Aliment. Pharmacal. Ther. (1992) 6, 609-618.
The effect of combined therapy with ranitidine and pirenzepine in the treatment of reflux oesophagit is
W. L O N D O N G * , J. PHILLIPSt, N. J. J O H N S O N t & J. R. W O O D t * 2nd Medical Deparfmenf,Krankenhaus a m Urban, Berlin, FRG, t Division of Gastroenterology, Glaxo Group Research Ltd, Greenford, Middlesex, U K Accepted for publication 1 May 1992
SUMMARY
The combination of a histamine H,-receptor antagonist and a muscarinic receptor antagonist has been reported to result in greater suppression of intragastric acidity than either agent alone. The present randomized, double-blind, multicentre trial compared the effects of the oral combination of 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. in the treatment of patients with reflux oesophagitis. All 157 patients had symptoms of gastro-oesophageal reflux with endoscopically confirmed oesophageal erosions (Savary and Miller grades 1-111). After four weeks of treatment, healing rates were 32/75 (43 %) in the combined treatment group and 34/76 (45 %) in the group receiving ranitidine alone. After eight weeks, the cumulative healing rates had increased to 48/72 (67%) and 51/75 (68%), respectively. More patients receiving ranitidine plus pirenzepine had complete relief of day- and night-time heartburn after four weeks compared with those receiving ranitidine alone (day: 59% vs. 38%, P = 0.02; night: 69 % vs. 52 %, P = 0.04). After eight weeks, symptom relief was comparable in both groups. Clinical adverse effects were reported by Correspondence to Professor Dr W. Londong, 2nd Medical Department, Krankenhaus am Urban, Dieffenbachstrasse I,D-1000 Berlin I, FRG. 609
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W. L O N D O N G ef aI. nine patients receiving ranitidine and by 19 patients receiving the combination. It is concluded that combining ranitidine with pirenzepine does not aid the healing of reflux oesophagitis but does improve symptom relief at four weeks.
INTRODUCTION The reflux of gastric contents into the lower oesophagus is a major factor in the pathogenesis of reflux oesophagitis.' As shown in six controlled trials, the histamine H,-receptor antagonist ranitidine accelerates the healing of reflux oesophagitis, but healing rates with 150 mg ranitidine b.d. were only 27-43 % after four weeks and 38-56% after eight Increasing the ranitidine dose to 300 mg b.d. does not improve the results,8-'' whereas 300 mg q.d.s. resulted in a more rapid healing and symptom relief of patients with reflux oesophagitis.6 In contrast to ranitidine, the anti-muscarinic agent pirenzepine has little effect on intragastric acidity.l2-I4 Pirenzepine given at recommended oral doses has no influence on oesophageal m ~ t i l i t y ' ~ and - ' ~ has seldom been tested as a treatment for reflux oesophagitis." Combined administration of therapeutic doses of ranitidine and pirenzepine has been shown in man to result in a significantly greater suppression of foodstimulated gastric acid secretion than either drug a l ~ n e , ' ~ and ~ ~ ' 'in a significant increase in 24-h intragastric pH over that achieved by ranitidine In addition, a combination of the two drugs produced a marked reduction of gastro-oesophageal reflux in patients with moderate to severe reflux oesophagitis." Such a combination may thus prove beneficial in the treatment of acid-peptic disease. The present study was undertaken to test this hypothesis. It was the aim of this randomized, double-blind, multi-centre trial to compare the efficacy and safety of a combination of 150 mg ranitidine b.d. and 50 mg pirenzepine b.d. with ranitidine alone in the treatment of patients with reflux oesophagitis. PATIENTS A N D M E T H O D S This controlled and randomized study was conducted in 22 centres in Germany, Holland, Ireland, and the UK. Patients with symptomatic and endoscopically proven reflux oesophagitis were recruited. The study was conducted in accordance with the Declaration of Helsinki, Venice Modification 1988. Ethics committee approval was obtained in each of the participating countries. Informed consent was given by all patients entering the study.
Sample size Before starting the trial a sample-size estimation predicted cumulative eight-week healing rates of 40% for 150 mg ranitidine b.d. alone and 65 % for 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. To detect such a difference at the 5 % significance
RANITIDINE P L U S PIRENZEPINE IN O E S O P H A G I T I S
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level with 8 0 % power a sample of at least 120 patients would be required. It was expected that approximately 20 Yo of patients might contribute un-evaluable data. Therefore, it was planned to recruit a minimum of 150 patients (75 per treatment group).
Paf ienfs Out-patients aged 18 years and over with a history of gastro-oesophageal reflux symptoms (heartburn, regurgitation, epigastric pain, odynophagia) and endoscopic confirmation of oesophagitis grades I-IIIz2 were selected for inclusion. The visual appearance of the oesophageal mucosa was to be assessed by the same endoscopist at each visit and graded according to the following criteria: grade 0, normal mucosa; grade I, one or more non-confluent mucosal erosions with erythema or exudate or superficial lesions above the gastro-oesophageal junction ; grade 11, confluent erosive and exudative mucosal lesions not covering the entire circumference of the oesophagus ; grade 111, circumferential erosive and exudative lesions covering the whole oesophageal mucous membrane. Endoscopy had to be performed within four days of starting study medication. Exclusion criteria were: age less than 18 years, patients with grade IV oesophagitis” (chronic mucosal lesion, i.e. ulcer, stricture or Barrett’s oesophagus), night-shift workers and patients unable to keep to the medication times, pregnant or lactating women, pre-menopausal women not using adequate contraception, patients with severe cardiovascular, pulmonary, hepatic, renal or metabolic disease, prior oesophageal or gastric surgery, pretreatment with any peptic ulcer medication other than occasional antacids or alginates during the week prior to study entry, concomitant treatment with drugs affecting the lower oesophageal sphincter tonicity such as metoclopramide, domperidone, cisapride or bethanechol, evidence of glaucoma or obstruction of urinary outflow, and patients whom the investigator considered likely to be non-compliant.
