Ranitidine bismuth citrate

About 15% of those infected with Helicobacter pylori will eventually develop peptic ulcer disease (1), and, according to global statistics, approximately 2% will develop gastric cancer (2). H pylori infection is responsible for up to 95% of duodenal ulcers (DU) and 80% of gastric ulcers, although H pylori-negative ulcers are increasing in North America as a proportion of ulcers diagnosed (1). A confirmed cure of the infection reduces the ulcer recurrence rate from between 60% and 80% to less than 5% the year after treatment (3). Because of the relationship between H pylori and the development of gastric cancer, eradicating the bacteria is anticipated, but not yet proven, to reduce the risk of this disease. Strategies for the management of H pylori infection have been proposed in Canada by the Canadian H pylori Study Group (4). Although H pylori is susceptible to a wide variety of antibiotics in vitro, the organism has proved to be difficult to eradicate in vivo. The eradication rate for any monotherapy is usually less than 20% (5). Clarithromycin is the only treatment that has been shown to achieve higher rates of eradication (6,7), but the use of a single drug is not recommended because of the high rate of developing antibiotic resistance (6). The determination of an ideal H pylori eradication regi-

men has been elusive.The first gold standard triple therapy of bismuth, metronidazole and tetracycline (BMT) (3,5) remains effective.However, the large number of pills that must be consumed and the reduced efficacy in metronidazoleresistant H pylori infections are problematic (8).Dual therapy with a proton pump inhibitor (PPI) and either amoxicillin or clarithromycin has fewer side effects, but lower efficacy (8).These treatments evolved to the present gold standard triple therapies of a PPI with clarithromycin and either amoxicillin or a nitroimidazole (metronidazole or tinidazole) bid for one week, as recommended by numerous worldwide consensus conferences (9)(10)(11)(12).However, these therapies are not uniformly effective, with somewhat variable efficacies in the presence of resistant H pylori strains.
There is still a need for the development of new drugs against H pylori.This paper reviews the clinical data regarding the efficacy and safety of a new agent, ranitidine bismuth citrate (RBC), developed specifically to eradicate H pylori infection.

RBC
Pharmacology: RBC is a novel complex of ranitidine (162 mg), bismuth (128 mg) and citrate (110 mg).It is an amorphous salt with consistent composition as shown by x-ray powder photography.RBC gives no characteristic diffractions and has no melting point, with decomposition beginning at about 150 o C (13).There are clear structural differences between RBC and the admixture of ranitidine and bismuth citrate, as shown through infrared and nuclear magnetic resonance spectroscopy (13).The 400 mg dose of RBC is as effective as a 150 mg dose of ranitidine in inhibiting both daytime and nocturnal intragastric acidity (14), as well as meal-stimulated gastric acid secretion (14,15).Inhibition of gastric acid output by RBC is both time-and dose-dependent, and is independent of H pylori status (15).A single dose of RBC does not affect plasma gastrin levels (15), and RBC does not attenuate the rise in mealstimulated gastrin levels compared with ranitidine (16).
RBC dissolves freely in water, particularly above pH 4, compared with an equimolar admixture of ranitidine and bismuth citrate, which forms an almost insoluble suspension (13).This solubility confers an increased activity against H pylori (17).Because the bismuth derived from RBC is far more soluble than bismuth subsalicylate, a lower dose of bismuth is needed for a therapeutic effect.For example, treatment with an RBC-based regimen includes a total of 258 mg of bismuth per day, compared with 2098 mg of bismuth (two tablets qid) when using bismuth subsalicylate.Absorption of bismuth is modest and increases in a dose-dependent fashion (14).
RBC is also more potent than its individual components for protection against indomethacin-induced gastric mucosal damage in the antrum and ethanol-induced fundic damage in a rat model (17).In addition, RBC inhibits human pepsin isoenzymes, while the admixture is inactive (13,17).
Thus, RBC is a novel molecule and new chemical entity that combines the gastric antisecretory activity of ranitidine with mucosal protective, antipepsin and anti-H pylori properties of bismuth.It is not simply an admixture of bismuth citrate with ranitidine.

