The effect of tripotassium dicitrato bismuthate on pepsin activity

We have studied the effect of tripotassium dicitrato bismuthate on the peptic activity of gastric juice, both basal and pentagastrin-stimulated, from five healthy volunteers using porcine pepsin solution as a control. Tripotassium dicitrato bismuthate showed no inhibition of the proteolytic activity of either the pure porcine or the human pepsin in the gastric juice. The ulcer healing efficacy of tripotassium dicitrato bismuthate is unlikely to be related to a gastric anti-protease effect.     

The effect of tripotassium dicitrato bismuthate on the rat stomach

Background: Bismuth has been used as symptomatic treatment of dyspepsia for many years. It promotes healing of peptic ulcers and reduces their recurrence. The beneficial effect of bismuth on duodenal ulcer disease is thought to be due to an effect on Helicobacter pylori, although it has a rather weak bactericidal effect on H. pylori in vitro. Eradication of H. pylori in duodenal ulcer patients by a combination of bismuth, tetracycline and metronidazole has been reported to increase the density of somatostatin-producing D cells in the antrum. A reduced D cell density in the antral mucosa of duodenal ulcer patients could explain their exaggerated gastrin release. Aims/methods: To test the possibility that bismuth could affect the neuroendocrine cells independently of the presence of H. pylori or not. we gave rats a diluted tripotassium dicitrato bismuthate solution by gastric gavage for 14 days. Results: Tripotassium dicitrato bismuthate treatment did not affect maximal pentagastrin-stimulated acid secretion or histamine release in isolated rat stomachs or the density of argyrophil cells in the oxyntic and antral mucosa. However, it significantly reduced the duodenal concentration of gastrin and calcitonin gene-related peptide, and the density of G cells in the antrum and duodenum. Conclusion: The effect of tripotassium dicitrato bismuthate on the G cell may be of significance for its beneficial effect on duodenal ulcer disease.     

Absorption and elimination of bismuth from oral doses of tripotassium dicitrato bismuthate

Summary The pharmacokinetics of bismuth subcitrate were studied in plasma and urine under conditions of single and multiple dosing (28–56 days) using atomic absorption technique.Single dose plasma pharmacokinetics showed peak concentrations of 5.5–57.5 µg·l^–1 (mean=24.7 µg·l^–1), reached between 30 and 60 min post dosing with an apparent biphasic elimination pattern. Multiple dose studies showed a continuing rise in plasma concentration and urine excretion rate reaching apparent steady-state levels over 7–29 days (mean=18 days). Washout studies in 6 individuals reciprocated accumulation. Maximum equilibrated plasma levels of 7.6–58.3 µg·l^–1 (mean=38.3 µg·l^–1) were well below those associated with encephalopathy. The half-life of bismuth elimination was 20.7 days.Present patterns of intermittent dosing with bismuth are unlikely to be associated with bismuth accumulation despite slow accumulation and elimination.Presented in part to 89th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, California, March 1988     

Helicobacter pylori: treatment with combinations of pivampicillin and tripotassium dicitrato bismuthate

Fifty Helicobacter pylori- (H. pylori) positive patients entered an open study and were assigned to one of four treatment regimens comprising: pivampicillin (500 mg b.d.) for 2 weeks +/- tripotassium dicitrato bismuthate (tablet or liquid form) for one month. The 14C-urea breath test was used to evaluate clearance (negative at the end of treatment) and eradication (negative at 1 month post-treatment) of H. pylori. Clearance rates were 20% (2/10) after pivampicillin alone, 86% (12/14) after tripotassium dicitrato bismuthate tablets (240 mg b.d.) plus pivampicillin, 67% (6/9) after tripotassium dicitrato bismuthate tablets (120 mg q.d.s.) plus pivampicillin, and 100% (13/13) after tripotassium dicitrato bismuthate liquid (120 mg in 5 ml q.d.s) plus pivampicillin. The eradication rates were 0% (0/10), 13% (2/15), 0% (0/11) and 54% (7/13), respectively. Combination of the results from the 2 tripotassium dicitrato bismuthate tablet/pivampicillin groups gave an eradication rate of 7.7% (2/26) which was significantly lower than the 53.9% (7/13) obtained with tripotassium dicitrato bismuthate liquid/pivampicillin (P less than 0.02). In conclusion, a liquid tripotassium dicitrato bismuthate pivampicillin combination may be of special use in the treatment of H. pylori-positive patients when triple therapy is contraindicated (e.g. patient sensitivity/allergy to metronidazole) or when the H. pylori isolate is resistant to metronidazole.     