Assessments and medication At the first visit a physical examination was performed and concurrent medication reviewed. A venous blood sample was taken for haematological and biochemical analysis at the first and last visit. Following endoscopic diagnosis and standardized documentation of demographic data, symptom assessment, endoscopic findings, and laboratory screen, each patient was randomly allocated to oral treatment with either 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. or 150 mg ranitidine b.d. plus placebo pirenzepine b.d. (at breakfast and at bedtime). The randomization was in a block size of 6 patients per centre using a computer-generated random code. Patients were given medication for each treatment period at follow-up examinations (72 tablets each for ranitidine, pirenzepine or pirenzepine placebo). Ranitidine was available as plain white oval tablets containing 150 mg ranitidine. Pirenzepine (or identical placebo) was available as plain white tablets containing 50 mg pirenzepine. Patients were advised to elevate their sleeping position and also to stop smoking, lose excess weight and avoid heavy meals, especially at night.
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Follow-up evaluations including overall assessment of symptoms, cardiovascular parameters, endoscopy, adverse events, and compliance checks were to be carried out at 28 & 4 and 56 4 days of treatment. Adverse events were volunteered by the patient and elicited by the investigator through the use of standard questions. The amount of unused study drug was recorded at each visit to assess compliance. The day- and nighttime severity of specific reflux symptoms experienced by the patient over the previous seven days was recorded by the investigator. Heartburn, acid regurgitation, and epigastric pain were graded as either no symptoms (grade 0 ) ; mild, i.e. occasional episodes (grade I);moderate, i.e. troublesome but not debilitating attacks (grade 2) ; or severe,-that is, completely debilitating attacks (grade 3). The presence of odynophagia was also recorded.
Statistical evaluation All patients with evaluable endoscopy and/or symptom data were included in the analysis of efficacy (modified intent-to-treat analysis). Safety data were collected and analysed for all treated patients. The data were statistically evaluated by Glaxo Group Research, UK. Oesophagitis healing after four weeks and cumulatively after eight weeks was compared using the Mantel-Haenszel test without continuity correction for differences between treatments adjusted for pre-treatment grade ;the 5 % level of significance was applied. The 95 % C.I. for differences were based on the calculation of relative odds. The proportion of patients who reported total remission of reflux symptoms at the four- and eight-week visits was compared statistic. Summary statistics were calculated for using the Mantel-Haenszel standardized laboratory values using analysis of covariance and log transformation to correct for any non-normality.
x2
xz
RESULTS One hundred and fifty-seven patients entered the study. Seventy-nine were allocated to receive 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. and 78 150 mg ranitidine b.d. plus placebo pirenzepine b.d. The two treatment groups were well balanced at study entry (Table I), with the exception of the incidence of epigastric pain and odynophagia. The proportion of patients with no and moderate epigastric pain was 11of 79 and 35 of 79 patients (for ranitidine plus pirenzepine) us. 24 of 78 and 24 of 78 patients (for ranitidine), respectively. The incidence of odynophagia was 15/79 vs. 26/78, respectively. Ten patients (6.4%) were excluded from the analysis. Five patients were lost to follow-up (ranitidine plus pirenzepine: n = 3, ranitidine plus placebo: M = 2). Five patients were excluded due to adverse events (ranitidine plus pirenzepine: M = 4, ranitidine plus placebo: n = 1). The compliance of the patients assessed by counting returned medication after four (2 = 96 to 98%) and eight weeks (2 = 98 to 100%) was good.
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Table 1. Baseline characteristics of the study population Ranitidine (150 mg) b.d. pirenzipine (50 mg) b.d. (n = 79)
Ranitidine (150 mg) b.d. pirenzipine (placebo) b.d.
49.5 k 16.1 49 :30 77.5 k 18.3 20:59 40:39 3.0
52.3 15.4 47:31 76.5 f13.7 25 :53 43:35 3.0 0.8-5.0 91 28-152 40 29:34: 15
+
Mean age (years fS.D.) Gender (male:female) Weight (kg fS.D.) Smokers :non-smokers Alcohol :no alcohol Duration of disease (years in i and IQR)" Current episode (days in I and IQR)" Hiatus hernia Oesophagitis grades I :I1 :I11 * IQR
= inter-quartile
1.0-6.0 91 28-183 45 31 :36: 12
+
( n = 78)
range.
Oesophagifis healing The healing rates shown in Table 2 are comparable for the two treatment groups. In the analysis oesophagitis had healed in 32 of 75 (43%) and 48 of 72 patients (67%) treated with ranitidine plus pirenzepine compared with 34 of 76 (45 Yo) and 51 of 75 patients (68%) treated with ranitidine plus placebo pirenzepine after four and cumulatively eight weeks of treatment. No statistically significant difference was found either after four weeks ( P = 0.80, odds ratio 0.92, 95 % C.I. 0.48-1.75) or eight weeks (P = 0.86, odds ratio 0.94, 95 % C.I. 0.47-1.88). In a sub-analysis the relative efficacy of treatments was found to be unrelated to pre-treatment Table 2. Four- and cumulative eight-week healing (number of patients with healed oesophagitis/number of patients evaluated; healing rates in brackets) and relative odds, stratified according to pre-treatment oesophagitis grade Ranitidine (150 mg) b.d. pirenzipine (50 mg) b.d.
Ranitidine (150 mg) b.d. pirenzipine (placebo) b.d.
32/75 13/28 16/35 3/12
(43%) (46%) (46%) (25 %)
34/76 16/27 15/34 3/15
(45 %) (59%) (44%) (20%)
0.92 (0.48-1.75) 0.60 (0.20-1.73) 1.07 (0.41-2.75) 1.33 (0.22-8.22)
48/72 (67%) 19/27 (70%) 26/34 (77%) 3/11 (270/)
51/75 25/27 21/33 5/15
(68%) (93%) (64%) (33%)
0.94 (0.47-1.88) 0.19 (0.04-1.00) 1.86 (0.64-5.38) 0.75 (0.14-4.13)
+
+
Relative Odds" (95 % C.I.)
4 weeks
All patients Grade I Grade I1 Grade 111 8 weeks All patients Grade I Grade I1 Grade 111
' Relative odds for healing on the combination.