ERADICATION OF H PYLORI INFECTION
A large, dose-finding, randomized, controlled trial (RCT) reported that RBC 200 mg bid, 400 mg bid and 800 mg bid healed DU as effectively and safely as ranitidine 150 mg bid (18).RBC is more effective than bismuth citrate and/or ranitidine against H pylori, and the bactericidal effect is more rapid (13,17).RBC suppresses but does not successfully eradicate H pylori infection by itself (18)(19)(20)(21) and enhances the efficacy of a combination of antibiotics against H pylori. Analysis of eradication rates in clinical trials: The efficacy of RBC combined with antibiotics has been evaluated in well designed clinical RCTs.Eradication rates from these studies have been calculated by three types of analyses: intention-totreat (ITT), per-protocol and observed.ITT analysis includes all patients who were infected with H pylori at the time of random assignment.Those who are not evaluated at least four weeks after the end of therapy and those whose test results are otherwise unevaluable are counted as treatment failures or as H pylori-positive.These patients are included in the denominator of the eradication equation, but not in the numerator.Per protocol analysis excludes patients with missing or unevaluable post-therapy results and those who did not comply with the study protocol from the denominator.The observed rate includes those who did not comply with therapy but excludes those with missing or unevaluable results.Other investigators have used the more familiar term of 'all patients treated', which appears to be essentially the same analysis.A criticism is that when studies are reported as the unfamiliar term 'observed' ITT, readers may be confused into thinking that this is the traditional ITT.
The eradication rates presented in the tables of this review are all ITT rates from fully published RCTs.All patients who were randomly assigned to treatment have been included in the denominator.If a patient had a negative H pylori test result at least four weeks after the end of therapy and no positive results at any time after treatment, the patient was included in the numerator as a treatment success.Ninety-five per cent confidence intervals are given where available.RBC plus one antibiotic: As an alternative to triple therapy with two antibiotics, dual therapy of RBC in combination with amoxicillin is ineffective, and data remain in abstract form only (22,23).However, RBC in combination with clarithromycin shows improved efficacy (Table 1) (23,24).Two studies have shown a synergistic effect when RBC and clarithromycin are used together, with the eradication rate being much greater than when the drugs are administered individually (19,25).Study designs, doses, scheduling and ITT eradication rates from 12 studies and 18 study arms of RBC and clarithromycin are shown in Table 1.The dose of RBC used in these studies was usually 400 mg bid for 14 to 28 days.Increasing the dose of RBC from 400 mg to 800 mg bid did not improve H pylori eradication rates (20,21).
The clarithromycin dose ranged from 250 mg qid to 500 mg tid for 14 days.Compared within the same studies, two weeks of RBC with clarithromycin either 250 mg qid or 500 mg bid gave equivalent results (26,27).No differences in adverse events were seen.However, the bid therapy would be pre- ferred due to its simplicity.Increasing the dose of clarithromycin to 500 mg tid is as effective as 500 mg bid for H pylori eradication and DU healing (28).Adverse events and dropout rates due to side effects (3% to 4%) were comparable between groups.Thus, the optimal dose of clarithromycin RBC in dual therapy is 500 mg bid.The ITT eradication rate ranges from 55% to 96%, and pooled results from the 1752 patients treated with RBC plus clarithromycin for 14 days in these studies is 76% (95% CI 70% to 82%).RBC dual therapy for one week has also been studied in one published study (29).Pozzato et al ( 29) compared RBC 400 mg bid plus clarithromycin 500 mg bid for seven or 14 days in DU patients.There were comparable ITT eradication rates of 75% for patients given the seven-day regimen compared with 80% for patients assigned to the 14-day regimen, and compliance was excellent for both treatment durations (29).Another study (only in abstract form) compared oneweek dual therapy using RBC and clarithromycin with triple therapy using RBC, clarithromycin and metronidazole.ITT eradication rates were 87% (48 of 55 patients; 95% CI 76% to 95%) for the dual therapy and 98% (54 of 55 patients; 95% CI 90% to 100%) for the triple regimen (30).Further data are required to determine whether the duration of RBC and clarithromycin dual therapy can be reduced to one week.
The efficacy of 14-day, RBC plus clarithromycin dual therapy in the eradication of H pylori infections shown to be resistant to clarithromycin is shown in Table 2 (31).In this study, the RBC and clarithromycin regimen appeared to be able to overcome the clarithromycin resistance, while the omeprazole and clarithromycin regimen did not (31).However, in a different American study, the same dual therapy was not effective against clarithromycin-resistant H pylori infections (32).Thus, the role of dual therapy in overcoming clarithromycinresistant H pylori strains remains to be clarified.
The development of antibiotic resistance by H pylori strains during treatment with RBC and antibiotics has been evaluated in vivo in two studies.Mégraud et al (31) evaluated the antibiotic sensitivities of H pylori strains before dual therapy with either RBC or omeprazole and clarithromycin 500 mg bid for 14 days.After treatment, one of 39 patients (3%) treated with RBC and eight of 44 patients (18%) treated with omeprazole acquired resistance to clarithromycin (P=0.046).Similarly, Osato et al (33), in a study of 466 patients with initially clarithromycin-susceptible H pylori, found that of those patients with treatment failures, 8% of those treated with RBC and clarithromycin, and 17% of those treated with omeprazole and clarithromycin had developed clarithromycin resistance (P<0.01).Thus, these data suggest that the emergence of antibiotic resistance may be less with RBC-based therapy.Further studies are important and are awaited with interest.Dual compared with triple therapy: RBC triple therapy for one week has been compared with dual therapy combining RBC and clarithromycin for two weeks (Tables 1, 3 and 4) (34)(35)(36)(37).One study (34) found one-week triple therapy with RBC 400 mg bid, clarithromycin 250 mg bid and tinidazole 500 mg bid to be significantly better (P=0.001)than two-week dual therapy with RBC 400 mg bid and clarithromycin 500 mg bid (34).However, in other studies using RBC and clarithromycin dual therapy for two weeks, the proportion of patients cured was equivalent to those using RBC, clarithromycin and metronidazole triple therapy for one (36) or two weeks (26,37).It is thus unclear whether triple therapy is superior to dual therapy.

