Reduction of Twenty-Four-Hour Gastric Acidity With Combination Drug Therapy in Patients with Duodenal Ulcer

Transcription

1 GASTROENTEROLOGY 77: , 1979 Reduction of Twenty-Four-Hour Gastric Acidity With Combination Drug Therapy in Patients with Duodenal Ulcer WALTER L. PETERSON, CORA BARNETT, MARK FELDMAN, and CHARLES T. RICHARDSON Department of Internal Medicine, Veterans Administration Medical Center, and University of Texas Southwestern Medical School, Dallas, Texas Four "extra-effort" drug regimens were tested to determine which most nearly eliminated 24-hr gastric acidity in 8 patients with duodenal ulcer. The regimens included two 00 mg cimetidine tablets with meals and at bedtime; one 00 mg cimetidine tablet plus an anticholinergic drug with meals and at bedtime; 00 mg cimetidine with meals and at bedtime plus liquid antacid 1 and hr after meals and at bedtime; and 00 mg cimetidine, an anticholinergic drug, and antacid, taken simultaneously as each meal was finished and at bedtime. No regimen completely eliminated gastric acidity. However, compared to standard cimetidine therapy (00 mg four times daily) which led to a median 24-hr ph of 2.6, each "extra-effort" regimen except cimetidine plus an anticholinergic was significantly better in reducing gastric acidity. During the daytime hours, cimetidine with meals plus antacid 1 and hr after meals was most effective (median ph 5.0). However, the more convenient regimen of cimetidine, an anticholinergic drug, and antacid was almost as effective (median ph 4.). None of the "extra-effort" regimens was significantly more effective than standard cimetidine therapy during the hours of sleep. Current therapy of duodenal ulcer is designed to reduce gastric acidity. Antacids (seven large doses a Received March 28, Accepted June 8, Address requests for reprints to: Walter L. Peterson, M.D., Gastroenterology (l11b), Dallas VA Medical Center, 4500 S. Lancaster, Dallas, Texas This study was supported by the Veterans Administration, grants AM-1728 to CURE (Center for Ulcer Research and Education) and AM from the National Institute of Arthritis, Metabolism, and Digestive Diseases, and Roche Laboratories, Nutley, N.J. The authors wish to thank Peggy Barnett. Jeanna Welborn, Brunette Moore, Tyree Anders, and Shirley Gabriel for dedicated technical assistance and Janice Fines for typing the manuscript by the American Gastroenterological Association /79/ $02.00 day) and cimetidine (00 mg four times a day) have been shown to reduce postprandial gastric acidity to comparable levels 1 and to promote healing of duodenal ulcers to a similar degree. 2-4 However, with either therapy about 25% of patients fail to respond with healing of the ulcer crater. Many of these patients without healing are asymptomatic 2 and under normal clinical conditions the persistence of the ulcer would not be recognized. On the other hand, some of these patients continue to experience ulcer symptoms or develop complications while undergoing therapy. Reasons for these failures are not known, but it is possible that in some patients even relatively small amounts of gastric acid that persist in the face of therapy with cimetidine or antacids can sustain an ulcer. More marked reduction in acidity might be accomplished by increasing the dose of a single agent or by using combinations of antacids, cimetidine, and anticholinergic drugs. The possibilities are almost innumerable, and no information exists as to which combination of drugs would most nearly accomplish the objective of complete elimination of gastric acidity. The purpose of this study was to compare the effects of the four trial regimens shown in Table 1 on 24-hr gastric acidity in patients with duodenal ulcer. For comparison, gastric acidity with standard cimetidine therapy and with no medication was also measured. Methods Subjects Eight outpatients (5 males, females) with inactive duodenal ulcer were studied. The average age was 42 yr (range from 29 to 54 yr). All were in good health and had discontinued antacids or antisecretory drugs for 6 hr before study. Mean (±SE) basal and peak acid output in response to 61'8/kg of pentagastrin (Peptavlon. Ayerst Labo-