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endoscopy grade at four weeks (P = 0.65), but approached statistical significance at eight weeks (P = 0.06). As is also shown in Table 2, the two treatments resulted in similar healing rates for the subgroups stratified for endoscopic grade at entry. Again, the differences proved not to be significant.
Symptom relief All patients in both treatment groups had daytime symptoms of gastro-oesophageal reflux. Sixty-eight of 79 patients (86%)in the combination group and 64 of 78 patients (82 Yo) in the ranitidine group also had nocturnal symptoms. Severity assessment of heartburn and regurgitation revealed comparability of the two groups. The relative efficacy of the two treatments for the remission of diurnal and nocturnal symptoms (heartburn, regurgitation, and epigastric pain) was not significantly dependent upon pre-treatment severity. Overall, there were lower frequencies of day- and nighttime symptoms in the combined treated group after four weeks of treatment (Fig. I); significantly more patients receiving ranitidine plus pirenzepine had complete relief of day- and nighttime heartburn compared with those receiving ranitidine alone (day: 39 of 66 patients (59%) us. 24 of 63 patients (38%), odds ratio 0.42, 95% C.I. 0.21-0.85, P = 0.02; night: 38 of 55 patients (69%) US. 27 of 52 patients (52%),odds ratio 0.42,95 % C.I. 0.18-0.96, P = 0.04). At four weeks more patients receiving ranitidine plus pirenzepine experienced complete relief of regurgitation (Fig. 1; day: 37 of 66 patients (56%) us. 27 of 64 patients (42%), odds ratio 0.57, 95% C.I. 0.29-1.15, P = 0.12; night: 39 of 57 patients (68%) us. 28 of 49 patients (57%), odds ratio 0.58, 95% C.I. 0.26-1.35; P = 0.20) and epigastric pain (Fig. I) (day: 37 of 5 7 patients (65%) vs. 29 of 53 patients (55%), odds ratio 0.70, 95% C.I. 0.31-1.60, P = 0.40; night: 41 of 49
~
. . ..
..... ... .. .. ..
... .......... .. .. ........ ..... ..... .
Heartburn
Regurgitation
.
I
Epigastric pain
Figure 1. Symptom relief after four weeks of treatment with 150 mg ranitidine b.d. plus pirenzepine placebo b.d. (diurnal relief: white bars, n = 63 with heartburn, n = 64 with regurgitation, and n = 53 with epigastric pain; nocturnal relief: dotted bars, n = 52, n = 49, and n = 38, respectively) and with 150 mg ranitidine b.d. plus 50 mg pirenzepine (diurnal: hatched bars, n = 66 with heartburn, n = 66 with regurgitation, and n = 5 7 with epigastric pain; nocturnal: black bars, n = 55, n = 57, and n = 49, respec*P = tive1y)-+" P = 0.02, 0.04.
RANITIDINE PLUS PIRENZEPINE I N O E S O P H A G I T I S Figure 2. Symptom relief after eight weeks of treatment with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. (diurnal relief: white bars, n = 37 with heartburn, n = 37 with regurgitation, n = 30 with epigastric pain; nocturnal relief: dotted bars, n = 32, n = 31, and n = 23, respectively) and with 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. (diurnal: hatched bars, n = 31 with heartburn, n = 36 with regurgitation, and n = 30 with epigastric pain; nocturnal : black bars, n = 25, n = 28, and n = 23, respectively).
615
... ... ... .. .. .. ...
... ... .. ..... .. .. .. ... ........ ....... .. .. .. Heartburn
Regurgitation
.. .. .. .. .. .. ...
...
.. .. .. ...
.......... ..... ........ ...
Epigastric pain
patients (84%) us. 29 of 38 patients (76%), odds ratio 0.63, 95% C.I. 0.21-1.84, P = 0.40) than those receiving ranitidine alone, but these differences were not significant. The incidence of odynophagia was reduced after four weeks of treatment to 5 % and 7% in the combined-treated and ranitidine-treated groups, respectively ( P = 1.00). After eight weeks of treatment symptom relief was comparable in both groups; however, the number of patients per group assessed at eight weeks was reduced (Fig. 2).
Safety assessment Clinical adverse events were reported by nine patients receiving ranitidine and 19 patients receiving ranitidine plus pirenzepine. More events were reported by patients in the combination group (38 us. 10 events). The investigators considered clinical events to be possibly related to treatment in 13 of the 19 patients in the ranitidine plus pirenzepine group and in two of the nine patients in the ranitidine group. Seven of the 79 patients receiving the combination experienced minor anticholinergic symptoms such as visual disturbances and dryness of mouth compared with one patient in the ranitidine group. However, none of these symptoms necessitated patient withdrawal. Blood pressure and pulse rate were not significantly affected by trial medication in either treatment group. Population summary statistics revealed no evidence of any clinically important effect of either treatment on any haematological or biochemical value.