RBC TRIPLE THERAPIES Eradication of H pylori with RBC plus clarithromycin and a nitroimidazole:
The designs, doses, scheduling, testing details and ITT eradication rates from nine studies and 12 study arms of RBC in combination with clarithromycin and a nitroimidazole (metronidazole or tinidazole) are shown in Table 3.The dose of RBC in these trials was 400 mg bid for seven to 14 days.No RBC was given after the end of the seven-day eradication regimens.
With RBC, clarithromycin and metronidazole, a treatment duration of seven days was as effective as 10 days (38) or 14 days (26).A short, four-day therapy was not an effective treatment, having a suboptimal 60% eradication rate (38).There was a trend toward more side effects with the longer duration of treatment; three of 55 patients dropped out because of drug side effects in the 10-day arm, compared with one of 55 patients in the seven-day arm and none in the four-day arm (38).In comparing studies, there does not appear to be any differences between the regimens that used clarithromycin 250 mg bid (38,39) and the regimens that used clarithromycin 500 mg bid (26,36,37).The dose of metronidazole ranged from 800 mg to 100 mg daily.
For seven-day regimens, the ITT eradication rate ranged from 80% to 94%, and pooled results in 357 patients gave a mean eradication rate of 84% (95% CI 77% to 90%).For all treatment durations pooled together in 540 patients, the mean ITT eradication rate was 82% (95% CI 77% to 87%).For RBC, clarithromycin and tinidazole, all four studies (34,(40)(41)(42) used the same doses of clarithromycin (250 mg bid) and tinidazole (500 mg bid).The ITT eradication rate ranged from 73% to 91%, and the pooled result in 264 patients was 82% (95% CI 69% to 94%).Pooled results are the same when metronidazole is used.Thus, either nitroimidazole can be used, depending on availability.Eradication of H pylori with RBC plus clarithromycin and amoxicillin: Triple therapy with RBC, clarithromycin and amoxicillin omits metronidazole, possibly important in situations where infection with metronidazole-resistant strains of H pylori are suspected or documented.Table 4 shows the designs, dose, scheduling, testing details and ITT eradication rates from six studies.The dose of RBC in these trials was 400 mg bid for seven days in five of the six trials and for 14 days in one American study (43).The antibiotics were given for seven days; the dose of clarithromycin was usually 500 mg bid and amoxicillin was given as 1000 mg bid.
For seven-day regimens, the ITT eradication rate ranged from 71% to 94%, and pooled results in 229 patients gave a mean eradication rate of 84% (95% CI 71% to 96%).The eradication rate with 14-day therapy was similar.Results were very similar to the RBC, clarithromycin and nitroimidazole triple therapy eradication rates.
One Italian randomized trial (40) directly compared RBC, clarithromycin and either tinidazole or amoxicillin.The tinidazole arm showed a trend toward better eradication with a smaller (250 mg compared with 500 mg bid) clarithromycin dose and better tolerability, with no dropouts, compared  with a 7% dropout rate due to side effects with the amoxicillin triple therapy.Another similar study, using clarithromycin 250 mg tid in both arms, showed that RBC, clarithromycin and either tinidazole or amoxicillin were equally effective (42).RBC plus two antibiotics compared with PPI plus two antibiotics: RBC triple therapy has been compared with PPI triple therapy.Designs, dose, scheduling, testing details and ITT eradication rates from three studies are listed in Table 5.In all studies, there was no significant difference in eradication rates between the treatment groups.In one study, there was no difference between the RBC and the lansoprazole triple therapy arms, but because a low dose of lansoprazole (15 mg bid) was used, a difference may have been missed (41).Using either RBC or omeprazole with clarithromycin and amoxicillin, DU healing was similar (44) and regimens were equally welltolerated (45).This suggests that either RBC or a PPI triple combination can be used as first-line therapy; such a recommendation was made in a recent Canadian consensus update (9).