2 1016 PETERSON ET AL. GASTROENTEROLOGY Vol. 77, No.5 ratories, New York, N.Y.) subcutaneously were 6.2 ± 2.8 and 46.8 ± 6.5 meq/hr, respectively. This study was approved by the Human Research Review Committee of the University of Texas Health Science Center on April 10, Each patient gave informed consent. During each study, the patients were "in residence" for 24 hr. Three meals were prepared in the immediate area so that appetizing aromas could reach the patients, after which the food was consumed in normal fashion. Routine activities of daily life (reading, viewing television, playing card games) were encouraged as was a normal period of sleep. Alcoholic beverages, coffee, and colas were forbidden, but smoking was permitted. Careful record was made of the time of day each cigarette or cigar was smoked during the patient's first study; this pattern was duplicated exactly for the remaining five studies. Measurement of Gastric Acidity Patients reported at 7 AM after a 10-hr fast. A 16 Fr. nasogastric tube (Andersen Products, Oyster Bay, N.Y.) was placed in the gastric antrum under fluoroscopic guidance. Gastric contents were emptied and at 7:0 AM the first 2 ml gastric sample was obtained, and ph was measured. Breakfast was then served, and, with the exception of the first half hour after each meal, gastric samples were withdrawn and ph measured every 0 min for the next 24 hr. Gastric ph was determined with a ph meter (Radiometer, London Company, Cleveland, Ohio) which had been calibrated with ph 1.00, 4.00, and 7.00 buffers. Each ph reading was also converted to hydrogen ion concentration ([H+]) from standard tables by the method of Moore and Scarlata. 5 Meals Breakfast consisted of two slices of fried bacon, one scrambled egg, two pieces of toast with 2 teaspoons apple jelly, and 240 ml of water. Lunch, eaten at 12:0 PM, included a 227 g hamburger patty, broiled and served with one slice of tomato and teaspoons of ketchup on a bun; 72 g of french fried potatoes; and 00 ml of water. Dinner was served a 6 PM and included a 227 g sirloin steak, a 227 g baked potato with one pat of butter, one-half canned cling peach, and 00 ml of water. During all meals patients were allowed salt and pepper to taste. No between meal or bedtime food or water was allowed. Medication's On separate days at least 1 wk apart, patients were given, in random fashion, medications as indicated in Table 1. Bedtime doses were administered at 11 PM. Placebos were not administered because of the complexity of blinding three different forms of medication, two doses of cimetidine, and the variable times of administration. Statistical Methods Statistical determinations were performed among mean hydrogen ion concentrations by analysis of vari- Table 1. Medications Trial regimens (abbreviations) Dosage and schedule 1. Double dose cimetidine 600 mg Cimetidine (TagameW (C600) with meals and at bedtime 2. Standard cimetidine plus 00 mg Cimetidine plus 5 mg anticholinergic therapy clidinium bromide (Quarzan)b (C+Q) with meals and at bedtime. Standard cimetidine plus 00 mg Cimetidine with meals standard antacid therapy and at bedtime, plus 0 ml (C+A+A) Mylanta nc 1 and hr after meals and at bedtime 4. Triple therapy with cimetidine, 00 mg Cimetidine, 5 mg an anticholinergic drug clidinium bromide, and 0 ml and antacid (C + Q + A) Mylanta II after each meal Standard cimetidine therapy (C00) Control and at bedtime 00 mg Cimetidine with meals and at bedtime No medication a SK&F Laboratories (Philadelphia, Pa.). b Roche Laboratories (Nutley, N.J.). C Stuart Pharmaceuticals (Wilmington, Del.) (0 ml Mylanta II contains approximately 144 meq of in vitro neutralizing capacity). ance. Differences at the 0.05 level were considered significant. Results Expression of Data Gastric acidity data obtained with each regimen are expressed in four ways (Table 2): (a) Mean hydrogen ion concentration (mean [H+]) (b) ph corresponding to mean [H+]; (c) mean ph obtained from averaging all actual ph measurements; and (d) the median of all the actual ph measurements. These values were computed for the 24-hr period, for daytime hours only (7:0 AM-11:00 PM), and for the hours of sleep only (11:0 PM-7:0 AM). It can be seen from Table 2 that the ph values corresponding to mean [H+] were always lower than the mean of the actual ph readings. This is explained by the logarithmic relationship between [H+] and ph. For example, suppose three samples of gastric contents had ph values of 1.0, 2.0, and.0. The arithmetic mean of these values is ph 2.0. When the individual ph readings are converted to [H+V the values are 128, 12, and 1 meq/liter, respectively. The mean [H+] is 47 meq/liter which corresponds to a ph of 1.4. Nevertheless, the results obtained with each regimen were qualitatively similar, regardless of the method of expression. Effectiveness of Regimens No regimen eliminated gastric acidity either during the day or during the hours of sleep (Table 2).

