Complete Inhibition of Food-Stimulated Gastric Acid Secretion by Combined Application of Pirenzepine and Ranitidine*

Gut: first published as 10.1136/gut.22.7.542 on 1 July 1981. Downloaded from

Gut, 1981, 22, 542-548

Complete inhibition of food-stimulated gastric acid secretion by combined application of pirenzepine and ranitidine*

W LONDONG,t V LONDONG, C RUTHE, AND P WEIZERT From the Medizinische Klinik Innenstadt, University ofMunich, Munich, W Germany

SUMMARY In a double-blind, placebo controlled and randomised secretory study the effectiveness of pirenzepine, ranitidine, and their combination was compared intraindividually in eight healthy subjects receiving intravenous bolus injections. Pirenzepine (0.15 mg/kg) plus ranitidine (0-6 mg/kg) suppressed peptone-stimulated gastric acid secretion from 69±11 to 2±0-4 mmol H+/3 h; the mean percentage inhibition was 97%. Postprandial gastrin was unaffected. There were only minor side-effects in a few experiments (reduction of salivation, brief blurring of vision), but no prolactin stimulation after ranitidine or ranitidine plus pirenzepine. The combined application of ranitidine and pirenzepine inhibited meal-stimulated acid secretion more effectively and produced fewer side-effects than the combination of cimetidine plus pirenzepine studied previously.

The combined application ofclassical anticholinergics Methods and H2-receptor antagonists inhibits basal and http://gut.bmj.com/ stimulated gastric acid secretion in man more than Each subject had four tests which had to be carried either drug alone.' In double-blind, placebo con- out within a fortnight; the interval between two tests trolled and randomised investigations we have was at least three days. On separate days each subject demonstrated79 that combined intravenous bolus received pirenzepine, ranitidine, pirenzepine plus injections ofthe antimuscarinic drug pirenzepine with ranitidine, and placebo in random order by slow cimetidine suppressed peptone-stimulated acid out- intravenous bolus on a double-blind basis according put more effectively (on average by 90%) than either to a predetermined randomisation code. Injections on September 24, 2021 by guest. Protected copyright. drug alone. We concluded from our data that the were given by a physician not otherwise involved in 'optimal effective dose"` of such an intravenous the study. Eight healthy volunteers (four female, four combination in man is 0-15 mg/kg pirenzepine plus male) with a mean age of 28 years (range 22-37 1-5 mg/kg cimetidine, producing a mean percentage years), a mean body weight of67 kg (range 56-84 kg), inhibition of 80% of peptone-stimulated acid secre- and a mean height of 177 cm (range 160-195 cm) were tion and a clear reduction of acute side-effects ofboth studied. They had no history of upper abdominal drugs. As the side-effects of cimetidine given as intra- disease, were not pregnant or breast-feeding, were venous bolus (endogenous prolactin stimulation) not taking any concurrent medication, and had no could not be eliminated completely, additional persistent abnormality of haematology (haemoglobin experiments with the new competitive H2-blocker concentration, haematocrit, white cell and platelet ranitidine seemed to be justified. We therefore count, erythrocyte sedimentation rate), biochemistry studied the effects of the combination of pirenzepine (total bilirubin, transaminases, total protein and plus ranitidine on peptone-stimulated gastric acid electrophoresis, prothrombin index, cholesterol, secretion, serum gastrin, serum prolactin, and side- electrolytes, creatinine, urea-nitrogen, uric acid) or effects, monitored or specified by the subjects. urine analysis screen (protein, sugar, urobilinogen, sediment). *These studies were presented in part at the International Congress of Gastro- The volunteers received 0-15 mg/kg pirenzepine enterology, Hamburg, 8-13 June 1980. tAddress for correspondence: Dr med Walter Londong, Medizinische and 0-6 mg/kg ranitidine intravenously given alone or Universitatsklinik Innenstadt, ZiemssenstraiSe 1, D-8000 Munchen 2, W in combination. The ranitidine dose was chosen Germany. according to Hagenmuller et al. " who demonstrated Received for publication 15 January 1981 that 40 mg ranitidine were equipotent to 200 mg 542 Gut: first published as 10.1136/gut.22.7.542 on 1 July 1981. Downloaded from