Bismuth accumulates in the body during treatment with tripotassium dicitrato bismuthate

Bismuth concentration was measured in plasma, dried leucocytes and urine in nine patients before, during and after treatment with tripotassium dicitrato bismuthate (De-Noltab 2 b.d.) for 6 weeks. During treatment there was an 8.5-fold rise in median plasma bismuth concentration (P less than 0.01), a non-significant doubling of leucocyte bismuth content, and a 349-fold rise in 24-h urinary bismuth excretion (P less than 0.01). The significantly increased urinary bismuth excretion continued for at least 3 months after cessation of treatment with tripotassium dicitrato bismuthate, indicating accumulation of bismuth during treatment with this drug.     

The absorption of bismuth from oral doses of tripotassium dicitrato bismuthate

Two studies measured plasma concentrations of bismuth during dosing with tripotassium dicitrato bismuthate (De-Noltab). The first study compared 24 h plasma bismuth concentration and urinary bismuth excretion in six patients who had already received 29-131 days (median 47 days) of treatment with De-Noltab 2 b.d., and six healthy subjects who only received De-Noltab 2 b.d. on the day of study. There was a prompt rise in plasma bismuth concentration after each dose of De-Noltabs. The median 24 h integrated plasma bismuth concentration was similar in both groups, but the median 24 h urinary bismuth excretion was 5.4-fold higher in the patients. The second study compared the plasma bismuth concentrations after the first and third doses of De-Noltab 2 b.d. in 16 healthy subjects. The median peak bismuth concentration occurred 30 min (range 15-105 min) post-dosing. The peak plasma bismuth concentration was greater than 50 ng/ml in 14 of the 16 subjects, and greater than 100 ng/ml in nine of the subjects. There was no significant difference in the median integrated 10-h plasma bismuth concentration after the first or third dose of De-Noltabs. The results of these studies confirm that bismuth is absorbed and sequestrated during dosing with De-Noltabs. Bismuth is absorbed rapidly after oral dosing with De-Noltabs, to produce peak plasma bismuth concentrations hitherto considered to be in the range associated with bismuth neurotoxicity.     

Helicobacter pylori infection treated with a tripotassium dicitrato bismuthate and metronidazole combination

Seventy-two patients with H. pylori infection in their antral mucosa took part in the study. Forty-three received metronidazole 400 mg t.d.s. for two weeks, plus De-Nol tabs 2 b.d. for four weeks, and the remaining 29 patients received metronidazole 400 mg t.d.s. for two weeks plus De-Nol liquid 5 ml q.d.s. for four weeks. Seven of 57 H. pylori isolates were found to have pre-treatment metronidazole resistance. Success, in terms of eradication of H. pylori, was assessed using a one-month post-treatment 14C urea breath test. Successful eradication of H. pylori was achieved in 72% and 79%, respectively, of the metronidazole/De-Nol tablet and metronidazole/De-Nol liquid groups. These figures increased to 87% and 84%, respectively, if the patients whose organisms were known to be metronidazole-sensitive were considered in isolation. H. pylori was successfully eradicated in only one of seven patients with a metronidazole-resistant organism.     

Some effects of tripotassium dicitrato bismuthate on gastric secretion and the mucus barrier

The effect of tripotassium dicitrato bismuthate (De-Nol) on the breakdown of the gastric mucus barrier was investigated by measuring the output of mucus glycoprotein in pentagastrin-stimulated secretion from 13 patients before and after treatment for peptic ulcer, and by examining the accumulation of dialysable peptides and amino acids (DPAA) in stimulated secretion from ten of these patients. The accumulation of DPAA was significantly reduced after De-Nol (by 54%) and to a greater extent than was the output of mucus glycoprotein (by 27%). These observations are consistent with a decrease in the rate of breakdown of the mucus barrier as a result of De-Nol treatment. De-Nol significantly reduced pepsin output (by 32%) in the same group of patients. Comparison of the change in pepsin output with the change in accumulation of DPAA in stimulated juice indicated that De-Nol increases the resistance of the mucus barrier to acid-pepsin proteolysis and/or inhibits the secretion of amino acids and peptides from gastric mucosa.     