3 November 1979 GASTRIC ACIDITY WITH COMBINATION THERAPY 1017 Table 2. Gastric Acidity During Entire 24-Hour Period, Daytime Hours, and Hours of Sleep with Control, C00, and Trail Regimens O Control C00 C+Q C+Q+A C+A+A C Hours 1. Mean ± SE [H+] (meq/liter) b 4. b 7.5 b ±.1 ±1.7 ±2. ±0.8 ±0.9 ± ph Corresponding to mean [H+] Mean ph Median ph Daytime hours (7:0 AM-ll:00 PM) 1. Mean ± SE [H+] b 1.5 b 8.8 b ±4.6 ±2.2 ±2.7 ±1.0 ±0.5 ± ph Corresponding to mean [H+] Mean ph MedianpH Hours of sleep (11:0 PM-7:0 AM) 1. Mean ± SE [H+] ±.4 ±2.4 ±4.1 ±I.l ±1.7 ± ph Corresponding to mean [H+] Mean ph Median ph Mean [H+] with C00 and with each trial regimen were significantly lower than control during the entire 24-hr period, daytime hours, and hours of sleep. b P < 0.05 compared to C00. However, gastric acidity with standard cimetidine therapy (C00) or any of the trial regimens was significantly less than when no medication was given, during both the daytime hours and the hours of sleep. The addition of an anticholinergic drug to cimetidine (C + Q) resulted in no significant improvement over C00. For the entire 24-hr period the combinations of C + Q + A, C + A + A, and C600 were not significantly different from each other but were each more effective than C00. During the daytime hours C + A + A produced the lowest levels of acidity. During the hours of sleep, C600 resulted in the lowest levels of acidity, but using analysis of variance among the groups, C600 was not significantly different from the other trial regimens or C00. Table displays the number of patients in whom each of the trial regimens was most effective during the daytime hours and hours of sleep. Patterns of Gastric Acidity The mean of the actual ph readings for each sampling time was selected to display the patterns of gastric acidity over the 24-hr period. During the control day (Figure 1) gastric ph changed little for the first hour after breakfast but thereafter fell sharply, reaching its lowest level hr after the meal. Ingestion of lunch and dinner produced a rapid rise in ph, consistent with the buffering effect of the meal, followed thereafter by another sharp fall. Gastric ph remained between 1.0 and 2.0 throughout the hours of sleep. Gastric ph rarely rose above 2.5 during the 24-hr study. Mean gastric ph with standard cimetidine therapy (C00) (Figure 1) was higher than control throughout the 24-hr period. During the daytime hours, ph was usually less than.5 whereas during the hours of sleep, ph was usually above.5. The patterns of gastric ph with the "extra effort" regimens compared to C00 are shown in Figure 2. ph Profiles The percent of ph readings occurring at or above a range of ph values from 1.0 to 7.0 are shown for each regimen during the entire 24 hr (Figure A), the daytime hours (Figure B), and the hours of sleep (Figure C). From these curves, the relative effects of the different regimens can be assessed with respect to any given ph end point. For example, ph 4 is the ph that must be achieved to abolish peptic activity if hemoglobin is used as a substrate. 6 During the 24-hr period gastric ph was 4 or higher about Table. C+Q+A C+A+A C600 Number of Patients in Whom Each Trial Regimen Was Most Effective During Daytime Hours and Hours of Sleep Daytime 2 Hours of sleep 4 1

4 1018 PETERSON ET AL. GASTROENTEROLOGY Vol. 77, No.5 Breakfast Lunch Dinner 6.0~ ~ ~ Figure 1. Mean gastric ph with no medication (control) and with standard cimetidine therapy (00 mg with meals and at bedtime, COO) during 24 hr. Values at each time point are the mean of the actual ph determinations for all 8 patients. 60% of the time with C + A + A, 55% of the time with C + Q + A, and only 25% of the time with standard cimetidine therapy. Discussion There are several ways in which gastric acidity data can be presented. Although some authors I. have argued for one method of expression as opposed to another,7 no method is clearly best. In this paper we have presented data in four ways. Fortunately, the order of effectiveness of the different regimens was the same regardless of the method of expression. The purpose of our study was to determine which of four "extra-effort" medical regimens, using an antacid, cimetidine, and an anticholinergic drug, most nearly eliminates gastric acidity over a 24-hr period. In three of the four trial regimens, drugs were used at times (in relation to meals) that seemed likely to result in maximal reduction of gastric acidity. For example, the antacid was given 1 and hr after meals and cimetidine and the anticholinergic were given at the onset of eating. In the remaining trial regimen (C + Q + A), all three drugs were given immediately following the meal. Although this timing was probably not ideal for any of these drugs, it offered the convenience of a reduced number of daily doses. Of the four trial regimens, the one that most nearly eliminated gastric acidity during the day was a combination of standard cimetidine with standard antacid therapy, i.e., 00 mg cimetidine with meals and antacids 1 and hr after meals. Almost as effective was 00 mg cimetidine, an anticholinergic and Breakfast Lunch Dinner 6.0, 5.5 I Breakfast N M N M2 46 Breakfast Lunch Dinner 6.0 J J I012N M N M 2 46 Figure 2. Mean gastric ph during 24 hr for A. C + Q Ys.COO; B. C + Q + A vs. B. COO; C. C + A + A vs. D. C00; and D. C600 vs. Coo. Values at each time point are the mean of the actual ph determinations for all 8 patients.