Acid after pirenzepine and ranitidine 543 cimetidine intravenously. Bolus injections of isotonic against human serum prolactin.'6 This assay has a saline were used as placebo. The study was approved lower detection limit of less than 20 ,U/ml. The by the Ethical Committee of the Medical Faculty of quality control of both assays equal those of inter- the University ofMunich. All volunteers gave written national standards. consent to participation in this study after full Side-effects were monitored by the subjects during explanation by the investigator. and after the secretory studies and also by careful Peptone-stimulated gastric acid secretion of the observation of the volunteers during the test by the volunteers who had fasted overnight was measured investigator. Peripheral pulse rate was counted at five by an in vivo intragastric titration method according minutes before and at two, seven, 15, 60, 120, and 180 to Fordtran and Walsh'2 modified by Becker'3 using minutes after the intravenous bolus. Only after the an automatic combititrator (Deutsche Metrohm secretory studies were completed in all volunteers, GmbH & Co, Filderstadt, FRG) for titration with 1 N was the randomisation code broken and the data sodium hydroxide with the end point of pH 5.5. The evaluated. Statistical analysis was done using intragastric stimulus was a 10% aqueous solution of Wilcoxon matched pairs signed rank test. Only P Bactopeptone (Difco Laboratories, Detroit/Michi- values less than 0-01 were considered to be significant gan, USA) which was adjusted to pH 5 5 before (two-tail reading). intragastric instillation and circulation through the stomach via a double-luminal gastric tube (Levine- Results type Ch 16) by a peristaltic pump (Blutpumpe BP 742 from Fresenius Apparatebau, Bad Homburg, FRG) Acid secretion showed an excellent reproducibility with an average speed of 280 ml/min. Continuous during the stimulatory phase from 30 to 70 minutes titration with monitoring of sodium hydroxide con- before single or combined application of the drugs at sumption at five minute intervals was carried out in all 70 minutes (Fig. 1). The pronounced inhibitory subjects lying in a left-lateral position and spitting out effects of both drugs or their combination occurred their saliva during the whole secretory study. Acid within 20 minutes after the bolus injection. Pirenze- outputs were expressed as mmol H+ per 15 minutes pine had the weakest effect, and this seemed to be and calculated as mmol H' per three hours. At the relatively stable throughout the test period. Com- beginning of each secretory study 300 ml of peptone pared with placebo its inhibition was significant http://gut.bmj.com/ solution were instilled via tube into the stomach. within 35 minutes after drug injection and lasted from Losses of peptone solution via the pylorus were 105 to 240 minutes. The inhibitory effect of ranitidine corrected during the test procedure. At the end of was stronger, being significant within 20 minutes after each test gastric volumes were aspirated completely. intravenous bolus, and lasted from 90 to 255 minutes, Before the start of each study an intravenous although its effect wore off during the course of the cannula was inserted into a forearm vein and isotonic test. The effects of pirenzepine and ranitidine were saline infused at 60 ml/h to keep the line patent. therefore significantly different only from 105 to 135 on September 24, 2021 by guest. Protected copyright. Fasting blood samples were taken at 0 and 15 minutes, minutes. The combination showed a more drastic after swallowing the tube at 30 minutes (before the reduction of stimulated acid output; within five start of intragastric titration of peptone-stimulated minutes after the bolus injection significant differ- acid output), and then every 15 minutes during the ences from placebo were noted (75 to 255 minutes). test procedure. The intravenous bolus was injected The differences versus ranitidine were significant via the cannula at 70 minutes-that is, 40 minutes from 135 to 255 minutes, when a rather stable and after the start ofintragastric titration when acid output practically complete inhibition of peptone-stimulated had nearly reached a sustained plateau. The blood acid secretion to mean values (x+SEM) of0-01+0-01 samples were cooled on ice before centrifugation. All mmol H+/15 min (at 150 minutes) and 0-2±0-1 mmol the deep-frozen sera from the four different secretory H+/15 min (at 240 and 255 minutes) was established. studies of one volunteer were thawed at the same Fasting serum gastrin values were well repro- time and analysed in the same assay. Serum gastrin ducible at the beginning of the four tests (mean of all was estimated by our radioimmunoassay'4 using the four tests at 30 minutes: 42 pg/ml). After intragastric specific rabbit antibody 4562 which detects com- instillation of peptone solution there was a significant ponent I, big (G 34), little (G 17), and mini gastrin increase to about 125 pg/ml (mean of all four tests at (G 14) in nearly equimolar potency'5 using synthetic 45 minutes). During the secretory studies gastrin human gastrin I (MRC) as standard and a double- values remained raised and were not altered by the antibody as technique for separation of bound and two drugs or their combination. free. The lower limit of detection is less than 2 pg/ml. The histograms of calculated acid output per 3 Radioimmunological measurements of serum pro- hours (75 to 255 minutes of the test period) (Fig. 2) lactin were performed using a specific antibody demonstrate the marked inhibitory effect of the com- Gut: first published as 10.1136/gut.22.7.542 on 1 July 1981. Downloaded from