Lack of evidence of neurotoxicity following 8 weeks of treatment with tripotassium dicitrato bismuthate

Objective: To search for evidence of subclinical neurotoxicity in patients treated with tripotassium dicitrato bismuthate. Design: Prospective, controlled, triplicate study using urinary bismuth concentration, magnetic resonance imaging (MRI), nerve conduction studies, visual evoked response and a battery of 10 neuropsychological screening tests. Setting: Out-patient clinics, Walsgrave Hospital, Coventry, UK. Subjects: Fourteen dyspeptic patients; 8 (treatment group) treated with tripotassium dicitrato bismuthate one tablet q.d.s and 6 (control group) treated with ranitidine 150 mg b.d. for 8 weeks. Main outcome measures: Changes in urinary bismuth, MRI, nerve conduction studies, visual evoked response, and neuropsychological tests performed before, immediately after and 8 weeks after the cessation of treatment. Results: In the treatment group the median (range) urinary bismuth concentration was 1 (1–12) ng/ml before treatment, increased to 560 (140–1300) immediately after treatment (P < 0.01, Wilcoxon Rank Sum test) and was still significantly elevated (23 (7–53) ng/ml) 8 weeks after the cessation of treatment. In the patient who recorded the highest urinary bismuth, a high intensity signal appeared in the globus pallidus immediately after treatment and was still present (though diminished in intensity) 8 weeks after the cessation of treatment. This isolated MRI finding was not associated with evidence of subclinical neurotoxicity. No changes in the MRI, nerve conduction studies, visual evoked response and neuropsychological tests were observed among the other patients studied. Conclusions: Bismuth accumulation occurs in patients receiving a conventional course of treatment with tripotassium dicitrato bismuthate but this is not associated with significant changes in the nervous system.     

Peptic ulcer therapy with cimetidine versus tripotassium dicitrato bismuthate in rheumatoid arthritis patients undergoing chronic NSAID treatment

Aim:

To compare the efficacy of cimetidine and tripotassium dicitrato bismuthate (TDB) in arthritic patients who had developed gastric (GU) or duodenal (DU) ulceration while taking non-steroidal anti-inflammatory drugs (NSAIDs).

Methods:

Eighty-six rheumatoid arthritis (RA) patients affected by endoscopically proven DU (n = 44) or GU (n = 42), and on chronic NSAID therapy which was not suspended during anti-ulcer therapy, were randomized to cimetidine (400 mg t.d.s.) or TDB (120 mg q.d.s.). A repeat endoscopy was planned after 4 weeks (and 8 weeks, in case of failed healing). The patients who were unhealed after 8 weeks of therapy were allocated to the alternative anti-ulcer drug for a further 8 weeks without interrupting the anti-inflammatory therapy.

Results:

At week 4 of therapy, 14/24 (58%) DU and 9/20 (45%) GU patients treated with cimetidine were healed, compared with 12/20 (60%) and 10/22 (45%) TDB-treated patients (N.S.). At week 8 of therapy, the DU healing rates were 15/24 (63%) with cimetidine and 14/20 (70%) for TDB. The corresponding GU healing rates were 12/20 (60%) with cimetidine and 13/22 (60%) for TDB (N.S.). At week 16, complete healing with cimetidine was observed in 67% of DU and 57% of GU patients unhealed with TDB; the corresponding figures in the patients crossed to TDB were 83% for DU and 63% for GU patients (N.S. vs. cimetidine).

Conclusions:

No statistically significant difference was found between the healing activities of cimetidine and TDB in rheumatoid arthritis patients with peptic ulcer who did not interrupt their NSAID treatment for arthritis. This trial showed that the continued consumption of NSAIDs appears to slow the ulcer healing process, especially in GU patients.

     

D-penicillamine does not increase urinary bismuth excretion in patients treated with tripotassium dicitrato bismuthate.

Twenty-four urinary bismuth excretion was measured in five patients who had been treated with tripotassium dicitrato bismuthate, before and after single 1 g oral dose of D-penicillamine. Before dosing with D-penicillamine, the median 24 h urinary bismuth output was 55 micrograms 24 h-1 (range 17-156 micrograms 24 h-1) and following dosing with D-penicillamine the median 24 h urinary bismuth output was 53 micrograms 24 h-1 (range 12-156 micrograms 24 h-1). D-penicillamine does not facilitate the urinary excretion of bismuth, hence it is unsuitable for use as an oral chelator in patients with bismuth intoxication.     

