How much less acid and no ulcer?

GASTROENTEROLOGY 1986:90:2027-33

SELECTED

SUMMARIES

ROBERT M. GLICKMAN Selected Summaries Columbia University

Editor

College of Physicians & Surgeons New York, New York 10032

STAFF OF CONTRIBUTORS Thomas A. Brasitus, Chicago, 111. Richard J. Deckelbaum, Jerusalem, Israel Serge Erlinger, Paris, France Hans Fromm. Washington, DC. W. G. M. Hardison, San Diego, Calif. Lucien R. Jacobs, Davis, Calif. Khursheed Jeeieebhov, Toronto, Canada Martin F. Kagnoff, San Diego, Calif.

Raymond S. Koff, Boston, Mass. Sumner C. Kraft, Chicago, Ill. Robert C. Kurtz, New York, N.Y. Richard P. MacDermott, Boston, Mass. James McManus, Temple, Tex. Ann Ouyang, Philadelphia, Pa. Sevmour M. Sabesin, Chicago, Ill.

HOW MUCH LESS ACID AND NO ULCER? Weberg R, Berstad A, Lange 0, et al. (Department of Medicine, Lovisenberg Hospital, Oslo, Norway) Duodenal ulcer healing with four antacid tablets daily. Stand J Gastroenterol 1985;20:1041-5 (September). This study reports a double-blind, randomized evaluation of a lower dose frequency treatment using antacids in symptomatic duodenal ulcer subjects. Endoscopy was carried out on entry into the study, at 4 wk, and if the ulcer was still unhealed, at 8 and 12 wk of treatment. Patients were evaluated for symptoms and drug compliance at 2 and 4 wk and, thereafter, after 8 and 12 wk if the ulcer was unhealed. On entry patients were randomly allocated to double-blind treatment with either one chewable aluminum-magnesium antacid tablet or placebo four times a day-l h after meals and at bedtime. The antacid had a buffering capacity of 30 mmol and the placebo had negligible acid buffering capacity. Patients were permitted to use supplementary antacid tablets as necessary. If the ulcer was still unhealed at 4 wk, patients were treated with ranitidine, 150 mg b.i.d., for up to 8 wk. There were 38 patients in each treatment group who completed

the study,

and they were comparable with regard to age, sex, smoking habit, duration of relapse, basal and maximal acid output, and ulcer diameter. The duration of disease was longer in the antacid group. At 4 wk, endoscopy showed ulcer healing in 28 patients (74%) receiving antacids and 11 patients (29%) in the placebo group. In those patients taking antacids in whom the ulcer had not healed, its size was significantly reduced at 4 wk, whereas ulcer size was unchanged in those patients taking the placebo. Patients with unhealed ulcer were older and took more supplementary antacids (23 vs. 10) than patients with healed ulcer. In patients with unhealed ulcer, ranitidine therapy accelerated healing in 31 of 34 patients (91%) at 4 wk and 32 of 34 patients (94%) after 8 wk. The total number of days with continued symptoms and the number of nights with pain was significantly less in the antacid group, and in both groups, the number of days with ulcer pain diminished during treatment. The use of supplementary antacids was less in the antacid-treated group: median buffering capac-

Melvin Schapiro, Los Angeles, Calif. Konrad Schulze-Delrieu, Iowa City, Iowa Michael L. Steer, Boston, Mass. Joseph Sweeting, New York, N.Y. Martin H. Ulshen, Chapel Hill, N.C. Ernest Urban, Pittsburgh, Pa. Milton M. Weiser, Buffalo, N.Y.

ity of 3.2 mmoliday

vs. 12.9 mmoliday in the placebo group. It is claimed that this is the lowest antacid dose (120 mmoliday) shown to be effective to promote duodenal ulcer healing and symptom relief. The results of other studies using lower dose antacid therapy are briefly dis-

cussed and it is speculated that the mechanism of acceleration of ulcer healing in these circumstances may not be related to acid neutralization.

Comment.

