GASTROENTEROLOGY

SPECIAL

REPORTS

1990;99:883-875

AND REVIEWS

Bismuth Therapy in Gastrointestinal Diseases SHERWOOD

L. GORBACH

Departments of Communitv Health and Medicine, Tufts University Massachusetts

Bismuth therapy has shown efficacy against two major gastrointestinal disorders: peptic ulcer disease and diarrhea. In peptic ulcer disease it is as effective as the Hz-receptor antagonists, costs considerably less, and offers a lower rate of relapse. When Helicobatter pylori is implicated, bismuth acts as an antimicrobial agent, suppressing the organism but not eliminating it. In recent studies, bismuth compounds have been used with conventional antibiotics, producing elimination of the organism, histological improvement, and amelioration of symptoms for periods longer than one year. Bismuth subsalicylate has shown modest efilcacy in treating traveler’s diarrhea and acute and chronic diarrhea in children, and it is effective prophylactically for traveler’s diarrhea. An epidemic of neurological toxicity was reported in France in the 1976’s with prolonged bismuth treatment, usually bismuth subgallate and subnitrate. Such toxicity has been rare with bismuth subsalicylate and colloidal bismuth subcitrate. However, recent studies have demonstrated intestinal absorption of bismuth (about 0.2% of the ingested dose) and sequestration of this heavy metal in multiple tissue sites, even occurring with conventional dosing over a 6-week period. These findings have inspired recommendations that treatment periods with any bismuthcontaining compound should last no longer than 6-6 weeks, followed by g-week bismuth-free intervals.

B

ismuth compounds are old drugs that have enjoyed great popularity for at least three centuries. Among the traditional medicaments containing bismuth are salves, ointments, injectables, liquids, colloidal suspensions, and tablets. These products have been used topically as emollients, astringents, and antiinfectives; parenterally as antisyphilitics; and orally for treatment of amebiasis, dyspepsia, and diarrhea. The therapeutic usefulness of bismuth for abdominal pain and dyspepsia was noted in the 1800s in Europe (1). Bismuth subsalycilate (BSS) has been

School of Medicine,

Boston,

available in the United States since 1901, when it was used in “cholera infantum,” a common diarrhea1 disease in children. Its subsequent commercial success has been such that it is now estimated by the manufacturer to be a fixture in the medicine cabinet in 60% of American households. Despite this venerable history, systematic investigation of the mechanism of action and clinical efficacy of bismuth compounds has only begun in recent years, stimulated in large part by scientific developments in the fields of diarrhea and peptic ulcer. As a result, these products are enjoying a renaissance of interest in gastrointestinal therapeutics based on substantive clinical and laboratory research. This review covers the pharmacology and mechanism of action of bismuth compounds, as well as their clinical indications and toxicity. Chemistry Trivalent bismuth preparations have therapeutic properties, and a number of these products are currently being marketed worldwide. Bismuth subsalicylate (Pepto-Bismol: Norwich-Eaton, Norwich, NY) and colloidal bismuth subcitrate (CBS: De-Nol, GistBrocades, The Netherlands) are perhaps the most familiar products and are discussed here in detail. Parenthetically, bismuth subcarbonate, bismuth subnitrate, bismuth subgallate, and a variety of other bismuth compounds are also available in various countries. Bismuth subsalicylate is a highly insoluble complex of trivalent bismuth and salicylate. A 30-mL dose of the liquid formulation contains 258 mg salicylate and 303 mg bismuth. Bismuth subsalicylate reacts with HCl in the intragastric environment (pH < 3.5) to form Abbreviations used in this paper: BSS, bismuth subsalycilate; CBS, colloidal bismuth sub&rate; HP, Helicobacter pylori. 0 1980by the American Gastroenterological Association 0018-5085/90/$3.00

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bismuth oxychloride (BiOCl) and salicylic acid. Some intact BSS passes unchanged into the duodenum, where it can react with other anions such as bicarbonate and phosphate to form bismuth subcarbonate and bismuth phosphate salts. The salicylate released from the hydrolysis of BSS is absorbed in the stomach and small intestine, while remaining unreacted BSS, BiOCl, and other bismuth salts react with hydrogen sulfide in the colon to produce bismuth sulfide, the black salt responsible for the darkening of stool that occurs with BSS use (2-4). Colloidal bismuth subcitrate is a complex bismuth salt of citric acid, which forms BiOCl and various structures containing free carboxyl groups and positively charged Bi+ when the bismuth-citrate bonds are opened in the stomach (5,6). Bismuth oxychloride is poorly soluble, whereas bismuth ions (B?+ and Bi3+) have physiological properties. The fate of these compounds in the lower bowel is similar to that of BSS, forming various bismuth complexes and bismuth sulfide in the stool.

Pharmacology More than 99% of ingested bismuth appears in the feces, and only small quantities are absorbed into the bloodstream. Lee (7) measured bismuth levels in healthy volunteers and ulcer patients with the sensitive technique of atomic absorption spectrometry. After ingesting 40 ml/day of CBS for 5 days followed by 80 ml/day for 5 more days, the volunteers had a mean bismuth blood level of 4.2pg/L on the last day. Ulcer patients, who were given 20 mL/day for 4-6 weeks, had a mean blood bismuth value of 12.3 &g/L at 4 weeks. Similar results were noted by Serfontein and Mekel (4)who studied a bismuth protein complex (bicitropeptide) and found average bismuth blood levels of 10 yg/L after three weeks. In patients with traveler’s diarrhea treated with BSS, blood and urine levels of bismuth fell below the detection level of the assay (~50pg/L) (8). Using the more sensitive atomic absorption spectrometry method, bismuth blood levels were measured in 30 volunteers taking three tablets of BSS q.i.d. (3.14 g/day] for 6 weeks; mean levels at the end of 6 weeks were 16.0+ 7.9pg/L, and the highest level was 34 pg/L (3). A recent review of bismuth blood levels after CBS administration to 298 persons found that only two exceeded the safety level of 50 pg/L, at levels of 51 and 72 pg/L (6). Accumulated bismuth in tissues is excreted slowly in the urine at a rate of 2.6%/day (7)with elimination half-lives of 5.2 and 4.5days in blood and urine, respectively (9). Recent studies have confirmed the low, but significant, intestinal absorption of bismuth. Nwokolo et al. (10) found that peak plasma levels of bismuth were achieved after 30 minutes of ingesting CBS. In 14 of 16