A seven-day Helicobacter pylori treatment regimen using clarithromycin, omeprazole and tripotassium dicitrato bismuthate.

AIM: To evaluate clarithromycin 500 mg t.d.s., tripotassium dicitrato bismuthate 240 mg b.d. and omeprazole 20 mg b.d. for 7 days as a Helicobacter pylori treatment regimen. METHODS: The H. pylori status of dyspeptic patients undergoing endoscopy was assessed by histology, culture and rapid urease testing of biopsies and by 13C-urea breath test. Fifty patients who were H. pylori-positive were treated with the above treatment regimen for 7 days. Those patients with active duodenal ulcers present at endoscopy were given omeprazole 20 mg nocte for a further 21 days. Not less than 28 days after completing treatment, all tests were repeated to reassess H. pylori status. Bacterial sensitivity of H. pylori cultures was determined and patients recorded any side- effects. RESULTS: On an intention-to-treat basis, H. pylori infection was cured in 90% (95% CI: 78-96%) of patients. Taste disturbance was experienced by 35% patients. Compliance was excellent, with 96% patients taking more than 95% of tablets. Metronidazole resistance was 41% but all cultures were sensitive to clarithromycin. CONCLUSIONS: This 7-day treatment achieved a high level of cure of H. pylori infection with relatively minor side-effects. It may have a role to play, particularly where there is a high level of metronidazole resistance.     

Comparison of plasma bismuth levels after oral dosing with basic bismuth carbonate or tripotassium dicitrato bismuthate

In 20 healthy subjects plasma bismuth concentration was measured after single oral doses of basic bismuth carbonate or tripotassium dicitrato bismuthate. The drugs were administered in the fasted state or immediately after ingestion of a standard breakfast. After basic bismuth carbonate, plasma bismuth rose to concentrations between 0.7 and 2.6 micrograms/L in the fasted state, while after the meal the maximal level was only 1.3 micrograms/L. In contrast to these very low levels after basic bismuth carbonate, the administration of tripotassium dicitrato bismuthate was paralleled by an increase of plasma bismuth to concentrations between 15 and 232 micrograms/L with a mean peak value of 64 +/- 15.3 (S.E.M.) micrograms/L in the fasted state. Postprandial ingestion of tripotassium dicitrato bismuthate attenuated the peak concentrations to 10.9 +/- 6.3 micrograms/L. One subject, however, had a value of 120 micrograms/L. This study demonstrates that basic bismuth carbonate leads to very low plasma bismuth concentrations, which are far below the critical range that might eventually be associated with bismuth neurotoxicity. Therefore this compound can be considered potentially useful for bismuth therapy of gastrointestinal disorders.     

The safety and efficacy of tripotassium dicitrato bismuthate (De-Nol) maintenance therapy in patients with duodenal ulceration

Seventy-one patients whose duodenal ulcers had healed after a 4-week treatment period with tripotassium dicitrato bismuthate (TDB) were randomly allocated to receive maintenance treatment with either one TDB swallow tablet nocte (equivalent to 120 mg Bi2O3) or an identical placebo. During 12 months of follow-up, no side-effects were reported by TDB-treated patients, blood bismuth levels did not rise above discontinuation threshold concentrations (greater than 50 micrograms/L in the first 6 months, or greater than 100 micrograms/L in the second 6 months), and there were no adverse effects on haematological or biochemical indices. Ulcer relapse was significantly less in TDB-treated patients (P less than 0.025). Cumulative relapse rates at 6 and 12 months were 51% and 66%, respectively, for placebo-treated patients and 26% and 31%, respectively, for those who received TDB. It is likely that TDB is a safe and effective maintenance treatment for patients with duodenal ulcer disease.     