544 Londong, Londong, Ruthe, and Weizert ACID OUTPUT mmol /15 min

Fig. 1 Effect ofplacebo, pirenzepine, ranitidine, and their combination (in same doses) given as slow intravenous bolus injection on peptone-stimulated gastric acid 3 secretion and serum gastrin in eight healthy volunteers (mean ±SEM). Asterisks indicate significant 2 differences (P<001) between the effects ofcombined application and ranitidine alone. l http://gut.bmj.com/ GASTRIN pg/mi 1604

120 - on September 24, 2021 by guest. Protected copyright. 40 0 30 60 90 120 150 180 210 240 270 t (min) bined application of pirenzepine and ranitidine. Table 1 summarises the side-effects that were Mean stimulated acid output per three hours reported. Reduction of salivation occurred more (x+SEM) was reduced from 68-8+11-0 mmol HI often after the combination (five times) than after (placebo) to 40-0±11V0 mmol HI by 0-15 mg/kg pirenzepine (three times) or ranitidine (once). Brief pirenzepine, to 14-1+3-5 mmol HI by 0-6 mg/kg blurring of vision occurred only once after the combi- ranitidine and to 1-9+0-4 mmol HI by their combination. Two subjects complained of palpitations for a nation. The mean percentage inhibition was 42% by few minutes directly after the injection of pirenzepine pirenzepine, 80% by ranitidine, and 97% by pirenze- and one after the combination, although there were pine plus ranitidine. no increases of peripheral pulse rates. Other un- The serum concentrations of prolactin (Fig. 3) specific side-effects were mild diarrhoea or loose were drawn as median because of a rather great stools in the afternoon of the test day or transient variance between individuals tested. All subjects had nausea and desire to urinate during the secretory normal basal values which declined continually studies. On average a total of 590 ml of 10% aqueous during the first 90 minutes of the investigations, but peptone solution was required during the secretory were not altered by injections, either by pirenzepine studies to maintain a constant speed of circulation for or ranitidine alone or by their combination. an exact titration of stimulated acid output. A mean Gut: first published as 10.1136/gut.22.7.542 on 1 July 1981. Downloaded from

Acid after pirenzepine and ranitidine 545 Table 1 Side-effects volunteered by the subjects during and ACID OUTPUT mmol/ 3h after the secretory studies t 80 Ranitidine Pirenzepine Ran. +Pir. Placebo 0-6 0.15 0.6+0.15 (mg/kg) (mg/kg) (mg/kg) 60 Reduction of salivation 1/8 3/8 5/8 1/8 Blurred vision 0/8 0/8 1/8 0/8 20 Palpitations 0/8 2/8 1/8 0/8 Diarrhoea 1/8 3/8 1/8 0/8 Others: nausea, desire to urinate 2/8 1/8 2/8 t/8 20

0I PIR. RAN. 0.15 0.6 of 460 ml of gastric volume was aspirated at the end of mglkg mg/kg the tests. There was no correlation between the different drug injection and the consumption of Fig. 2 Histograms ofpeptone-stimulated gastric acid secretion per three hours (mean±SEM) in eight healthy peptone solution. volunteers receiving placebo, 0.15 mg/kgpirenzepine, 0-6 The mean rates counted peripheral arterial pulse mg/kg ranitidine, and their cotnbination (in same doses) as before and at definite intervals after bolus injections slow intravenous bolus injection. are shown in Table 2. After ranitidine there were no significant alterations compared with placebo, whereas pulse rates increased (P<005) at two minutes after injection of pirenzepine. After pirenze- Discussion pine alone and in combination the pulse rates decreased slightly at one, two, and three hours after These experiments have shown that combined intra- the bolus injection. At two hours after the injection venous bolus injection of the antimuscarinic drug the difference between pulse rates after pirenzepine pirenzepine and the new H2-receptor antagonist plus ranitidine and ranitidine alone was statistically ranitidine inhibits food-stimulated gastric acid secre- http://gut.bmj.com/ significant (P<0-01). tion in man by 97% and for more than three hours.

hPRL pUlmI on September 24, 2021 by guest. Protected copyright.

