Sufotidine 600 Mg Bd Virtually Eliminates 24 Hour Intragastric Acidity in Duodenal Ulcer Subjects Gut: First Published As 10.1136/Gut.31.3.291 on 1 March 1990

Home , Sufotidine

Gut, 1990, 31, 291-293 291 Sufotidine 600 mg bd virtually eliminates 24 hour intragastric acidity in duodenal ulcer subjects Gut: first published as 10.1136/gut.31.3.291 on 1 March 1990. Downloaded from

J T L Smith, R E Pounder

Abstract (68 to 99-9 kg), their median height was 178 cm In a double blind study, 24 hour intragastric (164 to 189 cm), and two of the seven subjects acidity and 24 hour plasma gastrin concentra- smoked cigarettes (10 to 20 cigarettes per day). tions were measured simultaneously in seven Two other subjects withdrew from the study, duodenal ulcer subjects on the fifth day but both had been dosed only with placebo. The of receiving either sufotidine 600 mg bd or subjects were in symptomatic remission, and not placebo. Compared with placebo, during treat- taking antisecretory therapy. The study was ment with sufotidine 600 mg bd the median double blind, and dosing was given in a pre- integrated 24 hour intragastric acidity was determined random order. decreased by 95% (range 74% to 99%) from The subjects were studied twice, on the fifth 1000 to 51 mmol/h/l, whilst the median in- day ofdosing with either sufotidine 600 mg bd or tegrated 24 hour plasma gastrin concentration placebo. There was a nine day washout period increased from 416 to 927 pmol/h/l. between the studies, when the subjects received no treatment. Dosing was in the form of six identical tablets taken twice a day - at 0935 and First generation histamine H2-receptor blockers 1935 hours. Compliance with the dosing regimen cause a short lived pulse ofdecreased intragastric before the study day was encouraged by the use acidity.'1- Meta-analysis of the results of pub- of a long range paging system (British Telecom); lished studies has suggested that the more pro- each subject was paged at the recommended time found the drug induced decrease of nocturnal ofevery dose to remind him to take the tablets. intragastric acidity by a particular regimen, the The study was approved by the Ethics Com- greater the percentage of duodenal ulcers which mittee of the Royal Free Hospital and written are healed after four weeks oftreatment with that consent was obtained from each patient. Routine regimen. A new meta-analysis has suggested safety studies were performed before and after

that the four week duodenal ulcer healing rate treatment with both drugs. http://gut.bmj.com/ can be predicted most accurately by a drug's The subjects were studied using the Royal ability to maintain 24 hour intragastric pH above Free Hospital standard protocol for 24 hour 3 (H+ activity below 1 mmol/1),7 suggesting that studies.'6 They were admitted for each study control ofdaytime acidity may also be important. to a research ward after an overnight fast. A This finding is supported by the fact that the 10 French gauge salem sump nasogastric tube highest four week duodenal ulcer healing rates (Argyle Medical) was positioned in the stomach.