RBC triple therapy in PPI triple therapy failures:
In one Italian study, patients were initially treated for one week with a PPI (omeprazole, pantoprazole or lansoprazole), amoxicillin and clarithromycin triple therapy (46).The overall ITT eradication rate was 78% (95% CI 73% to 83%).The 38 treatment failures were then treated openly with RBC 400 mg bid, tetracycline 500 mg tid and tinidazole 500 mg bid for two weeks, and for which the ITT eradication rate was 82% (95% CI 75% to 97%).
H pylori resistance data were not collected.This RBC regimen may be useful for patients who experienced eradication failures without doing sensitivity testing.
Other RBC triple combinations: Traditional bismuth, metronidazole and tetracycline (BMT) triple therapy was the best early treatment regimen for H pylori infections (5), and efficacy was enhanced by coadministration of an antisecretory drug (47).RBC combines two of these four components and simplifies administration of the drugs.In one four-arm study, RBC (either 400 mg bid or 200 mg qid) was given with either oxytetracycline 500 mg qid or spiramycin 500 mg qid and metronidazole 400 mg qid for 10 days (48).The ITT eradication rates ranged from 88.6% to 93.6%, and results were equivalent whether RBC was given two or four times daily and whether spiramycin or oxytetracycline was used.
The authors suggested that spiramycin, which is less expensive than clarithromycin, deserves further study.
Triple therapy with RBC, metronidazole and tetracycline is less effective, and results are more variable, with an ITT eradication rate of 86% (35) to 92% (49) after seven days of therapy, 60% after 10 days of therapy (50), and 72% (51) to 80% (43) with 14 days of treatment.The best eradication rate was achieved in the studies that used the highest doses of metronidazole (1.5 g to 1.6 g daily) and tetracycline (500 mg qid) (35,49) rather than smaller doses of metronidazole (250 mg tid [43] to 500 mg bid [50,51]) or tetracycline (500 mg bid