400-

300-

PLACEBO RAN.+ PIR. RAN ITIDINE 200- PIRENZEPINE

100 r , , ,I , , , 0 30 60 90 120 150 180 210 240 270 t( min) Fig. 3 Serum concentrations ofmedian prolactin (hPRL) in eight healthy volunteers receiving placebo, pirenzepine, ranitidine, and their combination as slow intravenous bolus injection (for doses see legend ofFig. 2). Gut: first published as 10.1136/gut.22.7.542 on 1 July 1981. Downloaded from

546 Londong, Londong, Ruthe, and Weizert

Table 2 Peripheral pulse rates in minutes (±+SEM) before and after intravenous bolus injection

Before (min) After intravenous bolus injection (min) 2 2 7 15 60 120 180 Placebo 68+2 66+3 64+2 62+3 66±2 69±3 69±3 Pirenzepine (0 15 mg/kg) 67±3 73±3* 66±4 64±4 61±31 64±3 62+2t Ranitidine (0-6 mg/kg) 65±3 67±4 65±3 64±3 68±3 68±3 68±3 Pirenzepine+ranitidine (same doses) 64+2 68±2 65±2 64±2 61+2t 59±3*t 62+2t

*P<0-05 versus placebo. tp<0-05 versus ranitidine. tp<0O01 versus ranitidine.

This complete inhibitory effect was even more pro- more potent on a molar basis than cimetidine.26 nounced than those achieved previously7` with com- With present and previous acute experiments in binations of pirenzepine (0.075 to 0.3 mg/kg) and man neither cimetidine,927 ranitidine,28 nor pirenze- cimetidine (1P5 to 3.0 mg/kg) which suppressed food- pine,929 either alone or in combination, significantly stimulated gastric acid secretion in healthy volunteers alter postprandial gastrin. From these investigations and patients with duodenal ulcer and gastric hyper- with specific receptor antagonists it might be con- secretion by 80 to 90%. Except in one study49 such cluded that neither H2- nor muscarinic receptors are marked reductions have not been established with important for food-stimulated gastrin release. combinations of H2-receptor antagonists (metiamide Konturek et al.26 have recently pointed out differ- or cimetidine) and conventional anticholinergic drugs ences between atropine and pirenzepine on sham- (poldine, propantheline, etc'). An explanation for feeding induced gastrin responses as well. this difference seems to be that pirenzepine is a more Previous studies with increasing intravenous bolus selective antimuscarinic drug on parietal cell function injections in man showed that pirenzepine-in con- than conventional anticholinergic drugs, which have trast with other tricyclic compounds30-had no stimu- very similar binding affinities to muscarinic receptors latory effects on serum prolactin.7 In our study bolus http://gut.bmj.com/ in different organs`7 and therefore produce a number injections of ranitidine-in contrast with cime- of unpleasant side-effects, which set limits to their tidine7 9-had no prolactin stimulatory action. From clinical use. By contrast, pirenzepine distinguishes experiments in rats it is known that cimetidine is an between different subclasses of muscarinic receptors antiandrogen,3` whereas ranitidine is not.32 It is and has low-affinity binding in smooth muscle and possible that high peaks of blood concentrations of heart, but high affinity sites in exocrine glands. 8 cimetidine may relate to its antiandrogenic proper-