have been reported during treatment with 30 Aliquots (5-10 ml) of intragastric contents were on October 2, 2021 by guest. Protected copyright. to 40 mg/day of omeprazole,5 which inhibits aspirated hourly throughout the study (except at nocturnal and daytime acidity.9'0 Omeprazole 1000 and 2000 hours), and the pH ofeach aliquot has also had particular success in the manage- measured immediately to the nearest 0-01 pH ment of difficult duodenal ulceration, the more unit by means of a glass electrode and digital pH severe grades of oesophagitis, and the Zollinger meter (Radiometer, Copenhagen). The electrode Ellison syndrome," 14 because of the profound was calibrated with standard buffers (pH 7-00, antisecretory effect of this drug. 4-01, and 1-09: Radiometer, Copenhagen) before Sufotidine is a new competitive, long acting and halfway through each hourly batch of histamine H2-blocker.'5 Earlier healthy volunteer samples. studies, using single day dosing with sufotidine, Every hour from 0900 to 2400 hours, and two suggested that sufotidine 600 mg bd taken before hourly thereafter, blood was taken through a breakfast and at bed time could induce a sus- venous cannula for assay of plasma gasrin contained 24 hour decrease of acidity (J T L Smith centration. The blood was collected in lithium- and R E Pounder; H Merki; unpublished data). heparin tubes which contained 0-2 ml aprotinin The objectives of the present study were to (Trasylol, Bayer). The tubes were centrifuged observe the effects of repeat dosing with sufoti- immediately, the plasma transferred to plastic dine 600 mg bd on 24 hour intragastric acidity tubes and frozen to -20°C. All the plasma and plasma gastrin concentration in subjects samples from each subject were analysed for Academic Department of with a history of duodenal ulceration. in one Medicine, Royal Free gastrin batch, by radioimmunoassay Hospital School of using antibody GAS 179 in Professor Bloom's Medicine, London laboratory at the Hammersmith Hospital, J T L Smith Methods London. 17 R E Pounder During the study the subjects were fully Correspondence to: ENTS en- Dr R E Pounder, Royal Free PATI ambulant around the ward. The food and Hospital School of Medicine, Seven male subjects with a history ofendoscopic- vironmental conditions for both studies were Pond Street, London NW3 2QG ally confirmed duodenal ulceration completed identical to those used in earlier experiments at Accepted for publication the study; their median age was 53 years (range the Royal Free Hospital.'6 The following meals 6 June 1989 26 to 63 years), their median weight was 76 kg were served: breakfast, coffee, lunch, tea, dinner 292 Smith, Pounder

and plasma gastrin concentration was tested using Spearman rank correlation. Differences occurring with a probability of 5% of less were

considered significant. Gut: first published as 10.1136/gut.31.3.291 on 1 March 1990. Downloaded from

E Results E Two subjects withdrew from the study, but both : were found to be taking placebo. The remaining seven subjects completed each part of the study, and no clinically significant abnormality was observed in any of the routine haematology or biochemistry profiles, before or after dosing with either placebo or sufotidine.

9 10 11 12 13 14 15 16 17 18 19 2021 22 23 24 1 2 3 4 5 6 7 8 Time (h) INTRAGASTRIC ACIDITY Figure 1: Median hourly 24 hour intragastric acidity profile in seven subjects with a history of Figure 1 shows the hourly median intragastric duodenal ulcer on thefifth day ofdosing with placebo (-O* or sufotidine 600 mg bd (O-O). B=breakfast; C=coffee; L =lunch; T=tea; D=dinner; N=nightcap. acidity on the fifth day of dosing with either placebo or sufotidine 600 mg bd. It shows that during dosing with sufotidine 600 mg bd there and a bedtime snack at 0915, 1115, 1315, 1615, was a consistent and profound decrease ofacidity 1915, and 2215 hours, respectively. throughout the 24 hours. Figure 2 shows that the median integrated 24 hour intragastric for the seven duodenal STATISTICAL ANALYSIS acidity 1600 ulcer with a Twenty four hour profiles of intragastric acidity subjects history of duodenal ulcera- n=7 tion during dosing with placebo was 1000 and plasma gastrin concentration were obtained 1400 P<0 001 mmol/h/l (range618-1449 mmol/h/l). On thefifth for every subject in each study period. No gastric 1200\ day of dosing with sufotidine 600 mg bd, inte- aspirates were taken at 1000 or 2000 hours to grated 24 hour intragastric acidity was decreased avoid aspirating drug hence, to calculate the 1000 1000 in 24 hour integrated acidity profiles, intragastric every subject to a median value of 51 mmolIhIl E (range 5-158 mmol/h/l; 95%; p 0-001). For the acidity values of 1-30 and 0 13 mmol/l were used seven subjects the decreases of 24 hour intra- at these times, respectively. The 1 30 and 0-13 600-

gastric acidity ranged from 74% to 99%. http://gut.bmj.com/ mmol/l values represent the median intragastric The median intragastric acidity was above pH 400- acidity at 1000 and 2000 hours in 46 healthy 3 for 17% subjects, studied under identical conditions of the study, with an inter-subject 200 range of 8-33%. when receiving placebo at the Royal Free