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subjects, peak plasma levels were >50 pg/L, and in nine the levels were ~100 pg/L. Such rapid peaking of blood levels suggests a proximal site in the intestinal tract for absorption, probably in the duodenum, a supposition that is supported by electron microscopy studies of biopsies which show endocytosis of bismuth in the duodenum, but no penetration of the mucus barrier in the stomach by bismuth (11). Careful measurements by Gavey et al. (12) documented intestinal absorption and sequestration of bismuth in normal volunteers and patients undergoing treatment with CBS. Confirming previous observations, the median plasma bismuth level after 6 weeks of treatment was 17 pg/L, which fell to 5 pg/L 3 weeks after stopping the drug. However, urinary excretion was greater and more prolonged than noted in earlier studies (7); after 6 weeks the median urine concentration was 530 pg/L, and urinary excretion persisted for at least 12 weeks after discontinuation of therapy. It was estimated that 0.2% (35 mg) of the bismuth from the CBS preparations was absorbed. The heavy metal is thought to be sequestered in multiple tissue sites in the body (13), from which it is slowly excreted in the urine for 3 months or longer (12). Salicylate absorption is a consideration with BSS. The salicylate moiety is efficiently absorbed, and 95% of the oral dose is recoverable in the urine. Indeed, the pharmacokinetics of salicylate in BSS is identical to an equivalent dose of aspirin (14). At a low dose of BSS, the relationship between dose and recovery is linear, but multiple-dose regimens show a nonlinear relationship, with a tendency for salicylate accumulation. Following an eight-dose regimen of 30 mL administered every 30 minutes over 3.5 hours, average peak plasma salicylate levels were 137 pg/mL, considerably less than toxic levels (15). Dosing for 3 weeks of BSS at 2.1 g/day produced a steady state of average plasma levels at 24 pg/mL (3). In a study of children aged 3-30 gave months with chronic diarrhea, Gryboski et al. (16) BSS doses of 2.5-10mL every 4 hours for 7 days: none of the children had plasma salicylate levels >lO pg/mL. Thus, salicylate plasma levels have not been excessive in studies 13 weeks in duration, but caution should be exercised in children, in patients with renal disease, and in patients taking aspirin or related products.

Bismuth Therapy in Ulcer Disease Although ulcer healing has become far easier with the advent of the Hz-receptor antagonists, the fact that ulcers can develop when acid secretion is perfectly normal has prompted reexamination of established notions of the pathophysiology of ulcer disease and has renewed interest in the action of agents such as bismuth compounds that heal ulcers without reduc-

September 1990

ing acid. There is also concern about the long-term effects of gastric acid suppression caused by the chronic use of H, blockers as maintenance therapy to reduce ulcer relapse. The following are among the potentially serious consequences of chronic ingestion of H, antagonists: hypergastrinemia, increased risk of various infections, enterochromaffinlike cell proliferation, and possible neoplastic changes. The efficacy of bismuth compounds in ulcer disease has been established by numerous placebo-controlled studies, as well as comparative trials with H, antagonists and sucralfate. In a randomized, double-blind, crossover trial, Coughlin et al. (17) showed that 5 mL CBS diluted in 15 mL of water administered three times daily was effective in patients with either recently diagnosed or chronic duodenal ulcer. After 4 weeks, the endoscopically documented ulcers of 28 of 34 (82%) CBS-treated patients were completely healed (partial healing was counted a failure] compared with healing in 10 of 23 (43%) placebo-treated patients. Colloidal bismuth subcitrate also achieved symptomatic improvement which was highly significant against placebo therapy. This 80% response rate has been reproduced in subsequent studies with considerable consistency (18,19) and, moreover, is entirely comparable to the response rate of cimetidine (20-25) and randitidine (26,271. Lee et al. (26) found no difference in the healing rates of standard doses of ranitidine (150 mg b.i.d.) and CBS (1 tablet q.i.d.) after 4 weeks, and both reached 97% efficacy after 8 weeks, a result very similar to that of Ward et al. in their comparative study (27). Indeed, in Tytgat’s amalgamation of the results of a dozen published trials comparing CBS to cimetidine, 78% (214/275) of duodenal ulcer patients on CBS were healed in 4 weeks compared with 63% (107/272) of cimetidine-treated patients; in three trials comparing CBS with ranitidine, the healing rates were 84% vs. 78% in the same time frame (28) Trials with combined H, antagonists and bismuth compounds have been fewer in number, and the results remain inconclusive (29). Of considerable interest are the findings of Lam et al. (30) who reported in a randomized crossover trial that CBS was more efficacious in cimetidine-resistant duodenal ulcers than high-dose cimetidine. Of 212 patients treated with 1 g cimetidine daily, 25 had ulcers that underwent no reduction in size. Only 40% of nonresponders randomized to an increased cimetidine dose (1.6 g) healed, whereas 80% healed with CBS. The same 80% healing rate was achieved with CBS when those not responding to high-dose cimetidine were crossed over. This study suggests that although cimetidine-resistant duodenal ulcers constitute a relatively small subgroup (11%) of duodenal