DISCUSSION The results of this study indicate that the combined ranitidine and pirenzepine 33
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regimen is no more effective than the same dose of ranitidine given alone in healing reflux oesophagitis. Thus, this result seems not to confirm our hypothesis that such a combined treatment would increase the healing of reflux oesophagitis due to stronger gastric acid i n h i b i t i ~ n " (and ~ ~ lower intragastric acidity," which should reduce the oesophageal mucosal damage resulting from exposure to the acidic refluxate. The observed healing rates for 150 mg ranitidine b.d. after four and eight weeks of treatment are higher than predicted (40 % for eight weeks) and higher than those reported in previous studies. In six controlled and randomized trials median healing rates for 150 mg ranitidine b.d. of 34 % (range 27-43 %) at four weeks, and of 52 % (38-56%) at eight weeks have been published (Refs 2-7; data are cited as results of intent-to-treat analyses). In these most of the patients with oesophagitis graded I1 or I11 had been treated. Two studies4r7included patients with grade IV, which was defined as patients with oesophageal stricture not requiring dilatation; one study5 also included patients with grade I and documented healing rates of 37% at four and 54% at eight weeks for grade I to I11 compared to 26% and 39% respectively, for grades I1 and 111. In two other studies higher healing rates have been reported when only patients with grades I and I1 were treated with 150 mg ranitidine b.d.23~"4 In the present study most of our patients were stratified to oesophagitis grades I and I1 (Table I); this may account for higher than predicted healing rates with 150 mg ranitidine b.d. The combination of ranitidine and pirenzepine has a more marked effect on acid secretion and intragastric acidity than 150 mg ranitidine b.d. and, in this study, was associated with improved symptom relief after four weeks (Fig, I). In particular, there was a significant improvement in the relief of diurnal and nocturnal heartburn. However, by eight weeks symptom relief was comparable between the two treatment regimens (Fig. 2). In this connection, it has to be mentioned that only those patients receiving eight weeks of treatment were included in the analysis for symptom relief and so the numbers of patients per group were reduced. A similar improvement in symptom relief over standard dose is seen, if the dose of ranitidine is increased to 300 mg b.d.,25but again this is not associated with a substantial improvement in the proportion of patients with healed oesophagitis. Overall, our data confirm that resolution of reflux symptoms does ~? not correlate well with the healing of the oesophageal m u c o ~ a .9!26 The ranitidine and pirenzepine treatment regimens were well tolerated, and not associated with any abnormalities of cardiovascular or laboratory parameters. There was a higher frequency of adverse events reported in the combination group, and some patients reported clinical events consistent with anticholinergic therapy, but none necessitated patient withdrawal. The results show that combined treatment wikh ranitidine and pirenzepine improves symptom relief, especially heartburn, after four weeks, in patients with reflux oesophagitis. However, this is not associated with any increase in healing rate compared to that achieved with ranitidine alone. By eight weeks, neither
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healing rates nor symptom relief was significantly different between the two groups. The response to 150 mg ranitidine b.d. was good, and it may be that in this population any additive effect of pirenzepine on gastric acid suppression was insufficient to further enhance healing. Additional studies may clarify this.
ACKNOWLEDGEMENTS
The authors would like to thank the following investigators who participated in this study: Drs S. Ahnefeld, A. Ansari, U. Bar, S. Consemiiller, A. Dettmer, H. Frotz, W. Hochter, R. Kunze, L. Witzel (Germany); Drs F. Gleeson, J. Hegarty, T. O’Callaghan (Ireland); Drs P. M. de Vries, H.Geldof, K.Jie, D. L. van der Linde (The Netherlands); and Drs D. Hollanders, J. G. C. Kingham, J. P. Miller, R. P. H. Thompson, P. J. Whorwell, K. G. Wormsley (UK). We are also grateful to Dr R. Kullmann, Boehringer Ingelheim, Ingelheim, and Dr 0.Tauber, Dr. Karl Thomae GmbH, Biberach, Germany, for providing pirenzepine (and identical placebo) tablets. This study is dedicated to Professor Dr. M. M. Forell, Munich, on the occasion of his 75th birthday. REFERENCES 1 Gotley D C, Morgan A P, Ball D, Owen
R W, Cooper M J. Composition of gastrooesophageal refluxate. Gut 1991; 32: 1093-9. 2 Klinkenberg-Knol E C,
Jansen J M B J, Festen H P M, Meuwissen, S G M, Lamers C B H W. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet
1987; i: 349-51. 3 Havelund T, Laursen L S, Skoubo-Kristensen E ef al. Omeprazole and ranitidine in treatment of reflux oesophagitis : double blind comparative trial. Br Med J 1988; 296: 8992. 4 Sandmark S, Carlsson R, Fausa 0,Lundell L.
Omeprazole or ranitidine in the treatment of reflux esophagitis. Scand J Gastroenterol 1988; 23: 625-32. 5 Vantrappen G, Rutgeerts L, Schurmans P, Coenegrachts J-L. Omeprazole (40 mg) is
superior to ranitidine in short-term treatment of ulcerative reflux esophagitis. Dig Dis Sci 1988; 33 : 523-9. 6 Johnson N J, Boyd E J S, Mills J G, Wood J R. Acute treatment of reflux oesophagitis :
a multicentre trial to compare 150 mg ranimacol Ther 1989; 3 : 259-66. 7 Zeitoun P, Rampal P, Barbier P, Isal JP, Eriksson S, Carlsson R. Omeprazole versus ranitidine in erosive reflux oesophagitis. Gastroenterol Clin Biol 1989; 13 : 457-62. 8 Koelz H R, Birchler R, Bretholz A ef a1. Healing and relapse of reflux esophagitis during treatment with ranitidine. Gastroenterology 1986; 91: 1198-205. 9 Schaub N, Meyrick Thomas J, Misiewicz J J, Love11 D, Trotman I F. Investigation of ranitidine 150 mg b.d. or 300 mg b.d. in the
treatment of reflux disease. Hepato-Gastroenterol 1986; 33 : 208-13. LO Robertson D A F, Aldersley M A, Shepherd H, Lloyd R S, Smith C L. HI-antagonists in oesophagitis : can physiological studies predict the response? Gut 1987; 28: 9469. L 1 Bianchi Porro G, Pace F, Lazzaroni M.
Esophagitis healing with ranitidine. Gastroenterology 1987; 92: 2051-2. L2 Etienne A, Fimmel C J, Bron B A, Loizeau E, Blum A L. Evaluation of pirenzepine on gastric acidity in healthy volunteers using am33-2
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bulatory 24 hour intragastric pH monitoring. Gut 1985; 26: 241-5. 13 Mahachai V, Reill P, Thomson A B R. Comparative effects of pirenzepine alone and in combination on 24-hour gastric acidity in duodenal ulcer disease. Clin Ther 1984; 7: 98-1 11. 14 Williams J G, Deakin M, Ramage J K. Effect
of cimetidine and pirenzepine in combination on 24 hour intragastric acidity in subjects with previous duodenal ulcer. Gut 1986; 27: 428-32. 15 Dent J. Muscarinic receptors and esophageal motor function. Trends Pharmacol Sci 1984; (Suppl): 82-6. 16 Blackwell J N, Dalton C B, Castell D 0.