Generations of gastroenterologists have used antacids in the management of peptic ulcer disease. Antacids have been well accepted by patients and symptom relief has been very satisfactory. Intensive antacid therapy involves dosage as necessary for relief of pain or regular ingestion after meals. It seemed that this approach had a beneficial therapeutic effect, and each physician recommended his own particular favorite antacid preparation Medical student teaching in the era prior to fiberoptic endoscopy was also straightforward in that ulcer pain implied an active ulcer crater and neutralization of acid was the requisite to achieve ulcer symptom relief. The approach of Piper, with emphasis on the acid neutralizing capacity of antacid preparations, led to the studies by the Dallas group and a potency list which, in turn, resulted in the use of a powerful antacid in a double-blind study that demonstrated acceleration of healing of duodenal ulcers (Gut 1964;5:85-90, N Engl J Med 1973;288:923-8, 1977;297:341-5). Mylanta II liquid (Stuart Pharmaceuticals, Wilmington, Del.), in a dosage of 30 ml, 1 h and 3 h postcibal and at bedtime, was significantly more effective than the placebo preparation, and consequently, this intensive antacid regimen became the standard and any lesser dosage could not be contemplated. In this latter study, the earlier observations of Sturdevant were confirmed in that placebo was as effective as the antacid preparation in relieving symptoms. Our understanding of the whole pathophysiology of ulcer disease was further undermined by the lack of correlation between the presence or absence of symptoms and the presence or absence of an ulcer crater. Predictably, the seven dose per day antacid program was attended by a significant incidence of side effects, and poor patient compliance was to be anticipated. It was at this time that the HZ-receptor blockers became available and antacids became a poor relation of the therapist. Inhibition of acid secretion was emphasized and in the last decade, a succession of more potent acid inhibiting agents have been heralded, culminating in the preliminary studies with blockers of

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SELECTED SUMMARIES

the proton pump that almost achieved achlorhydria. It then became apparent that virtual anacidity was perhaps not so desirable in that it favored bacterial colonization of the stomach and formation of nitrosamine metabolites, and at least in the experimental animal, there was a risk of enterochromaffin tumors of the stomach (Br J Med 1984;2:717-9, Ann Intern Med 1983;99:761-6). The protagonists of the histamine blockers have, of course, vociferously proclaimed that only modest suppression of acid secretion is desirable and necessary, and most recently, they have emphasized that inhibition of nocturnal acid secretion is all that is required to promote ulcer healing, since normal food intake will effectively control acid secretion in the daytime. Prostaglandins have also been vigorously promoted and cytoprotection has become the password in discussion of optimal ulcer management. Agents of proven efficacy in ulcer control, e.g., cimetidine and sucralfate, have now been shown to have cytoprotective properties in addition to their long-established actions. Almost anticlimactically, however, it has now become evident that the efficacy in promoting ulcer healing of one of the latest prostaglandin preparations may be entirely explainable on the basis of its antisecretory properties without the need to invoke cytoprotection. In the background of all this furious development and promotion of acid inhibitors by the pharmaceutical industry, there have been a few isolated observations on antacid use. Thus, Lam in Hong Kong and later Berstad in Scandinavia observed that antacids with significantly lower acid neutralizing capacity resulted in ulcer healing that was similar to rates achieved with either a more potent intensive antacid dosage or cimetidine (Gastroenterology 1979;76:315-22, Stand J Gastroenterol 1982;17:953-9). It was argued, however, that in the Hong Kong based study the Chinese patients were of lower body weight and therefore had lower acid outputs than in the Western world. A similar explanation could also be exercised in the more recent Indian study where, again, relatively low acid neutralizing capability resulted in highly significant ulcer healing rates (Gut 1984;25:1199-202). In the United Kingdom, the role of intensive antacid therapy was questioned when it was observed that an intensive regimen met with poor compliance and poor healing rates whereas a “low dose” program involving only 10 ml of a magnesium hydroxidealuminum hydroxide liquid preparation taken as required for relief of pain was associated with a significant healing as compared with placebo (67% vs. 35%) (Br J Med 1984;2:869-71). This Norwegian study is simple in outline and has clearly demonstrated a significant acceleration of ulcer healing in patients taking relatively small amounts of antacid. The healing rate of patients taking placebo is low, but this seems to be a feature of European studies of ulcer disease. The placebo in this instance, however, did not have as significant an influence on ulcer symptoms as in earlier studies of antacids, although when daytime pain was considered on a weekly basis, the only difference was in the first week of treatment, and nocturnal pain was less efficiently relieved by placebo than antacid. It is perhaps regrettable that in those patients with unhealed ulcer at 4 wk, antacid treatment was not continued, since the ulcers in patients taking antacids had become smaller and, as with other ulcer medications, persistence with therapy or possible augmentation of the dose may have achieved ultimate healing. Because symptoms were effectively controlled, there does not seem to be compelling justification to change treatment after only 4 wk. If placebo is as effective as antacid in symptom relief, then this has to be explained. Now, low acid neutralizing capacity schedules heal as many ulcers as intensive dosage or HZ-receptor antagonists. Therefore, it may well be speculated that the beneficial effects of antacid are a reflection of actions other than acid neutralization. Alternative explanations are to be considered and