It is not clear whether the drastic reduction of acid ties.313334 on September 24, 2021 by guest. Protected copyright. secretion by the combination of pirenzepine and Reduction of salivation, which occurred mainly ranitidine is of any clinical relevance. Ranitidine after pirenzepine alone or in combination, and brief inhibits pentagastrin-stimulated gastric acid secretion blurred vision were weak and tolerable side-effects. in a dose-dependent manner-that is, high doses of In previous investigations9 dryness of the mouth ranitidine alone abolish stimulated acid output in occurred as often after 3.0 mg/kg cimetidine as after man. 1121 Such complete inhibition cannot be 0.3 mg/kg pirenzepine-that is, ranitidine caused this achieved by increasing the cimetidine dose. It was symptom less frequently than cimetidine. Palpitations shown that doubling the normal oral dose does were noticed by a few volunteers, but these subjects increase cimetidine blood levels, but does not reduce did not have any alteration of peripheral pulse rate, food-stimulated22 or nocturnal acid secretion23 to a and, in particular, no tachycardia. However, there greater extent nor does it increase ulcer healing.24 had been a slight and short-lasting mean increase two The duration of action on peptone-stimulated acid minutes after intravenous bolus of pirenzepine alone output of0-6 mg/kg ranitidine given as an intravenous and a decrease at one, two, and three hours after bolus in this study is comparable with that of 3.0 pirenzepine alone and in combination. At two hours mg/kg cimetidine in our previous investigations,79 after combination this decrease was significant and those of Sewing et al.2S However, the effect of 0-6 (p<001). Ranitidine alone had no such effect on mg/kg ranitidine intravenously is more potent, result- pulse rate, as already reported.2' The other side- ing in a mean percentage inhibition of80% compared effects cannot be attributed to the drugs adminis- with 60% by 3-0 mg/kg cimetidine intravenously` tered. Mild diarrhoea or loose stools at the afternoon that is, ranitidine, in our model of meal-stimulated of the secretory study may occur as a consequence of gastric acid secretion, is more than four to five times losses of hypertonic peptone solution via the pylorus Gut: first published as 10.1136/gut.22.7.542 on 1 July 1981. Downloaded from

Acid after pirenzepine and ranitidine 547 (on average about 10% of all subjects investigated). 4Saunders JHB, Cargill JM, Wormsley KG. Effects of Tolerable nausea is related to the gastric tube, and cimetidine and poldine on nocturnal gastric secretion in the desire to urinate could be due to the test lasting duodenal ulcer. Digestion 1977; 15: 452-6. nearly five hours. 'Scholten Th, Fritsch WP, Muller JE. Hengels KJ. have Langzeitsuppression der H+-Sekretion durch Kombi- Significant decreases of heart rate been nation von Cimetidine und Methanthelinbromid. Dtsch reported after parenteral3' or high oral36 doses of med Wschr 1979; 104: 1849-53. pirenzepine. This effect contrasts with cardiac effects 6Thjodleifsson B, Wormsley KG. Gastric response to of conventional anticholinergics and is hard to inter- metiamide. Br Med J 1974; 2: 304-6. pret, as pirenzepine was shown to have low affinity 'Londong W, Londong V, Prechtl R, Eversmann T. sites in the heart.`8 Nevertheless, there are experi- Vergleichende Untersuchungen der Pirenzepin- und mental data that pirenzepine may act in part by Cimetidinwirkung auf Pepton-stimulierte Sauresekretion sympathetic mechanisms.37 Recently, direct binding und Serumgastrin des Menschen. In: Blum AL, Hammer studies demonstrated muscarinic receptors in R, eds. Die Behandlung des Ulcus pepticum mit Pirenzepin. Grafelfing: Demeter-Verlag, 1979: 75-82. sympathetic ganglia which were characterised by high 8Londong W, Londong V, Weber Th, von Werder K. affinity pirenzepine binding.38 Interaction of an antimuscarinic and an H2-receptor In our previous papers79 the possible clinical antagonising drug in man. Gut 1980; 21A: 451. aspects of a combined application of cimetidine and 9Londong W, Londong V, Prechtl R, Weber Th, von pirenzepine were discussed in detail. Its clinical Werder K. Interactions of cimetidine and pirenzepine on relevance is under trial in high-risk patients after peptone-stimulated gastric acid secretion in man. Scand J bleeding from mucosal lesions stopped by laser- Gastroenterol 1980; 15: suppl 66: 103-112. coagulation. As the combination of pirenzepine and '`Sun DCH, Shay H. Optimal effective dose of anti- ranitidine showed a stronger antisecretory effect and cholinergic drug in peptic ulcer therapy. Arch Intern Med its 1956; 97: 442-52. fewer side-effects, clinical applicability should be '`Hagenmuller F, Zeitler-Abu-Ishira A, Classen M. studied, too. We agree with Langman et al.39: 'The Hemmung der Magensauresekretion durch den Histamin- choice between the drugs in treating duodenal ulcer is H2-Rezeptorantagonisten AH 19065 (Ranitidine) im likely to be influenced by their proneness to cause Vergleich zu Cimetidine-eine Doppelblindstudie. Z adverse effects rather than by their effect on healing'. Gastroenterol 1979; 17: 583. In this respect it has to be pointed out that a complete '2Fordtran JS, Walsh JH. Gastric acid secretion rate and http://gut.bmj.com/ inhibition of food-stimulated gastric acid secretion by buffer content of the stomach after eating: results in combined application of muscarinic and H2-receptor normal subjects and in patients with duodenal ulcer. J antagonists might induce bacterial overgrowth of Clin Invest 1973; 52: 645-57. gastric flora and its conse- '3Becker HD. Methodischer Fortschritt in der Funktions- potentially dangerous diagnostik des Magens: Magensekretionsanalyse, intra- quences.' Therefore, such a combination should be gastrale Titration, endokrine Provokationstests. Z applied only as short-term treatment in definable Gastroenterol 1978; 16: 118-25.

