepyloric gastric ulcer A double-blind rnm p;1rnt1ve tri al Gut 1988:29·249-53

76 Classen M. Dammann HG, Domschkc W. ct a l Abhc.!ilungsraten nach Omcpraml· und Raniudm·Bt'handlung de, Ulcus venmculr Dtsch Med Wochcnschr 1985.110:628· 33.

77 Saggioro A, de Ma,i E, Curzlo M. et al G;"tnc ulcer healing ;md relief of symptoms during treatment wnh omeprazole 20 mg once daily, or ranitidine 150 mg t\\'ICC daily for 4·8 weeks - A double-bl111cl multicentre study. Gut 1987;2H:A 1141 (Abstl

78. Carlsson R, W,1lan A. Muller-WolfD, er ;11. Omeprazole, Losee'" , m the treatment of patient:, with pept ic ulcer unhealed after treatme nt with H 2·rcceptor antago111sts fo r at least 8 weeks. AB Hassle· Internal Report, 1986

79 Klinkenbcrg·Knol EC, Jansen JMBJ. Festcn HPM. Mcuwisscn SGM, L1mcr, CBHW. Double-b lind multiccntre comparison of omeprazolc and ranitidine in the treatml'!ntof reflux esorhagitts. Lancet 1987 ,"349-5 1

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8 1. Vanrrapren G , CoenegrachtsJL, Rutgccns L. Schurmans P. Omcprazolc 140 mg) i, superior to raniticlinc 111 the ,hon term treatment of ulcerativt' rcAux l'!sophagtt,s. Ga,trocnterology 1987:92: 1681. (Abst)

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83 Hamecteman W. Tytgat GN Healmgof chro 111c Barrell ulcer, with omcprazolc Am J Gastrocnterol 1986:8 1: 764·6

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85 Solvell L SummMy of colcrability and safety of omcpra:olc in healthy , ubicm and patients. AB Hassle: Internal

Report. 19M ~6. Carb~on E, Solvell L. On 1ht'

mechaiw,m behind the de\clopment of ga,mc carcinrnds 111 rat w1th ,pen,11 reference 1(1 man. Safety aspects AB Ha,,le Internal Report . 19H6

li7 SunJler F, S1mon"11n M, Svcn"1m L Fasung pla,ma ga,trin k•wl, and h1,wlogy ot casmc h1op,1t', from pt'puc ulcer paucnt, helore and after trc:mnent wnh omepra:ole or H !·receptor antagonist, AB Ha,,le Internal Report. 1986

~8. Helander HF Oxynu.: mu.:u,a h1,1ology 111 omcpra:ole-treated pauents suffering from duodenal ulcer or Zollmger-Ell,,on ,,·ndromt· O,ge,uon 1986,35 (Suppl 11.12 3-9

S9 Lambert R, Creu1:kldt \V, Swckmann F.Jacuba,chke U. M.ia, S, 13runnl'r G Long-tcrm 1,mepramlc trL'atmeni 1n

man Ltfrct, on gasm, endocnne cell popul.1t1on, Oigc,uon 1988. 39 126-Vi

90 L11of L. Adam, HO. Gw,tav"1m S. Nyberg A. Nyren 0. Lundborg P. Omepra:olc: N11 evidence for frequent hepatic r1',1Cttt1m Lan..:ct 1984 ,1. l H 7-ii I Letter)

91 L6ilf I .. Ad,11111 110, Gu,ta\',son S, N, bt'rg A N~Tl'll O Rl'·Cxpo,ure to

omeprn:ole 111 rwo subjects having t•xh1b1tl'J incn•,tsed scrum tran,amma,e levcb during rrc\lous treatment w1th omerra:1,I<' AB Has,k lntl'rnal Report 19S4

9Z l k•nry D, Brt·n1 P. Whytc' I. M1halv C.,. Devcni,h-Mc•arc, S Proprarwl,,I ,tcady ,tatc pharman1k111ct1c, an.: unalrert·d by omeprawk Eur J Clan Pharmawl 1%7 B 3ti9-i,

9 3 Gugler R Effect of omc•pra:ole on theoplwllint' plasma lcn·l, alter <lral ;rnd

Omeprozole and 1nh1b11ion of the proton pump

1, thcorhvll,m· t\B Ha""° · ln1an.,I Report, 191\'i

94 Gugler R krbcn IC Onwpra:11k 1nh1h1ts ox1d.1t1,·t· drug nw1,1holt,m Studic, wtth d1a:epam .111d phl·nvt111n 111 ,·l\·o anJ 7·cthoxy,11um,mn tn, 1tr11 Ga,tnlt'lltc•mlugy 1985;89 12 3'i·41

95 Lundborg P. Hcggt•lund A, lnhn"on G Effect ot omt•pra:1,le and ct!Tll'lldllle on dt;lZl'pam plasma lcvds aftl'r 1 ,.

d,azcpam AB Hassle lninnal Rl•port , 1987.

% . Pmchard PJ. Walt RP, K1tch1ni:m,1r1 GK. Sc1mer\'llle KW, Lingman MJS Oral phl·ny10111 ph.1rmacok11ic1tes durl!lg lltncprawk· therapy. Br J Clm Pharmacol 1987 .24 54 Vi

97 Paulsen 0. l li\glunJ P. Bo,trii ! I, Sutfin T E:ffecr <1! omepra:olc on pla,m,1 lt•\cl, and ,mun,agulauon dfl·,1 of wartarin AB H.issle· Internal Report 1987

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