A new quadruple therapy for Helicobacter pylori using tripotassium dicitrato bismuthate, furazolidone, josamycin and famotidine

BACKGROUND: In our previous study, a triple therapy using tripotassium dicitrato bismuthate (TDB), josamycin and furazolidone achieved a suboptimal cure rate of Helicobacter pylori infection. AIM: To investigate whether the addition of an antisecretory agent raises the cure rate using this regimen. METHODS: One hundred and twenty H. pylori positive patients with peptic ulcer disease or functional dyspepsia were randomly assigned to receive 1-week quadruple therapy of TDB 240 mg b.d., furazolidone 100 mg b.d., josamycin 1000 mg b.d. and famotidine 20 mg b.d. (BFJF group), or triple therapy of TDB 240 mg b.d., furazolidone 100 mg b.d. and clarithromycin 250 mg b.d. (BFC group). H. pylori status was assessed by histology and culture of gastric biopsy specimens before and at least 4 weeks after completion of therapy. RESULTS: Seven patients (three in the BFJF group and four in the BFC group) dropped out. Eradication rates (intention-to-treat/per protocol) were 90%/95% in the BFJF group and 82%/88% in the BFC group, respectively (P > 0.05). Duodenal ulcer healing rates were 94% (16/17) in the BFJF group and 80% (20/25) in the BFC group, respectively (P > 0.05). Mild side-effects occurred in 11 (18%) patients in the BFJF group and 10 (17%) in the BFC group (P > 0.05). CONCLUSIONS: One-week quadruple therapy consisting of TDB, furazolidone, josamycin and famotidine achieves a high cure rate of H. pylori infection.     

Does a previous course of tripotassium dicitrato bismuthate afect the subsequent chances of successful Helicobacter pylori eradication?

We have performed a retrospective study of 103 patients with either peptic ulcer or non-ulcer dyspepsia, infected with metronidazole-sensitive strains of Helicobacter pylori (H. pylori), who were treated with a combination of tripotassium dicitrato bismuthate and metronidazole for a period of at least two weeks. Dual therapy with tripotassium dicitrato bismuthate plus metronidazole showed similarly high eradication rates (greater than or equal to 80%) of H. pylori from patients irrespective of age, gender or clinical diagnosis. Most importantly, dual therapy achieved a similar eradication rate of H. pylori infection in 41 patients who had previously been treated with tripotassium dicitrato bismuthate alone or in combination with an antibiotic other than metronidazole. It therefore appears that H. pylori does not become resistant to treatment with tripotassium dicitrato bismuthate.     

High cure rate of Helicobacter pylori infection using tripotassium dicitrato bismuthate, furazolidone and clarithromycin triple therapy for 1 week

BACKGROUND: When metronidazole is used in bismuth-based or proton pump inhibitor-based triple therapy, the cure rate of Helicobacter pylori is usually high. However, metronidazole-resistant H. pylori strains, which are increasing in frequency, are a major cause of failed H. pylori eradication. AIM: To evaluate the efficacy of non-metronidazole containing bismuth-based triple therapy for H. pylori infection. METHODS: One-hundred and eighty H. pylori-positive patients with endoscopically documented peptic ulcer disease or functional dyspepsia were randomly assigned to one of three 1-week regimens containing tripotassium dicitrato bismuthate (also called colloidal bismuth subcitrate) 240 mg b.d. and two antibiotics: furazolidone 100 mg b.d. plus clarithromycin 250 mg b.d. (Group A); or clarithromycin 250 mg b.d. plus amoxycillin 1000 mg b.d. (Group B); or furazolidone 100 mg b.d. plus josamycin 1000 mg b.d. (Group C). H. pylori status was assessed by rapid urease test, histology and culture of gastric biopsy specimens taken from both the antrum and corpus, both before and at least 4 weeks after completion of therapy. RESULTS: Thirteen patients dropped out (3 in group A, 5 in group B and 5 in group C). Based on an intention-to-treat analysis, the eradication rates achieved in groups A, B and C were 88% (53/60), 58% (35/60) and 77% (46/60), respectively. These differences were significant between groups A and B (P < 0.001), as well as between groups B and C (P < 0.05). Side-effects occurred in 7 (12%) patients in group A, 3 (5%) in group B and 8 (13%) in group C, and were mild, with the exception of vomiting in one patient (group C) that resulted in withdrawal from the study. CONCLUSION: One-week triple therapy, consisting of tripotassium dicitrato bismuthate, low-dose furazolidone and low-dose clarithromycin, achieves a high cure rate of H. pylori.     