patients with complicated peptic ulcer disease.79 '4Londong W, Geier E, Feifel G, Forell MM. Hypo- on September 24, 2021 by guest. Protected copyright. glykamieinduzierte Gastrinfreisetzung nach Vagotomie. We are very grateful to Professor Dr J F Rehfeld, Z Gastroenterol 1975; 13: 418-23. Aarhus/Denmark, and to Professor Dr K von `5de Magistris L, Rehfeld JF. A simple enzymatic procedure Werder, Endocrinological Department of our clinic, for radioimmunochemical quantitation of the large for providing us with their excellent antibodies. molecular forms of gastrin and cholecystokinin. Anal Biochem 1980; 102:126-33. 16von Werder K, Felixberger F, Gottsmann M, Kerner W, Glockner B. A homologous human prolactin (hPRL) radioimmunoassay with an antibody against 'little' hPRL. References In: Radioimmunoassay andrelatedprocedures in medicine. Vienna: Intern Atomic Energy Agency 1978: 43-54. 'Barbezat GO, Bank S. Effect of histamine-H2-receptor- `Ariens EJ, Beld AJ, Rodrigues de Miranda JF, Simonis antagonist and an anticholinergic on gastric acid secretion AM. The pharmacon-receptor-effector concept: a basis in man. S Afr med J 1976; 50: 849-51. for understanding the transmission of information in bio- 2Feldman M, Richardson CT, Peterson WL, Walsh JH, logical systems. In: O'Brian RD, ed. The receptors. New Fordtran JS. Effect of low-dose propanetheline on food- York: Plenum Press, 33-91. stimulated gastric acid secretion. N Engl J Med 1977; 26: `Hammer R, Berrie CP, Birdsall NJM, Burgen ASV, 1427-30. Hulme EC. Pirenzepine distinguishes between different 3Richardson CT, Bailey BA, Walsh JH, Fordtran JS. The subclasses ofmuscarinic receptors. Nature 1980; 283: 90-2. effect of an H2-receptor-antagonist on food-stimulated '9Domschke W, Lux G, Domschke S. Gastric inhibitory acid secretion, serum gastrin, and gastric emptying in action of H2-antagonists ranitidine and cimetidine. Lancet patients with duodenal ulcer. J Clin Invest 1974; 55: 1979; 1:320. 536-42. 20Simon B, Kather H. Hemmung der Pentagastrin- Gut: first published as 10.1136/gut.22.7.542 on 1 July 1981. Downloaded from