0- 51 Hospital. The area under the time-concentration Placebo Suf 600mg bd curve for each profile was calculated by the Figure 2: Twentyfour hour PLASMA GASTRIN CONCENTRATION integrated intragastric trapezoid rule, with integrated acidity expressed The 24 hour profiles of median plasma gastrin on October 2, 2021 by guest. Protected copyright. acidity in seven subjects on as mmollhIl and integrated plasma gastrin as concentration on the fifth of thefifth day ofdosing with pmoIIhIl. To make these values comparable with day dosing with placebo or sufotidine 600 mg either placebo or sufotidine 600 mg bd are shown bd. single point measurements of either acidity or in Figure 3, which shows a consistent rise of gastrin, each value should be divided by 23. median plasma gastrin concentration throughout The significance of the difference between the the 24 hours during dosing with sufotidine. integrated 24 hour values were assessed using Figure 4 shows that the median integrated 24 Wilcoxon's matched-pair signed rank test. The hour plasma gastrin concentration for the seven correlation between integrated 24 hour acidity subjects during dosing with placebo was 416 pmoIIhIl (range 208-947 pmol/h/l); the concen- 80 tratons on the fifth day of dosing with sufotidine 600 mg bd had risen in every subject to a median 70- B C L of 927 pmol/h/Il (range 629-1951 pmol/h/l; p 0-001). 60-

50- RELATIONSHIPS BETWEEN 0 INTRAGASTRIC a ACIDITY AND PLASMA GASTRIN 40- ,' / , CONCENTRATIONS (D 30 C Figure 5 shows a non-significant inverse correlation between integrated 24 hour intragastric acidity and integrated 24 hour plasma gastrin concentration in the 14 paired data sets from this study (r,=0 4418; p=0 1 14).

01 . , I I I 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6 7 8 Time (h) Discussion Figure 3: Median 24 hourplasma gastrin concentration profile in seven subjects on thefifth day ofdosing with placebo (- or sufotidine 600 mg bd (O----0). B=breakfast; C=coffee; This study shows that a twice daily regimen L =lunch; T=tea; D=dinner; N=nightcap. using an H2-blocker is capable of produc- Acid inhibition with sufotidine 293

2000 n=7 2500 p< 0.001 n=7 p=0-114 1500- 2000 0 0 E X Gut: first published as 10.1136/gut.31.3.291 on 1 March 1990. Downloaded from 1000 927 0 (9~~~~~~~2 1500 E 500- 416 *' 1000 o @0 0- 0000 Placebo Suf 600mg bd 0 Figure 4: Twentyfour hour 500 0 integrated plasma gastrin concentration in seven *. X subjects on thefifth day of dosing with placebo or O . sufotidine 600 mg bd. 0 200 400 600 800 1000 1200 1400 1600 Acidity (mmol/h/l) Figure 5: Correlation between 24 hour integrated intragastric acidity and 24 hour integrated plasma gastrin concentration in seven subjects, during dosing with placebo (0) or sufotidine 600 mgbd(O).