Pirenzepine does not affect esophageal pressures in man. Dig Dis Sci 1986; 31: 230-5. 17 Soffer E E, Kumar D, Mridha K, Das-Gupta A, Britto J, Wingate D L. Effect of pirenzepine on oesophageal, gastric, and enteric motor function in man. Scand J Gastroenter01 1988; 23: 146-50. 18 Niemela S, Jaaskelainen T, Lehtola J ef al. Pirenzepine in the treatment of reflux oesphagitis. A placebo-controlled, doubleblind study. Scand J Gastroenterol 1986;21 : 1193-9. 19 Londong W, Londong V, Ruthe C, Weizert P. Complete inhibition of food-stimulated
gastric acid secretion by combined application of pirenzepine and ranitidine. Gut 1981; 22: 542-8.
20 Lazzaroni M, Sangaletti 0, Parente F ef a/.
Inhibition of food stimulated acid secretion by association of pirenzepine and ranitidine in duodenal ulcer patients. Int J Clin Pharmacol Ther Tox 1986; 24 (Suppl. 2 2 ) : 685-8. 21 Londong W, Federle C, Richter W, Schindlbeck N E, Miiller-Lissner S A. Effect of combined ranitidine and pirenzepine on gastric pH: potential treatment for gastro-oesophageal reflux. Eur J Gastroenterol Hepatol 1990; 2: 119-25. 22 Savary M, Miller G. Der osophagus. In:
Lehrbuch und endoskopischer Atlas. Solothurn: AG Gassmann, 1977, 119-27. 23 Kimmig J G. Cimetidin und Ranitidin in der Behandlung der Refluxosophagitis. Z Gastroenterol 1984; 22: 373-8. 24 Rohner H G, Wienbeck M, RAN 2-1 Studiengruppe. Zwei oder eine Tagesdosis Ranitidin zur Behandlung der Refluxosophagitis. Z Gastroenterol 1986; 24: 396402. 25 Johnson N J, Laws S, Mills J G, Wood J R. Effect of three ranitidine dosage regimens in the treatment of reflux oesophagitis : results of a multi-centre trial. Eur J Gastroenterol Hepato1 1991; 3 : 759-74. 26 Sontag S J. The medical management of re-
flux esophagitis. Role of antacids and acid inhibition. Gastroenterol Clin North Am 1990: 19: 683-712.
The effect of combined therapy with ranitidine and pirenzepine in the treatment of reflux oesophagit is
W. L O N D O N G * , J. PHILLIPSt, N. J. J O H N S O N t & J. R. W O O D t * 2nd Medical Deparfmenf,Krankenhaus a m Urban, Berlin, FRG, t Division of Gastroenterology, Glaxo Group Research Ltd, Greenford, Middlesex, U K Accepted for publication 1 May 1992
SUMMARY
The combination of a histamine H,-receptor antagonist and a muscarinic receptor antagonist has been reported to result in greater suppression of intragastric acidity than either agent alone. The present randomized, double-blind, multicentre trial compared the effects of the oral combination of 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. in the treatment of patients with reflux oesophagitis. All 157 patients had symptoms of gastro-oesophageal reflux with endoscopically confirmed oesophageal erosions (Savary and Miller grades 1-111). After four weeks of treatment, healing rates were 32/75 (43 %) in the combined treatment group and 34/76 (45 %) in the group receiving ranitidine alone. After eight weeks, the cumulative healing rates had increased to 48/72 (67%) and 51/75 (68%), respectively. More patients receiving ranitidine plus pirenzepine had complete relief of day- and night-time heartburn after four weeks compared with those receiving ranitidine alone (day: 59% vs. 38%, P = 0.02; night: 69 % vs. 52 %, P = 0.04). After eight weeks, symptom relief was comparable in both groups. Clinical adverse effects were reported by Correspondence to Professor Dr W. Londong, 2nd Medical Department, Krankenhaus am Urban, Dieffenbachstrasse I,D-1000 Berlin I, FRG. 609
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W. L O N D O N G ef aI. nine patients receiving ranitidine and by 19 patients receiving the combination. It is concluded that combining ranitidine with pirenzepine does not aid the healing of reflux oesophagitis but does improve symptom relief at four weeks.
INTRODUCTION The reflux of gastric contents into the lower oesophagus is a major factor in the pathogenesis of reflux oesophagitis.' As shown in six controlled trials, the histamine H,-receptor antagonist ranitidine accelerates the healing of reflux oesophagitis, but healing rates with 150 mg ranitidine b.d. were only 27-43 % after four weeks and 38-56% after eight Increasing the ranitidine dose to 300 mg b.d. does not improve the results,8-'' whereas 300 mg q.d.s. resulted in a more rapid healing and symptom relief of patients with reflux oesophagitis.6 In contrast to ranitidine, the anti-muscarinic agent pirenzepine has little effect on intragastric acidity.l2-I4 Pirenzepine given at recommended oral doses has no influence on oesophageal m ~ t i l i t y ' ~ and - ' ~ has seldom been tested as a treatment for reflux oesophagitis." Combined administration of therapeutic doses of ranitidine and pirenzepine has been shown in man to result in a significantly greater suppression of foodstimulated gastric acid secretion than either drug a l ~ n e , ' ~ and ~ ~ ' 'in a significant increase in 24-h intragastric pH over that achieved by ranitidine In addition, a combination of the two drugs produced a marked reduction of gastro-oesophageal reflux in patients with moderate to severe reflux oesophagitis." Such a combination may thus prove beneficial in the treatment of acid-peptic disease. The present study was undertaken to test this hypothesis. It was the aim of this randomized, double-blind, multi-centre trial to compare the efficacy and safety of a combination of 150 mg ranitidine b.d. and 50 mg pirenzepine b.d. with ranitidine alone in the treatment of patients with reflux oesophagitis. PATIENTS A N D M E T H O D S This controlled and randomized study was conducted in 22 centres in Germany, Holland, Ireland, and the UK. Patients with symptomatic and endoscopically proven reflux oesophagitis were recruited. The study was conducted in accordance with the Declaration of Helsinki, Venice Modification 1988. Ethics committee approval was obtained in each of the participating countries. Informed consent was given by all patients entering the study.