5 November 1979 GASTRIC ACIDITY WITH COMBINATION THERAPY 1019 PERCENT '?~~ EACH ph PERCENT READINGS A~ ph Figure. Percent readings at or above ph values from 1.0 to 7.0 for all 8 patients with no medication (control). C00. and trial regimens during A. the entire 24 hr; B. daytime hours (7:0 AM-11:00 PM); and C. the hours of sleep (11:0 PM-7:0 AM). an antacid taken as each meal was finished. By contrast, none of the trial regimens was significantly more effective in reducing acidity during the sleeping hours than a single 00-mg cimetidine tablet taken at bedtime. It should be noted that the patients studied in this trial had inactive duodenal ulcer. Whether these regimens would produce similar results in patients with active ulcer disease refractory to cimetidine or antacid is not known. There is, however. no reason to believe that the relative effectiveness of the regimens would change. Selection of an "extra effort" regimen to test by ph clinical trial in patients with persistent ulcer symptoms not responding to standard therapy must be based on practical as well as on safety and potency considerations. We, therefore, suggest the following: cimetidine 00 mg, an anticholinergic, and an antacid after each meal and 00 mg cimetidine at bedtime. This has the convenience of four times a day dosing (as opposed to 10 times a day if standard cimetidine and standard antacid regimens are combined). The regimen takes advantage of the known additive effects of antisecretory and neutralization therapy in reducing postprandial gastric acidity.8 Furthermore, although our present results with cimetidine plus an anticholinergic and those of others9-10 suggest that anticholinergic drugs do not enhance the effect of cimetidine on gastric ph, there is evidence that the effects of the two drugs are additive when total acid secretion is measured.1o. ll This effect presumably occurs because the drug combination reduces volume of secretion better than either drug alone. Thus, a smaller volume of gastric acid may be more readily neutralized by a given dose of antacid. It is interesting to note that the addition of a bedtime dose of antacid to cimetidine was of no demonstrable value over cimetidine alone in reducing nocturnal acidity. This is evident from Figures 2 C and C, as well as the mean data on [H+] and ph during the sleeping hours (Table 2). Most likely this is because the bedtime dose of antacid was rapidly emptied from the stomach. In any case, our data suggest that the frequently prescribed bedtime dose of antacid may be of little value. It might be possible to design even more potent and perhaps more convenient regimens than were used in this study. In particular, the combination of 600 mg cimetidine plus an antacid 1 hr after each meal and 00 mg cimetidine at bedtime is attractive. However. even if it were more effective, the safety of such large daily doses of cimetidine over a period of weeks to months would have to be established before it could be recommended. References 1. Deering TB. Malagelada J-R: Comparison of an H2 receptor antagonist and a neutralizing antacid on postprandial acid delivery into the duodenum in patients with duodenal ulcer. Gastroenterology 7: Peterson WL. Sturdevant RAL. Frankl HD. et al: The healing of duodenal ulcer with an antacid regimen. N Engl J Med. 297: Ippoliti AF. Sturdevant RAL. Isenberg JI. et al: Cimetidine versus intensive antacid therapy for duodenal ulcer. A multicenter trial. Gastroenterology 74: Binder JH. Cocco A. Crossley RJ. et al: Cimetidine in the treatment of duodenal ulcer. A multicenter double blind study. Gastroenterology 74:

6 1020 PETERSON ET AL. GASTROENTEROLOGY Vol. 77. No.5 5. Moore EW. Scarlata RW: The determination of gastric acidity by the glass electrode. Gastroenterology 49: Goldberg HI. Dodds WJ. Gee S. et al: Role of acid and pepsin in acute experimental esophagitis. Gastroenterology 56: Lucas M: ph or hydrogen-ion concentration in statistics? Lancet 2: Peterson WL. Fordtran JS: Reduction of gastric acidity. In: Gastrointestinal Disease. Second edition. Edited by MH Sleisenger. JS Fordtran. Philadelphia. W.B. Saunders p Pounder RE. Hunt RH. Vincent SH. et al: 24 Hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer during oral administration of cimetidine and atropine. Gut 18: Saunders JHB. Cargill JM. Wormsley KG: Effects of cimetidine and poldine on nocturnal gastric secretion in duodenal ulcer. Digestion 15: Feldman M. Richardson CT. Peterson WL. et al: Effect of lowdose propantheline on food-stimulated gastric acid secretion. Comparison with an "optimal effective dose" and interaction with cimetidine. N Engl J Med 297: