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A 79-year-old man presented to the emergency department with a 1-week history of worsening confusion, falls and hearing impairment. An initial workup for infectious, metabolic and structural causes was unrevealing. However, further history discovered that he had been ingesting one to two bottles of Pepto-Bismol (bismuth subsalicylate) daily for gastro-oesophageal reflux symptoms. On his second day of admission, the plasma salicylate concentration was 2.08 mmol/L (reference range 1.10-2.20 mmol/L), despite no sources of salicylate in hospital. He was diagnosed with chronic salicylate toxicity and Pepto-Bismol use was discontinued. The patient was treated supportively with isotonic intravenous fluids only and plasma salicylate concentration fell to less than 0.36 mmol/L. Concurrently, all his symptoms resolved. This case highlights the potential adverse effects of over-the-counter medications. The diagnosis of chronic salicylate toxicity is challenging, specifically in the elderly and in undifferentiated presentations, as it can be missed if not suspected., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Bismuth (Bi) is a natural element present in the environmental media. Bismuth has been used medicinally for centuries, specifically for the treatment of gastrointestinal (GI) disorders. Although bismuth toxicity is rare in humans, an outbreak of bismuth-induced neurotoxicity was reported in France and Australia in the mid-1970s. The primary source of bismuth exposure in the general population is via food. US FDA (2019) estimated recommended daily intake (RDI) for bismuth as 848 mg bismuth/day (12.1 mg Bi/kg-d assuming a body weight of 70 kg) for GI tract disorders. Exposures to bismuth can be quantified by measuring concentrations in blood and urine. Biomonitoring equivalents (BEs) were derived based on US FDA's RDI as a tool for interpretation of population-level biomonitoring data. A regression between steady state plasma concentrations and oral intakes was used to derive plasma BEs. A whole blood: plasma partitioning coefficient of 0.6 was used to convert plasma BE into whole blood BE. A mass balance equation with a urinary excretion fraction of 0.0003 was used to derive urinary BE. The BE values associated with US FDA's RDI for plasma, whole blood and urine were 8.0, 4.8 and 0.18 μg/L, respectively. These BE values together with bismuth biomonitoring data may be used in screening and prioritization of health risk assessment of bismuth in the general population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Introduction: A fixed-dose association of bismuth subcitrate, metronidazole and tetracycline (BMT) (Pylera ® , Allergan, NJ, USA) was made available in France in 2013 for the eradication of Helicobacter pylori. Due to a historical issue of bismuth encephalopathy, the French Health Authorities requested a study of blood and plasma bismuth concentrations with BMT in daily practice., Aims: The aim of the study was to measure eventual bismuth accumulation and neurological toxicity in patients prescribed BMT., Methods: Patients initiating BMT for H. pylori between March 2014 and December 2015 were included. A blood sample was taken before first BMT intake and 24 h after the last intake, for assay of bismuth. A concentration > 50 μg/L was considered abnormal. Neurological complaints were assessed at inclusion, at the end of the 10-day treatment course, and 28 days later., Results: 202 patients were included, of whom 190 took at least one dose of BMT, and 167 provided both required blood samples. Mean blood bismuth concentrations after the BMT course were 16.9 μg/L (95% confidence interval 15.6-18.3). Concentrations were > 50 μg/L (56.0 μg/L and 50.9 μg/L) in two elderly patients, one of whom presented mild, transient memory impairment during treatment. Non-serious neurological symptoms occurred in 20% of all patients and treatment failure was documented in 5% of patients., Conclusions: In this study measuring blood bismuth concentrations in real-life practice, in < 1% of patients the BMT course resulted in blood bismuth concentrations > 50 μg/L. No serious neurological adverse events were observed., Study Registration: EU-PAS register EUPAS3142 at www.encepp.eu ; ENCePP study seal.

Introduction: Shotgun pellets containing bismuth (Bi) as substitute for lead (Pb) are increasingly being used due to environmental concerns. Information on toxicokinetics of Bi is lacking for the assessment of humans accidentally shot by Bi-containing shotgun alloy pellets., Methods: Male Wistar rats were exposed to miniature alloy pellets containing Bi, tin (Sn) and minor amounts of Pb by implantation in muscle tissues of the hind legs., Results: The concentrations of Bi in whole blood and urine increased up to 53 weeks after implantation. The highest concentrations of Sn in whole blood were observed three weeks after implantation, then declining to background levels 53 weeks after implantation. Lead in whole blood increased up to 13 weeks of exposure, and declined for the remaining observation period. Bismuth and Sn accumulated mainly in kidney, but also in liver, testicle and brain. Analytical field emission scanning electron microscopy of post-implant pellets showed depletion of Pb towards the pellet surface. Oxygen and chlorine accumulated in Sn rich lamellas in areas next to the pellet surface. The distribution of Bi remained visually unaffected as compared to pre-implant pellets., Conclusion: The concentration of Bi increased during the whole observation period in blood, urine, kidney, brain, testicle and liver. The decline in the concentrations of Pb and Sn in blood and urine after reaching the peak concentration may be related to alterations in the chemical composition and element distribution of the implanted alloy pellets., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Objective: To establish a method for determination trace bismuth in blood by atomic fluorescence spectrometry (AFS) . Methods: 4.0 ml nitric acid and 1.0 ml perchloric acid was added into 1.0 ml blood sample then through automation graphite digestion instrument digested, after that 1.0 ml thiocarbamide-vitamin (10%) was injected, 8% HCl constant volume to 10.0 ml, the bismuth was detected by atomic fluorescence spectrometry with 5.0 ml digestive sample. Results: The method showed a linear relationship within the range of 0.4-50.0 μg/L ( r =0.999 7) . The within-run and between-run relative standard deviations ( RSD ) of repetitive measurement at 10.0, 20.0, 40.0 μg/L concentration levels were 2.2%-4.9% and 3.0%-4.0%. The detection limit was 0.032 μg/L. The recoveries of bismuth were 93.0%-103.9%. Conclusion: This method is low detection limit, good accurate and high sensitivity. It has been applied for determination of trace bismuth in blood samples those who need occupation health examination or poisoning diagnosis.

A simple and reliable supramolecule-aggregated liquid solid microextraction method is described for preconcentration and determination of trace amounts of bismuth in water as well as human blood serum and hair samples. Catanionic microstructures of cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS) surfactants, dissolved in deionized water/propanol, are used as a green solvent to extract bismuth (III)-diethyldithiocarbamate complexes by dispersive microextraction methodology. The extracted solid phase is easily removed and dissolved in 50 μL propanol for subsequent measurement by electrothermal atomic absorption spectrometry (ET-AAS). The procedure benefits the merits of supramolecule aggregates' properties and dispersive microextraction technique using water as the main component of disperser solvent, leading to direct interaction with analyte. Phase separation behavior of extraction solvent and different parameters influencing the extraction efficiency of bismuth ion such as salt concentration, pH, centrifugation time, amount of chelating agent, SDS:CTAB mole ratio, and solvent amounts were thoroughly optimized. Under the optimal experimental conditions, the calibration curve was linear in the range of 0.3-6 μg L -1 Bi (III) with a limit of detection (LOD) of 0.16 μg L -1 (S/N = 3). The relative standard deviations (RSD) of determination were obtained to be 5.1 and 6.2 % for 1 and 3 μg L -1 of Bi (III), respectively. The developed method was successfully applied as a sensitive and accurate technique for determination of bismuth ion in human blood serum, hair samples, and a certified reference material.

Background: To eradicate Helicobacter pylori in human pylorus and to heal duodenal ulcers, recently, a new formulation of combination tablets containing metronidazole 125 mg, tetracycline hydrochloride 125 mg and bismuth oxide 40 mg has been developed., Objective: To investigate the pharmacokinetics of metronidazole, tetracycline and bismuth in healthy Chinese volunteers after oral administration of the test formulation., Methods: A one-sequence, 3-period study was conducted in 12 Chinese healthy volunteers (6 male, 6 female). Volunteers each received single low dose (1 tablet) under fed condition in period 1, single high dose (3 tablets) under fasted condition in period 2, and single high dose (3 tablets) and multiple doses (3 tablets at once, 4 times daily for 7 consecutive days) under fed condition in period 3. Blood samples were collected and determined over 48 h in every period., Results and Conclusion: After single high dose administration under fed condition, the C max of metronidazole, tetracycline and bismuth were 6.833 ± 0.742 μg/mL, 0.8513 ± 0.1253 μg/mL and 3.32 ± 1.89 ng/mL, respectively. The C max and AUC 0-48 of metronidazole increased in proportion to the doses within the tested dose range, but tetracycline and bismuth did not. Food caused 10% and 80% decrease of the C max for metronidazole and bismuth, respectively, but did not affect tetracycline. No gender effect was found on the pharmacokinetics of the 3 ingredients. In the steady state, the C av of metronidazole, tetracycline and bismuth were 20.75 ± 3.52 μg/mL, 1.900 ± 0.243 μg/mL and 5.61 ± 1.34 ng/mL, respectively., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: We developed and validated a simplified sample preparation for the analysis of antimony (Sb), bismuth (Bi), manganese (Mn), and zinc (Zn) in whole blood. This simplification included a reduction in sample volume, removal of a lengthy acidic digestion, and optimization of the internal standard., Design and Methods: Measurement of Sb, Bi, Mn and Zn in whole blood was conducted using inductively coupled-plasma mass spectrometry. Method performance characteristics, including intra- and inter-assay imprecision, accuracy, linearity, AMR, sensitivity, carryover, sample stability and assay stability were determined in accordance with clinical laboratory standards. In addition, analytical and clinical recoveries were assessed to investigate comparability between goat blood matrix and pooled patient blood., Results: Established assay performance characteristics included inter- and intra-assay imprecision <4.5% and carryover of <0.04% for all four elements, analytical measurement range of 1 to 25 μg/L (Sb and Bi), 1 to 80 μg/L (Mn), and 50 to 1500 μg/dL (Zn), limit of quantification of 1 μg/L (Sb, Bi, Mn) and 50 μg/dL (Zn) (coefficient of variation <14%), proportional bias of 0.96 and constant bias of -0.28 (Sb), 0.94 and -0.45 (Bi), 1.07 and -0.37 (Mn) and 0.96 and +18.05 (Zn) based upon repeat patient samples, proficiency testing samples, and comparison to an outside reference laboratory., Conclusion: This method overcomes the laborious acidic heat digestion previously used and replaces it with a simplified sample preparation involving an alkaline dilution. The method requires minimal sample preparation with the dilution of alkaline diluent and is validated to quantify Sb and Bi from 1 to 25 μg/L, Mn from 1 to 80 μg/L, and Zn from 50 to 1500 μg/dL in whole blood., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

The in vivo(212)Pb/(212)Bi generator is promising for application in targeted alpha therapy (TAT) of cancer. One main limitation of its therapeutic application is due to potential release of (212)Bi from the radioconjugate upon radioactive decay of the mother nuclide (212)Pb, potentially leading to irradiation of healthy tissue. The objective of the present work is to assess whether the chelate CHX-A''-DTPA (N-(2-aminoethyl)-trans-1,2-diaminocyclohexane-N,N',N''-pentaacetic acid) bound to a biological carrier molecule may be able to re-complex released (212)Bi under in vivo conditions to limit its translocation from the target site. CHX-A''-DTPA was bound to bovine gamma globulin (BGG) to mimic a model conjugate and the stability of the Bi-CHX-A''-DTPA-BGG conjugate was studied in blood serum by ultrafiltration. TRLFS experiments using Cm(III) as a fluorescent probe demonstrated that linking CHX-A''-DTPA to BGG does not affect the coordination properties of the ligand. Furthermore, comparable stability constants were observed between Bi(III) and free CHX-A''-DTPA, BGG-bound CHX-A''-DTPA and DTPA. The complexation constants determined between Bi(III) and the chelate molecules are sufficiently high to allow ultra trace amounts of the ligand to efficiently compete with serum transferrin controlling Bi(III) speciation in blood plasma conditions. Nevertheless, CHX-A''-DTPA is not able to complex Bi(III) generated in blood serum because of the strong competition between Bi(III) and Fe(II) for the ligand. In other words, CHX-A''-DTPA is not "selective" enough to limit Bi(iii) release in the body when applying the (212)Pb/(212)Bi in vivo generator.

A cloud point extraction method for the preconcentration of ultra-trace bismuth in human serum prior to its determination by inductively coupled plasma optical emission spectrometry had been developed in this paper. The cloud point extraction method was based on the complex of Bi(III) with 8-hydroxyquinoline and Triton X-114 was used as non-ionic surfactant. The main factors affecting cloud point extraction efficiency, such as pH of solution, concentration of complexing agent, concentration of non-ionic surfactant, equilibration temperature and time were investigated in detail. An enrichment factor of 81 was obtained for the preconcentration of Bi(III) with 25 mL solution. Under the optimal conditions, the detection limit of Bi(III) is 0.12 μg L(-1). The relative standard deviation (n = 7) of determination was 2.3%, values of recovery of bismuth were from 92.3% to 94.7% for three samples. This method is simple, accurate, sensitive and can be applied to the determination trace bismuth in human serum., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted α-radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding (205/6)Bi, and the corresponding (205/6)Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of (205/6)Bi-3p-C-DEPA-trastuzumab conjugate in tumor bearing athymic mice. (205/6)Bi-3p-C-DEPA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low organ uptake and high tumor uptake. The results of the in vitro and in vivo studies indicate that 3p-C-DEPA is a promising chelator for radioimmunotherapy of (212)Bi and (213)Bi.

A procedure for the separation and preconcentration of bismuth was developed in a sequential injection system by employing bamboo carbon as sorbent. The detection was facilitated by both hydride generation atomic fluorescence spectrometry and inductively coupled plasma mass spectrometry. With a sample volume of 1 mL, a detection limit of 13 ng x L(-1) was obtained, along with a precision of 0.9% (0.3 microg x L(-1), n = 9) with detection by HG-AFS, and a detection limit of 10 ng x L(-1) along with a precision of 2.8% (0.3 microg x L(-1), n = 5) was achieved with detection by ICP-MS. The present system was validated by analyzing a certified reference material of river sediment (CRM 320), and spiking recovery of bismuth in human whole blood was performed with hydride generation atomic fluorescence spectrometry. No significant difference was identified in the results of bismuth detection in blood samples by hyphenating the present solid phase extraction system with detection by hydride generation atomic fluorescence spectrometry and inductively coupled plasma mass spectrometry.

Percy Medicine is a nonprescription gastrointestinal suspension containing bismuth subsalicylate as the active ingredient (1050 mg/10-ml dose). A 3-month-old infant with colic developed salicylate toxicity requiring hospitalization in the pediatric intensive care unit (PICU) as a result of continued administration of this medicine. Bismuth subsalicylate has an aspirin equivalency conversion factor of 0.479 (approximately half the strength of aspirin). For 3.5 weeks the infant's parents administered the medicine, which provided the equivalent of aspirin 57-84 mg/kg/day with no reported problems. However, on the day of admission the baby presented with central nervous system depression and respiratory distress. Assessment at a local emergency facility revealed metabolic acidosis; his serum salicylate concentration was 747 mg/L. After acute management, the patient was transferred to our hospital, where he was treated with whole bowel irrigation and alkalinization therapy. Subsequently, the baby required 4 days of management in the PICU and 2 additional days of observation in a general nursing unit before he was discharged home without incident. The parents had chosen Percy Medicine based on the picture of a baby on the front of the package and because of its placement on the shelf next to a drug their family physician had recommended previously. Salicylate-containing products are not routinely recommended for children aged 1 year or younger. The general public may assume that over-the-counter products are safe because they do not require a prescription. Health care professionals must be responsible for educating the public regarding risks associated with over-the-counter products and the need to read and follow label directions.

For decades, drugs containing bismuth have been used to treat gastrointestinal disorders. Although a variety of adverse effects, including neurological syndromes, have been recorded, the biological/toxicological effects of bismuth ions are far from disclosed. Until recently, only quantitative assessments were possible, but resent research has made histochemical tracing of bismuth possible. The technique involves silver enhancement of bismuth crystallites by autometallography (AMG). In the present study, the localization of bismuth was traced by AMG in sections of paraffin-embedded brain tissue obtained by autopsy from 6 patients suffering from bismuth intoxication in a period ranging from 1975 through 1977. Tissue was analyzed at light and electron microscopical levels, and the presence of bismuth further confirmed by proton-induced x-ray emission (PIXE). Clinical data and bismuth concentrations in blood, cerebellum, and thalamus were measured by atomic absorption spectrophotometry (AAS) and are reported here. Histochemical analyses demonstrate that bismuth accumulated in neurons and glia cells in the brain regions examined (neocortex, cerebellum, thalamus, hippocampus). Cerebellar blood vessels stained most intensely. The PIXE and AAS data correlated with the histochemical staining patterns and intensities. At the ultrastructural level, bismuth was found to accumulate intracellularly in lysosomes and extracellularly in the basement membranes of some vessels.

Although toxicity due to acute and chronic use of bismuth salts is well known, nephrotoxicity after ingestion of colloidal bismuth has been reported in few cases so far. Here we report the first case of acute renal failure (ARF) due to colloidal bismuth subcitrate overdosage in childhood. A 2-year-old boy was admitted to the hospital 6 h after ingestion of 28 De-Nol tablets (colloidal bismuth subcitrate 8.4 g). On admission, physical examination was unremarkable and he showed no signs of encephalopathy. Initially gastric lavage was performed then appropriate fluid therapy was started. ARF associated with uremia and oliguria developed on day 2 and peritoneal dialysis therapy was prescribed on day 4 for 10 days. Blood and urine bismuth levels were 739 micrograms/l and 693 micrograms/l, respectively, 10 days after the pills had been taken. His urine volume gradually increased and plasma BUN and creatinine levels decreased during peritoneal dialysis. On day 20 post-admission, plasma BUN and creatinine were 14 mg/dl and 0.7 mg/dl, respectively. Blood bismuth levels were 96 micrograms/l on day 60 and 12 micrograms/l on day 105. Now the patient is well and has no problem. This case suggests that ARF may develop in children following colloidal bismuth subcitrate overdosage; the prognosis is good, and peritoneal dialysis may be useful in these cases.

Several bismuth compounds are currently used as antiulcer drugs, but their mechanism of action is not well established. Proteins are thought to be target sites. In this work we establish that the competitive binding of Bi(3+) to the blood serum proteins albumin and transferrin, as isolated proteins and in blood plasma, can be monitored via observation of (1)H and (13)C NMR resonances of isotopically labeled [epsilon-(13)C]Met transferrin. We show that Met(132) in the I132M recombinant N-lobe transferrin mutant is a sensitive indicator of N-lobe metal binding. Bi(3+) binds to the specific Fe(3+) sites of transferrin and the observed shifts of Met resonances suggest that Bi(3+) induces similar conformational changes in the N-lobe of transferrin in aqueous solution and plasma. Bi(3+) binding to albumin is nonspecific and Cys(34) is not a major binding site, which is surprising because Bi(3+) has a high affinity for thiolate sulfur. This illustrates that the potential target sites for metals (in this case Bi(3+)) in proteins depend not only on their presence but also on their accessibility. Bi(3+) binds to transferrin in preference to albumin both in aqueous solution and in blood plasma.

Objectives: The aim of this study was to compare the dissolution, bioavailability, and anti-Helicobacter pylori activity of bismuth subnitrate and colloidal bismuth subcitrate. This could, first, provide insights into the mechanism of action of bismuth and, second, help to develop optimal therapeutic strategies., Methods: Solubility and aquated size of bismuth species were determined in human gastric juice, while absorption into blood and urinary excretion of bismuth was determined in volunteers. Activity against H. pylori was determined in vitro in the presence and absence of antibiotics, while H. pylori eradication was compared in vivo., Results: Bismuth from colloidal bismuth subcitrate was at least 10% soluble and ultrafilterable and was absorbed in volunteers (>0.5%), whereas that from bismuth subnitrate was insoluble and not absorbed (<0.01%). Colloidal bismuth subcitrate was active against H. pylori (mean inhibitory concentration, 400 microg/ml); neither was synergistic with antibiotics. With in vivo triple therapy, bismuth subnitrate was as effective as colloidal bismuth subcitrate in eradicating H. pylori (74% and 70% eradicated, respectively)., Conclusions: Colloidal bismuth subcitrate, unlike bismuth subnitrate, is partially soluble, absorbed in humans, and directly toxic to H. pylori in vitro. Surprisingly, however, these preparations had similar efficacy in vivo against H. pylori within triple therapy, suggesting that bismuth compounds may also exhibit indirect antimicrobial effects. We propose that this is an effect on the gastric mucus layer. Nonabsorbable bismuth compounds should be preferentially considered in bismuth-based therapies against H. pylori, as they would minimize toxicity while maintaining efficacy.

Background: Bismuth is widely used for the eradication of H. pylori, especially in developing countries, although there are concerns over its neurotoxicity. Whether bismuth has to be absorbed in humans to act against H. pylori is not known. In this study, we compared "absorbable" (colloidal bismuth subcitrate) and "nonabsorbable" (bismuth subnitrate) bismuth as part of triple therapy in the eradication of H. pylori., Materials and Methods: A double-blind, randomized, placebo-controlled trial was carried out with 120 H. pylori-positive patients with nonulcer dyspepsia. Group CBS + Ab (n = 35) received colloidal bismuth subcitrate (one tablet qds), amoxicillin (500 mg qds), and metronidazole (400 mg tds). Group BSN + Ab (n = 35) received bismuth subnitrate (two tablets tds) and the same antibiotics. Group Ab (n = 35) received placebo bismuth (two tablets tds) and the antibiotics. Group BSN (n = 15) received bismuth subnitrate (two tablets tds) and placebo antibiotics. Bismuth was taken for 4 weeks and the antibiotics for the first 2 weeks. H. pylori eradication, side effects, compliance, pre- and post-treatment symptom scores, and bismuth absorption were assessed., Results: H. pylori eradication was 69%, 83%, 31%, and 0% in CBS + Ab, BSN + Ab, Ab, and BSN, respectively. Side effects, compliance, and symptom relief were similar in all groups, but blood bismuth levels were significantly greater in CBS + Ab than the other three groups., Conclusion: The efficacy of bismuth-based therapies as part of triple therapy in the eradication of H. pylori is unrelated to absorption. Hence, the use of effective but poorly absorbed bismuth preparations should be encouraged for bismuth-based eradication therapies.

Poorly absorbed bismuth preparations may benefit a variety of chronic colonic conditions including ulcerative colitis. Bismuth-induced neurotoxicity is a potential complication of the chronic use of these preparations, and a less-absorbable form of bismuth is needed. If bismuth absorption occurs primarily in the upper gut, a delayed-release bismuth preparation could reduce absorption. We studied the site of bismuth absorption from bismuth subsalicylate (BSS) in rats. For 15 days, BSS (50 mg/day) was ingested or infused directly into the cecum via a chronically implanted cannula. Oral BSS resulted in serum and urine bismuth levels many times higher (3.5 +/- 0.3 microg/liter and 1,570 +/- 286 microg/g creatinine, respectively) than with cecal administration (undetectable (<1.5 microg/liter) and 75 +/- 25 microg/g creatinine). Thus, bismuth absorption from BSS occurred almost entirely in the upper gut. These findings provide a rationale for a similar study of delayed-release bismuth preparations in humans.