Sample size Before starting the trial a sample-size estimation predicted cumulative eight-week healing rates of 40% for 150 mg ranitidine b.d. alone and 65 % for 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. To detect such a difference at the 5 % significance
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level with 8 0 % power a sample of at least 120 patients would be required. It was expected that approximately 20 Yo of patients might contribute un-evaluable data. Therefore, it was planned to recruit a minimum of 150 patients (75 per treatment group).
Paf ienfs Out-patients aged 18 years and over with a history of gastro-oesophageal reflux symptoms (heartburn, regurgitation, epigastric pain, odynophagia) and endoscopic confirmation of oesophagitis grades I-IIIz2 were selected for inclusion. The visual appearance of the oesophageal mucosa was to be assessed by the same endoscopist at each visit and graded according to the following criteria: grade 0, normal mucosa; grade I, one or more non-confluent mucosal erosions with erythema or exudate or superficial lesions above the gastro-oesophageal junction ; grade 11, confluent erosive and exudative mucosal lesions not covering the entire circumference of the oesophagus ; grade 111, circumferential erosive and exudative lesions covering the whole oesophageal mucous membrane. Endoscopy had to be performed within four days of starting study medication. Exclusion criteria were: age less than 18 years, patients with grade IV oesophagitis” (chronic mucosal lesion, i.e. ulcer, stricture or Barrett’s oesophagus), night-shift workers and patients unable to keep to the medication times, pregnant or lactating women, pre-menopausal women not using adequate contraception, patients with severe cardiovascular, pulmonary, hepatic, renal or metabolic disease, prior oesophageal or gastric surgery, pretreatment with any peptic ulcer medication other than occasional antacids or alginates during the week prior to study entry, concomitant treatment with drugs affecting the lower oesophageal sphincter tonicity such as metoclopramide, domperidone, cisapride or bethanechol, evidence of glaucoma or obstruction of urinary outflow, and patients whom the investigator considered likely to be non-compliant.
Assessments and medication At the first visit a physical examination was performed and concurrent medication reviewed. A venous blood sample was taken for haematological and biochemical analysis at the first and last visit. Following endoscopic diagnosis and standardized documentation of demographic data, symptom assessment, endoscopic findings, and laboratory screen, each patient was randomly allocated to oral treatment with either 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. or 150 mg ranitidine b.d. plus placebo pirenzepine b.d. (at breakfast and at bedtime). The randomization was in a block size of 6 patients per centre using a computer-generated random code. Patients were given medication for each treatment period at follow-up examinations (72 tablets each for ranitidine, pirenzepine or pirenzepine placebo). Ranitidine was available as plain white oval tablets containing 150 mg ranitidine. Pirenzepine (or identical placebo) was available as plain white tablets containing 50 mg pirenzepine. Patients were advised to elevate their sleeping position and also to stop smoking, lose excess weight and avoid heavy meals, especially at night.
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Follow-up evaluations including overall assessment of symptoms, cardiovascular parameters, endoscopy, adverse events, and compliance checks were to be carried out at 28 & 4 and 56 4 days of treatment. Adverse events were volunteered by the patient and elicited by the investigator through the use of standard questions. The amount of unused study drug was recorded at each visit to assess compliance. The day- and nighttime severity of specific reflux symptoms experienced by the patient over the previous seven days was recorded by the investigator. Heartburn, acid regurgitation, and epigastric pain were graded as either no symptoms (grade 0 ) ; mild, i.e. occasional episodes (grade I);moderate, i.e. troublesome but not debilitating attacks (grade 2) ; or severe,-that is, completely debilitating attacks (grade 3). The presence of odynophagia was also recorded.
Statistical evaluation All patients with evaluable endoscopy and/or symptom data were included in the analysis of efficacy (modified intent-to-treat analysis). Safety data were collected and analysed for all treated patients. The data were statistically evaluated by Glaxo Group Research, UK. Oesophagitis healing after four weeks and cumulatively after eight weeks was compared using the Mantel-Haenszel test without continuity correction for differences between treatments adjusted for pre-treatment grade ;the 5 % level of significance was applied. The 95 % C.I. for differences were based on the calculation of relative odds. The proportion of patients who reported total remission of reflux symptoms at the four- and eight-week visits was compared statistic. Summary statistics were calculated for using the Mantel-Haenszel standardized laboratory values using analysis of covariance and log transformation to correct for any non-normality.
x2
xz
RESULTS One hundred and fifty-seven patients entered the study. Seventy-nine were allocated to receive 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. and 78 150 mg ranitidine b.d. plus placebo pirenzepine b.d. The two treatment groups were well balanced at study entry (Table I), with the exception of the incidence of epigastric pain and odynophagia. The proportion of patients with no and moderate epigastric pain was 11of 79 and 35 of 79 patients (for ranitidine plus pirenzepine) us. 24 of 78 and 24 of 78 patients (for ranitidine), respectively. The incidence of odynophagia was 15/79 vs. 26/78, respectively. Ten patients (6.4%) were excluded from the analysis. Five patients were lost to follow-up (ranitidine plus pirenzepine: n = 3, ranitidine plus placebo: M = 2). Five patients were excluded due to adverse events (ranitidine plus pirenzepine: M = 4, ranitidine plus placebo: n = 1). The compliance of the patients assessed by counting returned medication after four (2 = 96 to 98%) and eight weeks (2 = 98 to 100%) was good.
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Table 1. Baseline characteristics of the study population Ranitidine (150 mg) b.d. pirenzipine (50 mg) b.d. (n = 79)
Ranitidine (150 mg) b.d. pirenzipine (placebo) b.d.
49.5 k 16.1 49 :30 77.5 k 18.3 20:59 40:39 3.0
52.3 15.4 47:31 76.5 f13.7 25 :53 43:35 3.0 0.8-5.0 91 28-152 40 29:34: 15
+
Mean age (years fS.D.) Gender (male:female) Weight (kg fS.D.) Smokers :non-smokers Alcohol :no alcohol Duration of disease (years in i and IQR)" Current episode (days in I and IQR)" Hiatus hernia Oesophagitis grades I :I1 :I11 * IQR
= inter-quartile
1.0-6.0 91 28-183 45 31 :36: 12
+
( n = 78)
range.