BISMUTHTHERAPYIN GI DISEASES 865

ulcers, a drug directed at mechanisms other than acid inhibition may be more useful in this setting. The results in trials with gastric ulcer patients have been much the same, although healing rates tend to be somewhat lower. Sutton (31) reported a 72% rate compared with 36% in placebo-treated patients at 4 weeks, which increased to 96% after 2 months. This compared with 66% healing after 6 weeks in another endoscopically controlled trial from Australia (321and 94% in 4 weeks in the trial of Glover et al. (33), although their figure breaks down to 10 of 16 completely healed and 5 large ulcers more than 50% healed. In a comparison of CBS, H, blockers, and placebo, Tytgat et al. (34) reported complete healing in 61% of CBS-treated patients compared with 43% of those on cimetidine and 18% on placebo: the combined figures from three studies indicate an average CBS healing rate of 64% as compared with 52% for cimetidine at 4 weeks, and 85% as opposed to 70% at 8 weeks (35). Serious side effects were not noted in these studies, although a blackening of the stool caused by the formation of bismuth sulfide was rather common. A reversible staining of the teeth was seen with the original CBS tablets but did not seem to occur with the current coated tablets. The liquid form of bismuth subcitrate used in some of the trials was found objectionable by patients because of its odor (32) but the tablet subsequently developed is reported to be highly acceptable to patients and to be as effective as the liquid (22,341. A detrimental effect of smoking on healing rates in CBS-treated patients has not been established in these studies, some of which show no effect (20,26), and at least one study of CBS in gastric ulcer inexplicably showed a beneficial effect of smoking on healing rates (5). The high rate of relapse upon withdrawal of treatment in ulcer disease makes the length of remission an important parameter in the evaluation of any therapeutic agent. Prolonged remission periods have been established for bismuth therapies in both duodenal (22,25,26,36) and gastric (20,31) ulcer, although the number of patients in the gastric ulcer studies is smaller and therefore less convincing (28). While one small trial showed a relapse rate for bismuth treatment of duodenal ulcer of only 10% after 3 months (20) and another reported 13% at 6 months (22) the findings of Lee et al. of relapse after 4, 8, and 12 months are not unusual at 41%, 55%, and 62%, respectively, which compares with 7470, 85%, and 89% for ranitidine for the same periods (26). In a trial of CBS using 120 mg daily (one quarter the usual dose) for 6 months maintenance after healing, Bianchi Porro et al. (36) found endoscopically confirmed relapse in 38.5% of the CBS

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group compared with 80% relapse in placebo-maintained patients. The therapeutic benefits of bismuth preparations in gastric and duodenal ulcer generally have been attributed to their cytoprotective and demulcent action. Studies in which rats have been subjected to the ulcerogenic stresses of ethanol, aspirin, and water immersion have shown that pretreatment with bismuth preparations such as CBS or BSS markedly reduced hemorrhagic lesions: this effect was dosedependent (37-40). The protection conferred by bismuth compounds is thought to result from the coating of the gastric mucosa, passively defending against the digestive activity of acid and pepsin. Koo et al. (411, using a chronic gastric ulcer model in the rat, found that CBS (but not other commonly used bismuth compounds] had a selective coating affinity for the ulcer that did not extend to normal gastric mucosa. By light and electron microscopy they also found an abundance of macrophages which had ingested the bismuth, and they suggested that the bismuth coat insulates the ulcer base from acid-pepsin digestion, while reparative processes are expedited by the influx of macrophages. Lee (421, administering CBS to two patients preoperatively, found a preferential accumulation of bismuth in gastric ulcer craters and their margins in the postoperative stomach specimens. However, this finding is disputed by Lambert et al. (43) in longer term studies of 4 and 8 weeks of therapy with CBS. Similar low concentrations of bismuth were found in plasma, gastric antral mucosa, and duodenal mucosa after a single dose and after 4 weeks and 8 weeks of treatment (specimens were obtained 24 hours after the last dose). This study failed to find preferential accumulation of bismuth in gastroduodenal tissues, suggesting that the major activity is related to luminal levels because bismuth concentrations are considerably higher in gastric juice and gastric mucus than in plasma or tissues (44). Current research has suggested that still other factors may be involved in the salutary effects of bismuth preparations in ulcer disease. In particular, earlier animal studies (45) demonstrating that endogenous prostaglandins play a role in gastric cytoprotection have now been amplified by recent work in an animal model showing that increased prostaglandin synthesis is stimulated by bismuth compounds (46,47). This effect was partially blocked by indomethacin (45,46). In addition, Lee found that CBS and gastric glycoprotein formed an in vitro complex that strengthens mucosal barriers by retarding hygrogen-ion diffusion (42). While neither acid neutralization nor acid production appears to be altered by CBS, Baron et al. (48) have observed that CBS caused diminished output and concentration of pepsin and have suggested that CBS has a prolonged effect on the mucosa. Bismuth

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activity against Helicobacter pylori (HP] will be discussed below, but it is pertinent to note here that CBS inhibits proteolytic enzyme activity elaborated by this organism toward gastric mucus (49). These studies indicate that bismuth compounds have at least equal and perhaps superior efficacy to H, antagonists in short-term therapy of ulcer disease. However, relapse rates are high in all treatment groups, and it is clear that additional strategies are needed. Consideration of HP will reveal alternative approaches in certain patients.

Bismuth and Helicobacter

pylori

Like so many scientific discoveries, the recently described association between spiral bacteria and gastric ulceration (50) was actually a rediscovery of observations that had been reported in the medical literature on many occasions in this century (51). To the credit of Barry Marshall and his colleagues, this work was pursued vigorously in the laboratory and clinic, and their findings have been confirmed and amplified by scores of investigators. As a result, HP (521,formerly Campylobacter pylori and Campylobacter pyloridis, now occupies a central place in contemporary views on pathophysiology of ulcer disease (53-57). Interest in HP has advanced pari passu with a reexamination of the role of bismuth compounds. Helicobacter pylori has a strong association with type B gastritis, and it is found in up to 75% of patients with gastric ulcer and in more than 90% of duodenal ulcer patients, most of whom have concomitant antral gastritis (51-57). Two volunteer ingestion experiments demonstrated that HP causes acute histological gastritis and achlorhydria and that although the organism may clear spontaneously, as it did in one volunteer within 2 weeks (58), it may also become chronic despite vigorous treatment (59), as it did in the second volunteer. In one of the earliest drug studies, McNulty et al. (60) showed a close correlation between the presence of HP and histologically proven gastritis, both in the initial phase and after treatment of HP when gastritis improved in patients in whom the organism was cleared. Three treatment groups were compared: BSS, erythromycin, and placebo; at the end of 3 weeks on these regimens, endoscopy showed HP clearance in 14 of 18 patients (78%) in the BSS group, 1 of 15 in the erythromycin group (7%], and none of 17 in the placebo group. Several studies have now established that suppression of HP by bismuth compounds is accompanied by improvement in gastritis scores (54,6064]. Dooley et al. (541, for example, reported that cimetidine had little effect on either HP or gastritis, whereas BSS significantly reduced the prevalence of both, a finding confirmed in the study by Eberhardt

September 1990

and Kasper (64). Lanza et al. (65) also found significant improvement in histological gastritis and clearance of HP in patients treated for 3 weeks with BSS compared with placebo controls. Despite these encouraging results for short-term therapy with bismuth compounds, longer follow-up has shown a high relapse rate, with overall HP eradication of IO%-50% with these compounds as solitary therapy (61,62,64,66). Recurrence of HP is usually associated with clinical relapse. Coughlan et al. (67) treated patients with duodenal ulcers for a longer period (6 weeks) with either CBS or cimetidine. In both groups, 70% had initial ulcer healing. These “successful” cases underwent endoscopy again at 12 of the months, and ulcer relapse was seen in 52% CBS-treated group and 67% in the cimetidine-treated group. Overall, 12-month cures in the original group were approximately 35% for CBS and 20% for cimetidine. To investigate combination therapies, Marshall et al. (61) performed studies in patients with peptic ulcer disease and HP colonization, comparing groups treated with cimetidine, CBS, or CBS plus an antimicrobial drug for 6 weeks. As expected with monotherapy, cimetidine was ineffective; CBS, while significantly reducing the HP population, did not entirely eradicate it, and relapse of both HP and gastritis commonly occurred upon withdrawal of CBS. Long-term eradication of HP and the concomitant gastritis was achieved when CBS was combined with either amoxycillin or tinidazole. In a larger trial, 100 patients with duodenal ulcer and HP infection were randomly assigned to 8 weeks of cimetidine or CBS therapy with concurrent tinidazole or placebo during the first 10 days (68). Cimetidine, even when combined with tinidazole, was ineffective against HP. However, the organism was eradicated in 27% of patients receiving CBS plus placebo and in 70% of patients receiving the CBS plus tinidazole. Treatment success, defined as ulcer healing without relapse for 12 months without maintenance therapy, was 19% for cimetidine alone, 32% for CBS plus placebo, and 56% for CBS plus tinidazole. Persistence of HP after the lo-week therapy was a strong predictor of relapse: when HP persisted, 84% of these patients relapsed at 12 months whereas when HP cleared, only 21% relapsed. A bismuth-antibiotic combination for HP infection has also been used in children with antral gastritis, most of whom had associated duodenal ulcers; BSS plus ampicillin gave a 75% success rate (69). The best results reported to date, with HP eradication rates of over 90%, have been achieved after 4 weeks of combination treatment with CBS and tetracycline (2 g/day], along with metronidazole (800 mg/day) for 2 weeks, in duodenal ulcer patients who have been

BISMUTHTHERAPYIN GI DISEASES 867

followed up without relapse for more than 18 months (70). With this “triple therapy” regimen, nearly a third of the patients experienced nausea, 7% had diarrhea, and smaller numbers complained of burning mouth or throat, dizziness or drowsiness, oral/vaginal thrush, and a single instance of Clostridium dificile diarrhea. While the therapeutic results are impressive, the side effects may render this approach unacceptable to some patients. Triple therapy (BSS, tetracycline, and metronidazole) was evaluated carefully by endoscopy, histology, and measurements of gastric acid secretion in six HP-infected patients with type B gastritis (71). Helicobatter pyiori was eradicated in every patient, and all showed marked improvement in histological signs of acute and chronic inflammation. Moreover, a significant increase in basal and pentagastrin-stimulated acid output was noted in the successfully treated patients. In a small study involving 32 children with HP gastritis, Oderda et al. (72) reported good results with antimicrobial drugs alone, without bismuth compounds. Using amoxycillin and tinidazole for 6 weeks, they achieved 94% clearance of HP and 84% improvement in gastritis at the l-month follow-up. Unfortunately, only 12 children could be restudied at a later date (6 months), but 9 of them remained free of HP. Previous studies with amoxycillin alone gave disappointing results, with high relapse rates in children (73) and adults (74). While a single antimicrobial drug may prove ineffective, a combination of antimicrobial drugs could provide an alternative to bismuthcontaining compounds. However, the lack of adequate follow-up in the study by Oderda et al. (72) makes it difficult to accept this particular therapeutic approach without reservation. Nevertheless, this avenue of research deserves close attention. In contrast, combination therapy of H, blockers with various antimicrobial drugs shows either no influence on HP or only a short-term suppression of HP in a minority of patients (75). One study found that biopsy samples of a small number of patients were more heavily colonized with HP after treatment with H,receptor blockers than before, lending some clinical weight to the disheartening suggestion that acidreducing drugs actually promote bacterial infection by allowing the intragastric pH to increase (75,76). Another potential drawback of H, blockers is that they may interfere with the efficacy of bismuth therapy, which depends in part on the presence of acid in the stomach (77). Heavy metals are known to possess antimicrobial properties, and bismuth is no exception to this rule. In vitro studies from three laboratories have shown that all strains of HP studied thus far are sensitive to bismuth compounds at concentrations achieved in the

888 SHERWOOD L. GORBACH

upper gastrointestinal tract (i.e., 132 pg/mL) (78-80). No bismuth-resistant HP strains have been encountered. Synergy between bismuth subcitrate and rifampin and fi-lactam antibiotics has been described (80). Resistance to antimicrobial drugs can occur during therapy; Goodwin et al. (81)noted that 17% of HP strains were resistant to tinidazole at the first endoscopy; this resistance rate increased to 70% after therapy with tinidazole and CBS. Ultrastructure studies of endoscopic biopsies in patients treated with CBS have shown three types of bismuth changes in HP within l-2 hours of ingestion (611. The organism was loosened from the antral epithelium, seemingly losing its adherence properties. The bacterial structure was distorted by condensation and fine and gross vacuolization of its contents. In addition, deposits of electron-dense material, apparently bismuth complexes, were observed on the external surface and beneath the cell wall of the organism (61,63). It appears that bismuth compounds have direct antibacterial action, as well as the ability to interfere with epithelial attachment of the organism. Several unanswered questions remain about the therapy of HP infections. The high initial failure rate and relapse rate with monotherapy using bismuth or an antibiotic are puzzling, as is the apparent therapeutic synergy with a combination of bismuth and antimicrobial drugs or perhaps antimicrobial drugs in combination. Erythromycin. for example, is highly active in vitro against HP, with no evidence of resistance (78-801, yet this drug as a single agent produced clearance in only 1 of 15 HP-infected patients in the trial by McNulty et al. (60). Part of the answer may be related to the niches in which this bacterium sequesters itself (82): HP is a well-protected organism. In the stomach, it is found only on the epithelial surface, buried in gastric mucus, attached to mucus glands, or lodged in the junctions between cells, where it is sheltered from stomach contents, including ingested drugs and gastric acid. In the duodenum the only sites HP colonizes are areas of gastric metaplasia, where most ulcers occur: therefore, HP-induced duodenitis is actually a gastritis in the duodenum (82). Moreover, HP differs from most other organisms in the gut by possessing large amounts of the enzyme urease, and Goodwin et al. (76) suggest that by converting urea into a shield of ammonia, HP is further protected from stomach contents and acid. Perhaps HP, lying between adjacent mucosal cells and in the mucus larger, surrounded by ammonia, escapes the tidal action of bismuth or antibiotics, and relapse then follows withdrawal of treatment. The reason combination therapy is more effective than either agent alone remains a conundrum. Linking HP infection to ulcer disease does not resolve the complex issues of ulcerogenesis or the role

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of acid, but it does provide an explanation for the high relapse rate of H, blockers and antacids, which have no activity against HP. If ulcer disease is related to HP infection, the high failure rates would be attributable to the fact that either the organism has not been eradicated (relapse] or, less likely, a new infection has intervened (recurrence) (83).

Bismuth Subsalicylate in Diarrhea1 Disease Drug treatment of infectious diarrhea entails two modalities: an antimicrobial agent to suppress the pathogen, if it is amendable to treatment, and antisecretory therapy to reduce fluid and electrolyte losses (84). Bismuth subsalicylate seems to possess both properties, at least experimentally, although it is unclear whether one or both is active in the therapeutic setting. Travelers’ diarrhea has been used as the model system for many studies of acute infectious diarrhea (85,86). The majority of cases are caused by toxigenic Escherichia coli, but in at least one third no pathogen can be identified (87). DuPont et al. (88) reported a field trial in which American students who developed diarrhea at a Mexican university were treated with either placebo or BSS, 30 mL every I/Z hour for eight doses (4.2 g/day) or double that amount (8.4 g/day). Treatment provided significant subjective relief and decreased the number of unformed stools. The average number of unformed stools in the initial 24 hours after treatment was 1.9 vs. 3.0 for low-dose BSS and placebo, respectively, and 1.4 vs. 2.5 in the high-dose BSS group. The students with a positive culture for toxigenic E. coli had an even better response: 1.2 vs. 3.5 unformed stools in 24 hours in the BSS and placebo groups, respectively. In a similar study by Steffen et al. (89) and DuPont et al. (88), BSS in the liquid form (4.2 g/day) was selfadministered by European tourists to West Africa and American students in Mexico after diarrhea had developed (89). The average time to passage of the last unformed stool was decreased by 25% in the BSS groups compared with placebo controls at both sites. Similarly, the average time for total resolution of all symptoms was down 14% in West Africa and 23% in Mexico in those using BSS. The average number of unformed stools was reduced 18% in West Africa and 16% in Mexico. The response to BSS was similar in those with severe illness (seven or more bowel movements per day] and those with mild illness. In another study of travelers’ diarrhea among American students in Mexico, Johnson et al. (90) compared BSS with loperamide, an antimotility drug. Loperamide-treated subjects had fewer unformed stools than those in the BSS group in the first and second days of illness with all types of pathogens. The only notable side effect

September 1990

was constipation in eight patients receiving loperamide compared with one patient in the BSS group. These studies demonstrate that BSS has modest efficacy in ameliorating symptoms and reducing fluid losses in traveler’s diarrhea, with a low incidence of side effects (86). Infectious diarrhea is both more common and potentially more serious in children, and BSS has shown promising results in acute and chronic pediatric diarrhea, although the studies are rather limited. SorianoBrucher et al. (91) studying 123 infants and children with acute diarrhea in Chile, administered BSS (100 mg - kg-’ - day-‘) for 5 days in a placebo-controlled trial. The BSS group had significant improvements over the placebo group in the following parameters: number of stools per day, requirements for IV fluids, stool weight and consistency, and length of hospital stay. No cultures were taken during this study, although the authors state that previous surveys in their community have shown that rotavirus is the major pathogen, present as the only organism in 50% of children with diarrhea and mixed with pathogenic bacteria in another one third of cases; toxigenic E. coli and other bacterial pathogens are found in the remainder of cases. The efficacy of BSS in chronic, nonspecific diarrhea in children aged 2-70 months was studied by Gryboski et al. (16). The children were treated for 7 days; the dosage, administered every 4 hours, varied according to age from 2.5 mL for the youngest to 10 mL for the oldest children. The BSS-treated patients gained significantly more weight and passed stools that were firmer and fewer in number. In an overall clinical assessment by physicians and nursing staff, 86% of the BSS group was judged to have had a moderate to excellent response, while none of the placebo group received these ratings. Symptoms recurred in two thirds of the patients after treatment was discontinued, but this was prevented by tapering the medication over a 4-8-week period. Measurement of serum salicylate levels showed undetectable quantities in the blood throughout the study. In a preliminary study, Ghent et al. (92) noted that diarrhea in children with elevated fecal bile acid excretion, characterized by green-colored stool, seemed to improve during BSS therapy. This observation was followed up by an in vitro study on the ability of the commercial preparation Pepto Bismol, or its components, BSS and Veegum (magnesium aluminum silicate), to sequester bile acids (93). Compared with a standard sequestering agent (cholestyramine), PeptoBismol had similar capacity to absorb bile acids. Both Veegum and BSS also sequestered bile acids, but Veegum was somewhat more efficient, and the efficacy of the combination as Pepto-Bismol was greater than the individual components alone. These observa-

BISMUTH THERAPY IN GI DISEASES 669

tions were applied to a clinical trial of chronic diarrhea, comparing the results in children with brown stools to those with green stools (94). The BSS was effective in children with green stools in terms of reducing the frequency of stools per day, the percent water concentration, and in extending the intestinal transit time. However, in the group with brown stools, BSS produced no changes in these parameters. As expected, those with green stools excreted larger amounts of bile acids in the feces than those with brown stools. Although the cause for increased bile acid excretion was unclear, it appeared that BSS sequested bile acids in the intestinal tract, thereby reducing this form of choleraic diarrhea. When diarrhea can be anticipated, an obvious strategy would be prophylaxis, and this has been the rationale underlying studies of prevention of travelers’ diarrhea (95). The liquid form of BSS or placebo was taken just after arrival in a double-blind, randomized fashion by American students traveling to Mexico (96). Diarrhea developed in 23% of students receiving BSS in a daily dose of 4.2 g as opposed to 61% of those receiving a placebo, a 62% reduction. The students receiving BSS also reported fewer intestinal complaints and tended to pass fewer watery stools. These findings were corroborated by a study of Swiss travelers to tropical countries for periods of 12-28 days in which each participant was given 1.05 g or 2.1 g of BSS in two doses daily in tablet form or placebo (97). The lower dose achieved a 35% rate of protection when compliance to the BSS regimen was excellent and this was marginally improved to 41% with the doubled dose. When compliance to the BSS regimen was judged only “fair,” no protection was gained. The same dose regimen was followed in a more closely supervised trial of American tourists in Mexico who received either one tablet q.i.d. (1.05 g/day) or 2 tablets q.i.d. (2.1 g/day) in a double-blind, placebo-controlled trial. Diarrhea was reduced 40% in those who received the lower dose and 65% for the higher dose subjects (98). It appears that BSS provides modest protection against travelers’ diarrhea, but only when the traveler is very conscientious about taking the higher dose (2 tablets q.i.d.). A severe form of travelers’ diarrhea was reproduced in a laboratory setting by Graham et al. (99) who administered toxigenic E. coli to 32 volunteers in a test of BSS efficacy as a prophylactic agent. Each subject received 600 mg of BSS 8 hours and 2 hours before challenge and four times daily for 3 days after challenge. Diarrhea occurred in 2 of 15 (13%) BSStreated subjects, compared to 9 of 16 (56%) of those receiving placebo. These studies confirm the efficacy of BSS as a prophylactic agent in the setting of severe diarrhea induced by a toxigenic E. coli pathogen.