CLO plus H plus culture (A and C)
A Antrum; C Corpus; 13 CUBT 13 Carbon urea breath test; H Histology; ITT Intention-to-treat; RUT Rapid urease test [50,51] or tid [43]).Furthermore, baseline metronidazole resistance significantly (P=0.026)reduced eradication efficacy from 97% in patients with a metronidazole-sensitive strain to 57% in those with a resistant strain of H pylori (35).A Chinese study compared RBC or colloidal bismuth citrate with metronidazole and tetracycline triple therapy (RBCmetronidazole tetracycline [RBC-MT] compared with BMT) and reported contrasting results (49).The RBC-MT combination showed a trend toward a better eradication rate (46 of 50 patients, 92%) than with traditional BMT triple therapy (41 of 50 patients, 82%, P=0.23).Metronidazole resistance was defined as a minimal inhibitory concentration (MIC) greater than or equal to 32 mg/L using the E-test.In this study, 25 of 25 (100%) metronidazole-resistant strains were eradicated with the RBC-MT regimen, compared with 12 of 16 (75%, P=0.018) with traditional bismuth triple therapy.
Reasons for the conflicting results between the different studies are unknown.Treatment with RBC, tetracycline and clarithromycin for one to two weeks has been reported by two authors, with ITT eradication rates of over 90% in more than 100 patients (52,53).
One study compared RBC and amoxicillin for one week combined with azithromycin 500 mg od or 1 g od for three days (54).The higher dose of azithromycin was more successful, with ITT eradication in 27 of 36 patients (75%), compared with only 14 of 32 patients (44%) using the lower, 500 mg daily dose.The higher dose was associated with a trend toward more side effects, and two patients stopped treatment because of side effects, but the difference was not significant.

RBC AND ANTIMICROBIAL RESISTANCE In vitro effects of RBC against H pylori:
Resistant strains of H pylori are increasingly recognized (55).In vitro data have shown that RBC is effective in killing 14 different strains of H pylori.The MIC 90 of RBC against H pylori is 15 µg/mL to 16 µg/mL (55,56).Both in vitro (57,58) and in a mouse model (57), the combination of RBC with clarithromycin resulted in a synergistic increase in the activity against H pylori strains, even in those resistant to clarithromycin (58).Osato et al (55), demonstrated in 10 of 11 H pylori isolates that clarithromycin MIC 90 values could be reduced by ninefold, on average, when combined with RBC, and still achieve microbial killing.Thus, RBC and clarithromycin acted synergistically to overcome resistance to clarithromycin (55).In another in vitro study (59), RBC showed synergy with clarithromycin and tetracycline against both sensitive and resistant strains of the bacterium.The mechanism of synergy remains unknown (59).RBC combined with metronidazole in vitro also demonstrated either total or partial synergy against metronidazole-resistant strains (60).
In vitro emergence of antibiotic resistance: An in vitro study analyzed the emergence of resistance in H pylori strains subcultured with metronidazole and clarithromycin (56).
Coculturing H pylori with RBC was found to reduce significantly the rate of emergence of resistance to metronidazole, more than clarithromycin; resistance to spiramycin was unaltered.Why this occurs is unknown; however, the authors observed that in the strain that showed a larger reduction in resistance, there was a higher density of bismuth molecules surrounding the H pylori organisms (56).RBC triple therapy in metronidazole-and clarithromycinresistant H pylori: Antibiotic resistance, particularly to metronidazole, can reduce the efficacy of H pylori treatment regimens containing metronidazole.However, dual therapy with RBC and clarithromycin may be effective, with reported eradication in 11 of 11 metronidazole-resistant H pylori strains (36).In this study, metronidazole resistance was defined as an MIC greater than 8 µg/mL by the E-test.In the same study, triple therapy with RBC, clarithromycin and metronidazole overcame metronidazole resistance in nine of 10 strains.Similar results were reported by Bardhan et al (30), who reported that triple therapy with RBC, clarithromycin 500 mg bid and metronidazole 400 mg bid for seven days successfully eradicated baseline metronidazole-resistant H pylori strains in nine of 10 patients (30).
In another clinical trial, the effects of two different RBC triple therapies on resistant H pylori strains were evaluated (61).Patients were treated for one week with RBC 400 mg bid, metronidazole 500 mg bid and clarithromycin 500 mg bid (RMC) or RBC 400 mg bid, metronidazole 500 mg bid and amoxicillin 1 g bid (RMA).In this study, metronidazole resistance was defined as an MIC greater than 8 m g/mL by the E-test, and clarithromycin resistance was defined as an MIC greater than 2 m g/mL.With RMC, the overall eradication rate was 96% (107 of 111 patients) and was unaffected by prestudy metronidazole resistance (95% eradication in 20 patients).H pylori was also eradicated in three patients with baseline clarithromycin-resistant strains and in a pa-tient infected by a strain resistant to both metronidazole and clarithromycin.For RMA, the overall eradication rate was 79% -87% in metronidazole-susceptible strains but only 22% in resistant strains.This suggests that RMC triple therapy may overcome the in vitro metronidazole or clarithromycin resistance to eradicate H pylori.However, substituting clarithromycin with amoxicillin was not successful.
With RBC, clarithromycin and amoxicillin (35) triple therapy, efficacy was not reduced by baseline metronidazole resistance.Further studies will be important to substantiate these observations and to help identify the role of RBCbased treatments in patients who have failed initial therapy.Side effects and safety: Side effects reported with RBC are few and generally mild.Less than 1% of bismuth administered orally is absorbed systemically, and after repeated dosing with RBC 200 mg, 400 mg or 800 mg bid, trough bismuth concentrations do rise in a dose-dependent fashion in patients with and without renal impairment.However, levels remained below 50 µg/L (14,18,62), which is considered the upper limit of safety.Peak bismuth levels do not appear to rise as high as with tripotassium dicitrato bismuthate, another commonly used bismuth compound (62).
A randomized, double-blind, parallel group study compared the safety of RBC 400 mg bid with that of ranitidine 150 mg bid for up to one year (63).Adverse events were few and comparable between the two groups.Of patients treated with RBC, 29% reported drug-related adverse events, compared with 35% of those treated with ranitidine.Three per cent of RBC-treated patients experienced a serious event, compared with 2% of those treated with ranitidine.Trough plasma levels of bismuth increased slightly over time in patients treated with RBC (63).However, these levels returned to pretreatment values within three months after the end of treatment, and no patient had a plasma bismuth level of more than 50 ng/mL (63).
Pipkin and colleagues (64) summarized the adverse events reported in studies of RBC alone or in combination with antibiotics (Table 6).The adverse events associated with RBC are few and comparable with those associated with ranitidine hydrochloric acid, which has a well established safety record.The only effects directly attributable to the bismuth  component of RBC were dark stools and discoloration of the tongue.The addition of either clarithromycin or amoxicillin increased the frequency of diarrhea marginally.Serious adverse events were seen in less than 1% to 2% of all study arms.The presence of renal failure and pregnancy are considered contraindications for the use of RBC.