Oesophagifis healing The healing rates shown in Table 2 are comparable for the two treatment groups. In the analysis oesophagitis had healed in 32 of 75 (43%) and 48 of 72 patients (67%) treated with ranitidine plus pirenzepine compared with 34 of 76 (45 Yo) and 51 of 75 patients (68%) treated with ranitidine plus placebo pirenzepine after four and cumulatively eight weeks of treatment. No statistically significant difference was found either after four weeks ( P = 0.80, odds ratio 0.92, 95 % C.I. 0.48-1.75) or eight weeks (P = 0.86, odds ratio 0.94, 95 % C.I. 0.47-1.88). In a sub-analysis the relative efficacy of treatments was found to be unrelated to pre-treatment Table 2. Four- and cumulative eight-week healing (number of patients with healed oesophagitis/number of patients evaluated; healing rates in brackets) and relative odds, stratified according to pre-treatment oesophagitis grade Ranitidine (150 mg) b.d. pirenzipine (50 mg) b.d.
Ranitidine (150 mg) b.d. pirenzipine (placebo) b.d.
32/75 13/28 16/35 3/12
(43%) (46%) (46%) (25 %)
34/76 16/27 15/34 3/15
(45 %) (59%) (44%) (20%)
0.92 (0.48-1.75) 0.60 (0.20-1.73) 1.07 (0.41-2.75) 1.33 (0.22-8.22)
48/72 (67%) 19/27 (70%) 26/34 (77%) 3/11 (270/)
51/75 25/27 21/33 5/15
(68%) (93%) (64%) (33%)
0.94 (0.47-1.88) 0.19 (0.04-1.00) 1.86 (0.64-5.38) 0.75 (0.14-4.13)
+
+
Relative Odds" (95 % C.I.)
4 weeks
All patients Grade I Grade I1 Grade 111 8 weeks All patients Grade I Grade I1 Grade 111
' Relative odds for healing on the combination.
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endoscopy grade at four weeks (P = 0.65), but approached statistical significance at eight weeks (P = 0.06). As is also shown in Table 2, the two treatments resulted in similar healing rates for the subgroups stratified for endoscopic grade at entry. Again, the differences proved not to be significant.
Symptom relief All patients in both treatment groups had daytime symptoms of gastro-oesophageal reflux. Sixty-eight of 79 patients (86%)in the combination group and 64 of 78 patients (82 Yo) in the ranitidine group also had nocturnal symptoms. Severity assessment of heartburn and regurgitation revealed comparability of the two groups. The relative efficacy of the two treatments for the remission of diurnal and nocturnal symptoms (heartburn, regurgitation, and epigastric pain) was not significantly dependent upon pre-treatment severity. Overall, there were lower frequencies of day- and nighttime symptoms in the combined treated group after four weeks of treatment (Fig. I); significantly more patients receiving ranitidine plus pirenzepine had complete relief of day- and nighttime heartburn compared with those receiving ranitidine alone (day: 39 of 66 patients (59%) us. 24 of 63 patients (38%), odds ratio 0.42, 95% C.I. 0.21-0.85, P = 0.02; night: 38 of 55 patients (69%) US. 27 of 52 patients (52%),odds ratio 0.42,95 % C.I. 0.18-0.96, P = 0.04). At four weeks more patients receiving ranitidine plus pirenzepine experienced complete relief of regurgitation (Fig. 1; day: 37 of 66 patients (56%) us. 27 of 64 patients (42%), odds ratio 0.57, 95% C.I. 0.29-1.15, P = 0.12; night: 39 of 57 patients (68%) us. 28 of 49 patients (57%), odds ratio 0.58, 95% C.I. 0.26-1.35; P = 0.20) and epigastric pain (Fig. I) (day: 37 of 5 7 patients (65%) vs. 29 of 53 patients (55%), odds ratio 0.70, 95% C.I. 0.31-1.60, P = 0.40; night: 41 of 49
~
. . ..
..... ... .. .. ..
... .......... .. .. ........ ..... ..... .
Heartburn
Regurgitation
.
I
Epigastric pain
Figure 1. Symptom relief after four weeks of treatment with 150 mg ranitidine b.d. plus pirenzepine placebo b.d. (diurnal relief: white bars, n = 63 with heartburn, n = 64 with regurgitation, and n = 53 with epigastric pain; nocturnal relief: dotted bars, n = 52, n = 49, and n = 38, respectively) and with 150 mg ranitidine b.d. plus 50 mg pirenzepine (diurnal: hatched bars, n = 66 with heartburn, n = 66 with regurgitation, and n = 5 7 with epigastric pain; nocturnal: black bars, n = 55, n = 57, and n = 49, respec*P = tive1y)-+" P = 0.02, 0.04.
RANITIDINE PLUS PIRENZEPINE I N O E S O P H A G I T I S Figure 2. Symptom relief after eight weeks of treatment with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. (diurnal relief: white bars, n = 37 with heartburn, n = 37 with regurgitation, n = 30 with epigastric pain; nocturnal relief: dotted bars, n = 32, n = 31, and n = 23, respectively) and with 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. (diurnal: hatched bars, n = 31 with heartburn, n = 36 with regurgitation, and n = 30 with epigastric pain; nocturnal : black bars, n = 25, n = 28, and n = 23, respectively).
615
... ... ... .. .. .. ...
... ... .. ..... .. .. .. ... ........ ....... .. .. .. Heartburn
Regurgitation
.. .. .. .. .. .. ...
...
.. .. .. ...
.......... ..... ........ ...
Epigastric pain
patients (84%) us. 29 of 38 patients (76%), odds ratio 0.63, 95% C.I. 0.21-1.84, P = 0.40) than those receiving ranitidine alone, but these differences were not significant. The incidence of odynophagia was reduced after four weeks of treatment to 5 % and 7% in the combined-treated and ranitidine-treated groups, respectively ( P = 1.00). After eight weeks of treatment symptom relief was comparable in both groups; however, the number of patients per group assessed at eight weeks was reduced (Fig. 2).