870 SHERWOOD L. GORBACH

There is considerable evidence to indicate that BSS has direct antimicrobial activity against diarrhea1 pathogens, and it may act, as in HP-related ulcer disease, by suppressing the etiologic agent. Several bacterial pathogens are inhibited in vitro by BSS or its metabolic products, including toxigenic E. coli, Salmonella, Campylobacter jejuni, and Clostridium dificile (9%101), at concentrations that can be achieved in the intestinal tract. The isolation of bacterial pathogens from the stools of patients with infectious diarrhea is markedly reduced in BSS-treated patients compared to placebo-treated controls. For example, in their study of BSS treatment of travelers’ diarrhea in Mexico, DuPont et al. (88) isolated pathogens from the feces of 4 of 12 patients receiving BSS compared to 27 of 38 in placebo controls. The study by Graham et al. (881, in a metabolic unit where all volunteers were carefully monitored, reported the recovery of toxigenie E. coli from stools in 2 of 14 patients given BSS prophylaxis, compared to recovery from 13 of 15 stools in the placebo-treated group. Similarly, in the prophylaxis study by Steffen et al. (97) among travelers to Africa, pathogens could not be isolated in the stools of any of the 6 patients given BSS, but positive cultures were found in 6 of 12 subjects receiving placebo. These studies support the proposition that at least some of the beneficial results with BSS are related directly to its antibacterial activity. Although bismuth compounds inhibit bacterial pathogens (9%101), as well as many of the aerobic and anaerobic bacteria in the normal microflora when tested in vitro (1001, there seems to be no change in overall composition of the normal flora of the stomach (102) or feces (103) during bismuth administration in therapeutic doses. In the colon BSS is converted to a variety of metabolic products, and these products have some, although less, antimicrobial activity than the parent BSS (lOO,lOl]. While the overall concentrations and types of colonic bacteria are unchanged by ingestion of bismuth compounds (103), these drugs do exert a degree of suppression of their metabolic activity, as shown by reduced fermentation of lactose and raffinose by colonic bacteria in patients treated with bismuth compounds (104). This biochemical finding was accompanied by salutary effects in treating flatulence and diarrhea. Another mechanism of BSS action in diarrhea is direct binding to enterotoxins elaborated by toxigenic E. coli or cholera vibrios, as demonstrated by Ericsson et al. (105,106) in a tissue culture system. These observations were expanded in an animal model of diarrhea in which BSS inhibited fluid production by toxigenic E. coli when BSS was introduced before or just after challenge with the organism or its toxins (107). However, BSS was ineffective when adminis-

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tered from 5-60 minutes after challenge, indicating that the toxin had already bound to its receptor sites, The activity of BSS in viral infections has been studied in the laboratory and in a volunteer trial. Using four enteric viruses in a tissue culture system, it was found that BSS inhibited plaque formation, but only at high concentrations slightly below those that caused extensive damage to the cells (108). The BSS appeared to have no direct activity against the viruses; rather this compound seemed to damage the host cell, causing secondary inhibition of viral replication. In a therapeutic trial reported by Steinhoff et al. (log), 59 volunteers were given an oral inoculum of Norwalk agent. There were significant reductions in severity and duration of abdominal cramps, and the median duration of intestinal symptoms in the treated group were compared with placebo controls. However, there were no differences in frequency or volume of stools or in the extent of viral excretion in feces between the treatment and placebo groups. As noted above, BSS decreased stool weight and IV fluid requirements in cases of infantile diarrhea (caused by rotavirus in 50% -70% of cases) in the study of Soriano-Brucher et al. (91). The data in viral infections are too preliminary to make any definitive statement, although it appears that any benefit that may accrue with BSS treatment is probably related to the salicylate component, rather than being antiviral in nature. There is additional evidence that the salicylate moiety of BSS may play a role in ameliorating fluid losses in acute diarrhea. Aspirin, biotransformed to salicylate, has been shown to reduce intestinal secretions caused by experimental cholera in animals, perhaps by blocking prostaglandin synthesis (110-112). The antiprostaglandin mechanism has also been thought to explain the reduction of symptoms in aspirin-treated children with chronic diarrhea (113). Other studies suggest that the physiological effect of aspirin is inhibition of intestinal secretion by stimulation of sodium and chloride reabsorption (114,115). The net effect of this activity would be reduction of fluid losses in diarrhea. In rats challenged with several types of bacteria isolated from intestinal secretions of malnourished Indonesian children with diarrhea, salicylate was shown to increase fluid absorption and decrease net intestinal fluid losses (116). In a clinical trial of malnourished Indonesian infants and young children hospitalized withgastroenteritis and dehydration, aspirin therapy significantly reduced fecal fluid losses and enhanced weight gain as compared with a placebo-treated group (117). Taken together, these observations suggest that the salicylate in BSS exerts a beneficial effect in acute diarrhea. Clostridium dificile is sensitive in vitro to BSS or its metabolites at concentrations that can be achieved in the lower bowel (100). This observation led to an

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investigation of BSS in the standard hamster model of pseudomembranous colitis induced by C. dificile and clindamycin (118). The BSS reduced mortality in this model in a dose-dependent fashion, although the maximum dose administered (15 mg b.i.d.) was still less active than the protection seen with vancomycin. Gryboski and Kocoshis (119) performed a preliminary study in six children with chronic diarrhea caused by this organism and showed that BSS decreased diarrhea and either eliminated or reduced fecal toxin titers in all six children. The beneficial effect on toxin production indicates that at least some of the therapeutic efficacy of BSS is related to its antimicrobial activity against C. dificile. These encouraging results must be subjected to a larger trial before BSS can be recommended for treatment of C. dificile diarrhea.

Toxicity The question of bismuth toxicity gained attention in the mid-1970s when a lOWcase epidemic of neurological disorders associated with oral intake of bismuth salts emerged in France. This outbreak occurred almost simultaneously with a smaller one in Australia, and there were scattered reports from a number of European countries as well (120-123). The clinical picture that appeared included apathy, mild ataxia, and headaches in the early phases, progressing to myoclonic jerks, dysarthria, severe confusion, hallucinations, epileptic seizures, and even death (124-128). Neuropathological findings include extremely high levels of bismuth distributed diffusely in the brain, with greater concentrations in the grey matter than in the white matter, and widespread loss of Purkinje cells in the cerebellum (121,125,126). It is widely agreed that the only effective treatment for this syndrome is total interruption of bismuth ingestion, which generally results in a complete remission of symptoms with no sequelae. The majority of blood bismuth levels in a study of 310 patients with encephalopathy (129) fell between 100-1000 pg/L, but some were higher than 2000 pg/L (untreated t10 pg/L; normal with intake of bismuth salts in the “safe zone,” t50 pg/L) (128,130). Intestinal absorption of bismuth, which is relatively low (3,10,11), may be increased in patients with colitis, a situation suggested by a fatal case of bismuth encephalopathy in an acquired immunodeficiency syndrome (AIDS) patient with cytomegalovirus colitis (131). However, the interpretation of increased absorption is obscured by the large daily dose (5.2-9.4 g/day for 7 days), which is two to five times higher than the maximum dose used in previous studies (86,95). Although bismuth absorption from the intestine is rapid, reaching peak levels within 30 minutes (lo), there is an unexplained hiatus of 7-10 days between ingestion of a toxic dose, as in a