GASTROENTEROLOGY Vol. 90, No. 6

must include binding of pepsin, bile acids, lysolecithin plus a possible direct cytoprotective effect (Antacids in 80’s. Halter F, ed. Munich: Urban and Schwarzenburg, 1982:17-28). It may also be wondered whether a larger nocturnal dosage of antacids may be all that is necessary to promote healing as has been found for cimetidine and ranitidine. The crucial problem in ulcer disease, however, is the prevention of ulcer recurrence. Whether nighttime antacid therapy could influence gastric acidity for the duration of sleep is questionable, although this in turn is in part related to the issue if the beneficial effects are related to simple neutralization of acid. Certainly, such a modified dose schedule may be anticipated to be almost free from side effects and considerably cheaper. Therefore, in terms of cost effectiveness, safety, and acceptance, antacids could provide a considerable challenge to all the new contenders, i.e., HZ-antagonists, sucralfate, prostaglandins, muscarinic blockers, and proton pump inhibitors. Could this be labeled “antacid rebound?” J. P. McMANUS. M.D.

COMPONENTS OF BILE EFFECT GROWTH OF Giurdia Zamblia Farthing MJG, Keusch GT, Carey MC (Departments of Medicine, Tufts University School of Medicine and Brigham and Women’s Hospital, Boston, Massachusetts) Effects of bile and bile salts on growth and membrane lipid uptake by Giardia Iamblia. J Clin Invest 1985;76:1727-32. A series of experiments were performed to elucidate the possible mechanisms by which mammalian bile promotes growth of Giardia lamblia. The growth of this parasite was examined in a lecithin-containing growth medium with the following additions: (a) ox, pig, guinea pig, and human bile; (b) pure bile salts; and (c) egg and soybean lecithins. These studies revealed that dilute native bile as well as pure sodium taurocholate (TC), glycocholate (GC), and taurodeoxycholate (TDC), all promoted parasite growth. Growth was most marked with biles of high phospholipid content, with biles enriched in more hydrophobic bile salts, and with micellar concentrations of GC and submicellar concentrations of TC and TDC. Furthermore, by quantitating uptake of radiolabeled biliary lipids from bile and bile salt-supplemented medium, the parasite was shown to be capable of consuming bile lipids (lecithin > bile salts). While bile and bile salt-stimulated growth was associated with enhanced lecithin uptake, reduction in the generation time of this parasite was seen at low bile and bile salt concentrations when lecithin uptake was similar to bile-free controls. Based on these observations, the authors suggest that (a) bile salts may initially stimulate G. lamblia growth by a mechanism independent of enhanced membrane phospholipid uptake and (b) since this parasite has no capacity to synthesize membrane lipid, biliary lecithin may be a major source of phospholipid for growth of G. lamblia. Giardia Jamblia is the most common pathogenic Comment. protozoan of the human gastrointestinal tract [Stand J Gastroenterol 1972;7(Suppl. 14):7-441. This parasite is most frequently found to inhibit the upper small intestine (Gastroenterology 1974;66:16-21). The reasons behind predilection of this parasite for this particular site have been relatively unclear. In this