Safety assessment Clinical adverse events were reported by nine patients receiving ranitidine and 19 patients receiving ranitidine plus pirenzepine. More events were reported by patients in the combination group (38 us. 10 events). The investigators considered clinical events to be possibly related to treatment in 13 of the 19 patients in the ranitidine plus pirenzepine group and in two of the nine patients in the ranitidine group. Seven of the 79 patients receiving the combination experienced minor anticholinergic symptoms such as visual disturbances and dryness of mouth compared with one patient in the ranitidine group. However, none of these symptoms necessitated patient withdrawal. Blood pressure and pulse rate were not significantly affected by trial medication in either treatment group. Population summary statistics revealed no evidence of any clinically important effect of either treatment on any haematological or biochemical value.
DISCUSSION The results of this study indicate that the combined ranitidine and pirenzepine 33
BAP 6
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regimen is no more effective than the same dose of ranitidine given alone in healing reflux oesophagitis. Thus, this result seems not to confirm our hypothesis that such a combined treatment would increase the healing of reflux oesophagitis due to stronger gastric acid i n h i b i t i ~ n " (and ~ ~ lower intragastric acidity," which should reduce the oesophageal mucosal damage resulting from exposure to the acidic refluxate. The observed healing rates for 150 mg ranitidine b.d. after four and eight weeks of treatment are higher than predicted (40 % for eight weeks) and higher than those reported in previous studies. In six controlled and randomized trials median healing rates for 150 mg ranitidine b.d. of 34 % (range 27-43 %) at four weeks, and of 52 % (38-56%) at eight weeks have been published (Refs 2-7; data are cited as results of intent-to-treat analyses). In these most of the patients with oesophagitis graded I1 or I11 had been treated. Two studies4r7included patients with grade IV, which was defined as patients with oesophageal stricture not requiring dilatation; one study5 also included patients with grade I and documented healing rates of 37% at four and 54% at eight weeks for grade I to I11 compared to 26% and 39% respectively, for grades I1 and 111. In two other studies higher healing rates have been reported when only patients with grades I and I1 were treated with 150 mg ranitidine b.d.23~"4 In the present study most of our patients were stratified to oesophagitis grades I and I1 (Table I); this may account for higher than predicted healing rates with 150 mg ranitidine b.d. The combination of ranitidine and pirenzepine has a more marked effect on acid secretion and intragastric acidity than 150 mg ranitidine b.d. and, in this study, was associated with improved symptom relief after four weeks (Fig, I). In particular, there was a significant improvement in the relief of diurnal and nocturnal heartburn. However, by eight weeks symptom relief was comparable between the two treatment regimens (Fig. 2). In this connection, it has to be mentioned that only those patients receiving eight weeks of treatment were included in the analysis for symptom relief and so the numbers of patients per group were reduced. A similar improvement in symptom relief over standard dose is seen, if the dose of ranitidine is increased to 300 mg b.d.,25but again this is not associated with a substantial improvement in the proportion of patients with healed oesophagitis. Overall, our data confirm that resolution of reflux symptoms does ~? not correlate well with the healing of the oesophageal m u c o ~ a .9!26 The ranitidine and pirenzepine treatment regimens were well tolerated, and not associated with any abnormalities of cardiovascular or laboratory parameters. There was a higher frequency of adverse events reported in the combination group, and some patients reported clinical events consistent with anticholinergic therapy, but none necessitated patient withdrawal. The results show that combined treatment wikh ranitidine and pirenzepine improves symptom relief, especially heartburn, after four weeks, in patients with reflux oesophagitis. However, this is not associated with any increase in healing rate compared to that achieved with ranitidine alone. By eight weeks, neither
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healing rates nor symptom relief was significantly different between the two groups. The response to 150 mg ranitidine b.d. was good, and it may be that in this population any additive effect of pirenzepine on gastric acid suppression was insufficient to further enhance healing. Additional studies may clarify this.
ACKNOWLEDGEMENTS
The authors would like to thank the following investigators who participated in this study: Drs S. Ahnefeld, A. Ansari, U. Bar, S. Consemiiller, A. Dettmer, H. Frotz, W. Hochter, R. Kunze, L. Witzel (Germany); Drs F. Gleeson, J. Hegarty, T. O’Callaghan (Ireland); Drs P. M. de Vries, H.Geldof, K.Jie, D. L. van der Linde (The Netherlands); and Drs D. Hollanders, J. G. C. Kingham, J. P. Miller, R. P. H. Thompson, P. J. Whorwell, K. G. Wormsley (UK). We are also grateful to Dr R. Kullmann, Boehringer Ingelheim, Ingelheim, and Dr 0.Tauber, Dr. Karl Thomae GmbH, Biberach, Germany, for providing pirenzepine (and identical placebo) tablets. This study is dedicated to Professor Dr. M. M. Forell, Munich, on the occasion of his 75th birthday. REFERENCES 1 Gotley D C, Morgan A P, Ball D, Owen
R W, Cooper M J. Composition of gastrooesophageal refluxate. Gut 1991; 32: 1093-9. 2 Klinkenberg-Knol E C,
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superior to ranitidine in short-term treatment of ulcerative reflux esophagitis. Dig Dis Sci 1988; 33 : 523-9. 6 Johnson N J, Boyd E J S, Mills J G, Wood J R. Acute treatment of reflux oesophagitis :
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Lehrbuch und endoskopischer Atlas. Solothurn: AG Gassmann, 1977, 119-27. 23 Kimmig J G. Cimetidin und Ranitidin in der Behandlung der Refluxosophagitis. Z Gastroenterol 1984; 22: 373-8. 24 Rohner H G, Wienbeck M, RAN 2-1 Studiengruppe. Zwei oder eine Tagesdosis Ranitidin zur Behandlung der Refluxosophagitis. Z Gastroenterol 1986; 24: 396402. 25 Johnson N J, Laws S, Mills J G, Wood J R. Effect of three ranitidine dosage regimens in the treatment of reflux oesophagitis : results of a multi-centre trial. Eur J Gastroenterol Hepato1 1991; 3 : 759-74. 26 Sontag S J. The medical management of re-
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