Tripotassium dicitrato bismuthate enemas in the treatment of ulcerative proctitis

Eleven patients with active proctitis or proctosigmoiditis completed one month's treatment with tripotassium dicitrato bismuthate enemas administered at night. Symptoms, sigmoidoscopic appearances, and the histological grade of acute inflammation were assessed at the commencement of therapy and after one month. An overall score of these features showed improvement in 9 of 11 patients, which encourages further investigation of bismuth in controlled trials for patients with inflammatory bowel disease.     

Comparative pharmacokinetics of bismuth from ranitidine bismuth citrate (GR122311X), a novel anti-ulcerant and tripotassium dicitrato bismuthate (TDB)

GR122311X (ranitidine bismuth citrate, Glaxo Group Research Ltd.) is a salt of ranitidine with a complex of bismuth and citric acid which is being developed for the treatment of peptic ulceration. In this study, 4 groups of 12 healthy male subjects were dosed for 10 days with either GR122311X 500 mg bid (301 mg bismuth per day), GR122311X 1.0 g bid (602 mg bismuth per day), tripotassium dicitrato bismuthate (TDB, DeNoltab, Gist Brocades Ltd., Weybridge, England) 240 mg bid (431 mg bismuth per day) or placebo.After the last dose the geometric mean for C_max for 500 mg bid of GR122311X was 5 ng·g^–1, for 1.0 g bid GR122311X it was 12 ng·g^–1 and it was 21 ng·g^–1 for 240 mg TDB bid. The corresponding trough plasma levels were 2 ng·g^–1, 4 ng·g^–1 and 4 ng·g^–1, respectively.The AUC over a dosing interval after the last dose (AUC) were 34 ng·h·g^–1, 71 ng·h·g^–1 and 79 ng·h·g^–1, respectively. The bismuth urinary recoveries over the last dosing interval (Ae) were 97 g, 227 g and 309 g, respectively, which is less than 1 % of the administered doses. The renal clearance of bismuth was less than the glomerular filtration rate. After adjustment for bismuth dose, the C_max for GR122311X 500 mg was 35 % that of TDB, while for GR122311X 1.0 g the C_max was 42 % that of TDB. Similar differences were observed for Ae.In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Ae and C_max, with a much narrower C_max range than those observed for TDB.     

Tripotassium dicitrato bismuthate: absorption and urinary excretion of bismuth in patients with normal and impaired renal function

We have investigated the absorption and urinary excretion of tripotassium dicitrato bismuthate during a treatment course of 4 weeks in 7 patients with normal renal function (creatinine clearance 115 +/- 29 ml/min; mean +/- S.D.), in 7 patients with impaired renal function (creatinine clearance = 34 +/- 19 ml/min) and in 4 dialysed patients. Following the first dose of tripotassium dicitrato bismuthate (216 mg bismuth b.d.), and after 2 and 4 weeks of treatment (dialysed patients received only 108 mg/b.d.), plasma and urine concentrations of bismuth were monitored for 2 and 24 h, respectively. After stopping therapy plasma and urine concentrations of bismuth were followed for 4 and 6 weeks, respectively. In all three groups of patients small amounts of bismuth (mean values 0.26 to 0.28% of dose) were rapidly (transient mean peak concentrations between 40 and 134 micrograms/L) reached within about 30 to 40 min, absorbed and plasma levels demonstrated a wide intra- and inter-individual variability. Absorption profiles were not altered during the treatment course; however, the trough plasma concentration of bismuth demonstrated an about 3- to 5-fold accumulation (correlated to creatinine clearance) from about 5 micrograms/L to 15 micrograms/L (normal renal function) or to 20-25 micrograms/L (impaired renal function). Pre-study bismuth levels could be detected within 2 to 4 weeks after stopping therapy in all subjects whereas urinary concentrations were still elevated 6 weeks after the course of treatment. Our results indicate that tripotassium dicitrato bismuthate is absorbed in very low amounts during standard therapy. However, dependent on renal function, accumulation to non-toxic levels does occur during a course of treatment. It appears prudent to halve tripotassium dicitrato bismuthate dosage in patients with severe renal insufficiency (creatinine clearance less than or equal to 20 ml/min) to avoid any possible toxic risks. In such patients monitoring of the plasma bismuth concentration might be helpful, especially if longer or repeated treatment is anticipated.