CONCLUSIONS
In Canada, the approved dose of RBC is 400 mg twice daily with clarithromycin 250 mg four times daily (dual therapy) for two weeks for the treatment of patients with duodenal and gastric ulcer disease associated with H pylori infection.This may be followed by two weeks of RBC alone to facilitate ulcer healing.Adverse events are generally mild, treatment is well tolerated and bismuth toxicity is unlikely to arise.Studies to date of RBC triple therapy bid for one week show that when RBC is administered with clarithromycin and metronidazole or amoxicillin, eradication results are as effective as those achieved with the current first-line PPI-based triple therapy regimens.There is some suggestion that RBC combination treatments may overcome metronidazole resistance and possibly even clarithromycin resistance.Additionally, there appears to be a relatively low rate of acquired antibiotic resistance.Further data on the role of RBC combination therapies in antibiotic resistance and in the treatment of eradication failures are awaited with interest.
In the Canadian H pylori Consensus Conference update (9), recommended therapies include a regimen of a PPI (omeprazole 20 mg, lansoprazole 30 mg or pantoprazole 400 mg) or RBC 400 mg, clarithromycin 500 mg and amoxicillin 1000 mg bid for seven days; or a regimen of a PPI or RBC, clarithromycin 500 mg or 250 mg, and metronidazole 500 mg bid for seven days.

TABLE 1 Summary of dual therapy of ranitidine bismuth citrate (RBC) in combination with clarithromycin Author (reference) Patient conditions Study design Drugs, dosages and durations Eradication (%) with ITT analysis 95% CI with ITT analysis Helicobacter pylori tests Pre- treatment Post- treatment
A Antrum; C Corpus;13CUBT13Carbon urea breath test; H Histology; ITT Intention-to-treat; RUT Rapid urease test

TABLE 3 Summary of triple therapy of ranitidine bismuth citrate (RBC) plus clarithromycin and a nitroimidazole (metronidazole or tinidazole) Author (reference) Patient conditions Study design Drugs, dosages and durations Eradication (%) with ITT analysis 95% CI with ITT analysis Helicobacter pylori tests Pre- treatment Post- treatment
13Carbon urea breath test; H Histology; ITT Intention-to-treat; RUT Rapid urease test