548 Londong, Londong, Ruthe, and Weizert

stimulierten Magensekretion durch Ranitidin. Dtsch med stimulation and L-dopa suppression of plasma prolactin in Wschr 1979; 104:1676-8. man. J Clin Endocrinol Metab 1971; 33: 873-6. 2`Woodings EP, Dixon GT, Harrison C, Carey P, Richards 3`Winters SJ, Banks JL, Loriaux DL. Cimetidine is an anti- DA. Ranitidine-a new H2-receptor antagonist. Gut androgen in the rat. Gastroenterology 1979; 76: 504-8. 1980; 21:187-91. 32Brittain RT, Daly MJ. A review of the animal pharma- 22Pounder RE, Williams JG, Hunt RH, Vincent SH, cology of ranitidine-a new selective histamine Milton-Thompson GJ, Misiewicz JJ. The effects of oral H2-antagonist. Drug Symposium on Ranitidine, IV cimetidine on food-stimulated gastric acid secretion and European Congress of Gastrointestinal Endoscopy, 14th 24-hour intragastric acidity. In: Burland WL, Alison June 1980, Hamburg. Simkins M, eds. Cimetidine. Amsterdam: Excerpta 33Graf KJ, von Kleist D, Meyer zum Buschenfelde KH. Medica, 1977; 189-204. Different effects of two histamine H2-receptor antagonists 23Blackwood WS, Northfield TC. Nocturnal gastric acid on prolactin secretion in man. Acta Endocr (Kbh) suppl secretion: effect of cimetidine and interaction with anti- 234,94:4. cholinergics. In: Burland WL, Alison Simkins M, eds. 34Spence RW, Celestin LR. Gynaecomastia associated with Cimetidine. Amsterdam: Excerpta Medica, 1977: 124-30. cimetidine. Gut 1979; 20: 154-7. 24Multicentre Trial. Comparison of two doses of cimetidine 11Stacher G, Steinringer H, Bauer P, Ehn I, Schmierer G. and placebo in the treatment of duodenal ulcer. Gut 1979; Die Wirkung von intramuskularem Pirzenzepin, Atropin 20:68-74. und Placebo auf die mahlzeitstimulierte Motilitat des 25Sewing K-Fr, Billian A, Malchow H. Comparative study Kolons. Eine Doppelblindstudie. In: Blum AL, Hammer of ranitidine and cimetidine on gastric secretion in normal R, eds. Die Behandlung des Ulcus pepticum mit volunteers. Gut 1980; 21: 750-2. Pirenzepin. Grafelfing: Demeter Verlag, 1979: 139-44. 26Konturek SJ, Obtulowicz W, Kwiecien N, Dobrzaniska M, `Fink M, Irwin P. EEG and behavioral effects of pirenze- Swierczek J, Knopp B, Oleksy J. Effects of pirenzepine pine in normal volunteers. ScandJ Gastroenterol 1980; 15: and atropine on gastric secretory and plasma hormonal suppl 66: 39-46. responses to sham-feeding in patients with duodenal ulcer. `Kitagawa H, Kurahashi K, Fijiwara M, Kohei H. Anti- Scand J Gastroenterol 1980; 15: suppl 66: 63-69. ulcerogenic effect of a pyrido-benzodiazepine derivative (L-S 519) on experimental ulcers. Arzneim Forsch 1978; 27Longstreth GF, Malagelada JR, Go VLW. Postprandial 28:2122-7. gastric, pancreatic, and biliary response to histamine H2- 3`Hammer R. Muscarinic receptors in the stomach. Scand J receptor antagonist in active duodenal ulcer. Gastro-

Gastroenterol 1980; 15: suppl 66: 5-12. http://gut.bmj.com/ enterology 1977; 72: 9-13. 39Langman MJS, Henry DA, Bell GC, Burnham WR, 28Konturek SJ, Obtulowicz W, Kwiecien N, Sito E, Mikos Ogilvy A. Cimetidine and ranitidine in duodenal ulcer. Br E, Oleksy J. Comparison of ranitidine and cimetidine in Med J 1980; 281: 473-4. the inhibition of histamine, sham-feeding, and meal- 'Ruddell WSJ, Axon ATR, Findlay JM, Bartholomew BA, induced gastric secretion in duodenal ulcer patients. Gut Hill MJ. Effect of cimetidine on the gastric bacterial flora. 1980; 21: 181-6. Lancet 1980; 1: 672-4. 29E1-Sabbagh HN, Bloom SR, Adrian TE, Prinz RA, Baron `Richardson CT, Bailey BA, Walsh JH, Fordtran JS. The JH, Welbourn RB. The effect of pirzenzepine on meal- effect of an H2-receptor antagonist on food-stimulated stimulated gastrointestinal hormones. Scand J Gastro- acid secretion, serum gastrin, and gastric emptying in on September 24, 2021 by guest. Protected copyright. enterol 1980; 15: suppl 66: 57-61. patients with duodenal ulcer. J Clin Invest 1975; 55: 30Kleinberg DL, Noel GL, Frantz AF. Chlorpromazine 536-42.