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self-induced overdose (132) and the onset of neurological symptoms. Urinary excretion of bismuth achieves a steady state of approximately 2.6% per day (7). Most bismuth is excreted in the urine within 2 months, although some excretion persists for 3 months (7,121, supporting the recommendation of a 2-month period of bismuth abstinence between bismuth treatment periods, which should last no longer than 6-8 weeks (129). A key question posed by this history of bismuth encephalopathy has been why bismuth salts, used on a large scale and often in extremely large quantities over years, should be associated with so much toxicity within a short period in the 1970s. Of the explanations proposed, the slow accumulation of bismuth through long-term or high-dose usage, or both, appears reasonable: Bader supports this hypothesis by observing that the onset of the epidemic in France, where bismuth subnitrate and subgallate were the main culprits, coincided with new highs in bismuth sales (129). However, an epidemiological study of 942 patients showed no correlation between amount or duration of bismuth intake and neurotoxicity, and no correlation with age or sex (123). Indeed, a control group of bismuth users with no symptoms of intoxication consumed bismuth for a longer time and at somewhat higher daily doses than the affected patients. The major difference between the two groups was the therapeutic indication, which was most frequently constipation for the encephalopathic patients. Lagier has observed that the outbreak in Australia was characterized by toxicity at lower daily doses than in France; that the salt ingested was usually bismuth subgallate, which may be toxic at lower doses because of its relative liposolubility; and that those afflicted were patients who had undergone colostomy or ileostomy (122) Most cases of bismuth neurotoxicity have been associated with bismuth subnitrate or bismuth subgallate, not with the two most widely used bismuth preparations in recent times, BSS and CBS. Thus far, there are only three recorded cases of encephalopathy related to therapeutic uses of these bismuth preparations, excluding overdoses (104,132). One of the two cases associated with BSS was in a 60-year-old man who had used the drug in large doses for many years for an unspecified reason (133). He became withdrawn and disoriented and developed muscle twitches and frontal lobe neurological signs. His blood bismuth level was 72 pg/L on admission and fell to 10 pg/L after 2 weeks in the hospital, and the patient recovered completely after 4 weeks. The other case reported in association with BSS treatment is that of the patient with AIDS and associated colitis mentioned above, who had a fatal neurological reaction to highdose therapy (131). The single case reported with CBS

872 SHERWOOD L. GORBACH

occurred in a 40-year-old man who had taken the drug for 2 years before he developed paraesthesias, poor concentration, and impaired short-term memory (134). All of the symptoms resolved completely over the lo-12months after he stopped taking the drug. When bismuth preparations such as bismuth sodium tartrate were administered parenterally for treatment of syphilis in the 1920s and 193Os, many cases of renal damage were reported [as reviewed by Serfontein and Mekel (4)], but this complication is not seen with the current commercial preparations taken by mouth. Other components of bismuth compounds have potential toxic effects, particularly the salicylate moiety of BSS. In the studies of salicylate pharmacokinetits in adults and children (14,151, a single dose of BSS produced a mean salicylate blood level of 40 pg/mL, and eight 525-mg doses of BSS produced blood levels of 107-137pg/mL. These values are below the salicylate blood levels associated with side effects (200-400 pg/mL) or toxicity (>400 pg/mL). A 3-week study was conducted in adult volunteers receiving 525 mg q.i.d. (2.1 g/day]: steady-state blood salicylate levels were noted at 2 weeks, averaging 24 pg/mL (3). Because two tablespoons of BSS contain 263 mg salicylate, or the equivalent of 342 mg aspirin, a multiple-dose regimen could entail the risk of salicylate accumulation and intoxication in children because of the nonlinear kinetics of salicylate (1415). As noted above, salicylate levels were not elevated in the small series of children nor treated with BSS studied by Gryboski et al. (16), are there any reports of salicylate toxicity associated with BSS ingestion in the literature. Nevertheless, caution should be exercised when BSS is administered to young children, individuals with salicylate sensitivity or bleeding disorders, and those taking drugs that have clinically significant interactions with salicylate. While aspirin is associated with gastric ulcerations and blood loss, salicylate, which is a weak acid, is less likely to cause such mucosal damage (135). Using a rat model, Glenn et al. (136) showed that aspirin but not salicylic acid caused gastric ulcers. Indeed, BSS or sodium salicylate actually protected animals against gastric ulceration induced by various insults such as aspirin, alcohol, or bile salts (45,137). The safety records of BSS as an over-the-counter medication and CBS as a prescription drug have been excellent, especially considering the billions of doses consumed over the last few decades. There have been no new epidemics of bismuth toxicity since those reported in the 197&s, but this experience has instilled a heightened vigilance in the use of bismuth-containing compounds and inspired recommendations for bismuth-free intervals and avoidance of long-term unsupervised usage (129,138).

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Received July 20.1989. Accepted March 7.1990. Address requests for reprints to: Sherwood L. Gorbach, M.D., Departments of Community Health and Medicine, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111. The excellent editorial assistance of Miriam Reik is gratefully acknowledged.