ing virtual elimination of intragastric acidity 4 Lanzon-Miller S, Pounder RE, Ball SG, Dalgleish DJ, Coward J, Jackson AO. The effects of famotidine, 40 mg at throughout the day and night in subjects with a night, on 24-hour intragastric acidity and plasma gastrin history ofduodenal ulceration. Hitherto, studies concentration in healthy subjects. Scand J Gastroenterol 1988; 23: 244-50. using twice daily regimens of H2-blockers have 5 Lanzon-Miller S, Pounder RE, Chronos NAF, Raymond F, failed to control day time acidity, particularly in Hamilton MR, Dalgleish D. 24-hour intragastric acidity and plasma gastrin concentration in healthy volunteers taking the late afternoon.' 2 nizatidine 150 mg, nizatidine 300 mg, ranitidine 300 mg, or The subjects in this study responded to dosing placebo at 2100h. Gut 1988; 29: 1364-9. 6 Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. with sufotidine with a median 95% decrease of24 Acid suppression in duodenal ulcer: a meta-analysis to define hour acidity, ranging from 74% to 99%. When optimal dosing with antisecretory drugs. Gut 1987; 28: 1120-7. 12 duodenal ulcer patients were dosed with 7 Chiverton SG, Burget DW, Hunt RH. A meta-analysis omeprazole 20 mg daily for a month under to predict duodenal ulcer healing from acid suppression [Abstract]. Gastroenterology 1988; 94: A68. identical conditions at the Royal Free Hospital, 8 Pounder RE. The pharmacological control of gastric acid they showed a median 97% decrease of 24 hour secretion. In: Pounder RE, ed. Recent advances in gastro- but enterology - 7. Edinburgh: Churchill Livingstone, 1988: acidity, their individual responses ranged 245-60. http://gut.bmj.com/ from 30% to 100%.9 When higher doses of 9 Sharma BK, Walt RP, Pounder RE, Gomes M de FA, Wood EC, Logan LH. Optimal dose of oral omeprazole for omeprazole are given (30 mg/day, or more), maximal 24 hour decrease of intragastric acidity. Gut 1984; all patients respond with a consistency similar to 25: 957-64. 10 Lanzon-Miller S, Pounder RE, Hamilton MR, et al. Twenty- that seen with sufotidine 600 mg bd.5 four hour intragastric acidity and plasma gastrin concentra- Five days of dosing with sufotidine 600 mg bd tion before and during treatment with either ranitidine or omeprazole. Aliment Pharnacol Therap 1987; 1: 239- were tolerated without any adverse reaction by 52. the seven subjects. The present and 11 Tytgat GNJ, Lamers CBHW, Hameeteman W, Jansen regimen JMBJ, on October 2, 2021 by guest. Protected copyright. Wilson JA. Omeprazole in peptic ulcers resistant to hista- lower dose regimens are suitable for testing mine H2-receptor antagonists. Aliment Pharnacol Therap by clinical trial for their use in the treat- 1987; 1: 31-8. 12 Hinchliffe RFC, Thompson M, Morris P, Daly MJ, Carroll ment of resistant peptic ulceration, and severe NJH, Walan A. Treatment of refractory peptic ulcer with oesophagitis. omeprazole [Abstract]. Gut 1988; 29: A724. 13 Hetzel DJ, Dent J. Oesophageal disease. In: Pounder RE, ed. Supplies of sufotidine and placebo, and financial support, were Recent advances in gastroenterology - 7. Edinburgh: Churchill provided by Glaxo Group Research Ltd. Ms Doris Elliott pre- Livingstone, 1988: 261-89. pared this manuscript. Technical assistance for this study was 14 Lloyd-Davies KA, Rutgersson K, Solvell L. Omeprazole in provided by D Smart, J Sercombe, P Braidley, J Coward, the treatment of Zollinger-Ellison syndrome: a 4-year D Dalgleish, A Jackson, R Walker. international study. Aliment Pharmacol Therap 1982; 2: 13- 1 Pounder RE, Williams JG, Milton-Thompson GJ, Misiewicz 32. JJ. Twenty-four hour control of intragastric acidity by 15 Humphray JM, Bays DE, Brittain, RT, Reaves JJ, Stables R. cimetidine in duodenal ulcer patients. Lancet 1975; ii: 1069- Sufotidine: a competitive and long-acting H2-antagonist 72. [Abstract]. Br Pharmnacol Soc 1988: C54. 2 Walt RP, Male PJ, Rawlings J, Hunt RN, Milton-Thompson 16 Lanzon-Miller S, Pounder RE, Hamilton MR, et al. Twenty- GJ, Misiewicz Jj. Comparison of the effects of ranitidine, four hour intragastric acidity and plasma gastrin concentra- cimetidine and placebo on the 24 hour intragastric acidity tion in healthy subjects and patients with duodenal or gastric and nocturnal acid secretion in patients with duodenal ulcer. ulcer, or pernicious anaemia. Aliment Pharmacol Therap Gut 1981; 22: 49-54. 1987; 1: 228-38. 3 Gledhill T, Howard OM, Buck M, Paul A, Hunt RH. Single 17 Bryant MG, Adrian TE. Gastrin. In: Bloom SR, Long RG, nocturnal doses of an H2-receptor antagonist for the treat- eds. Radioimmunoassay of gut regulatory peptides. London: ment of duodenal ulcer. Gut 1983; 24: 904-8. Saunders, 1982: 51-9.