Two groups of 12 human volunteers, who had been treated with colloidal bismuth subcitrate, because of Helicobacter pylori-associated gastritis, participated in the study. The patients received a single dose of meso-2,3-dimercaptosuccinic acid (DMSA) or D,L-2,3-dimercaptopropane-1-sulfonic acid (DMPS) at a dose of 30 mg kg-1 in a randomized single blind study. In contrast to DMPS, increasing concentrations of bismuth in blood were observed during the first 4 h after intake of DMSA. In urine, both chelators induced a 50-fold increase in urinary bismuth excretion compared with the control urines. The treatment was well tolerated. The results indicate that both DMSA and DMPS effectively increase the elimination of bismuth in human urine. Consequently, both chelators may be of benefit in the treatment of patients with bismuth intoxication.

The mass balance of 14C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague-Dawley rats after single oral doses of 1.0 g kg-1. Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post-dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post-dose. In a separate experiment, bismuth was monitored in bile of bile-duct-cannulated animals for 48 h post-dose. Fecal excretion of bismuth averaged 95.8 +/- 5.30% bismuth dose, while 99.2 +/- 3.63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0.051 +/- 0.028% bismuth dose, and 1.83 +/- 1.08% radioactive dose. Biliary excretion of bismuth averaged 0.0003 +/- 0.0006% bismuth dose, and 0.026 +/- 0.030% radiolabeled dose. An average 0.005 +/- 0.002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quantifiable limits. Though BISOS contains 57.3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (Cmax for BISOS averaged 110 +/- 55.4 micrograms eq mL-1, while for bismuth it was 26.1 +/- 10.3 ng mL-1). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits differential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration.

Background: Mucosal inflammation of the ileal pouch (pouchitis) is the major long-term complication after ileal pouch-anal anastomosis for ulcerative colitis. Broad-spectrum antibiotics are the mainstay of treatment, however, 15% of patients with pouchitis have a chronic, treatment-resistant disease., Aim: To determine the safety and efficacy of bismuth carbomer enemas in achieving and maintaining remission in treatment-resistant chronic pouchitis., Methods: Twelve patients with treatment-resistant chronic pouchitis were treated nightly for 45 days with enemas containing elemental bismuth complexed with carbomer. Diagnosis of pouchitis and response to treatment were evaluated with the Pouchitis Disease Activity Index (PDAI), which includes clinical, sigmoidoscopic and histological criteria. Serum bismuth concentrations were determined by atomic absorption., Results: Ten of 12 patients (83%) went into remission, with a significant decrease of mean total PDAI score from 12 (range 9-15) to 6 (4-15) (P < 0.002), and were continued on bismuth carbomer enemas administered every third night for 12 months. Patients were monitored clinically, sigmoidoscopically and histologically every 2 months for evidence of recurrence (increase > or = 2 in the clinical symptom portion of the PDAI). Six of 10 patients (60%) were able to maintain remission throughout the 12-month trial; 4/10 had an exacerbation, two of which occurred soon after discontinuing daily treatment. Serum bismuth levels were negligible in all patients and no side-effects were registered., Conclusions: Our findings suggest that bismuth carbomer enemas are safe and effective in achieving and maintaining remission in patients with treatment-resistant chronic pouchitis.

Disposition pharmacokinetics of bismuth following oral dosing of ranitidine bismuth citrate are complicated and variable. An analysis of data from healthy volunteers suggests a model with three disposition compartments and first-order absorption. Patient data are pooled from 10 separate studies and consist of 1140 trough concentrations measured in 802 patients following dosing of 2 to 12 weeks duration. There are therefore insufficient data to obtain reliable parameter estimates for the full model and we use instead a much reduced model and an informative prior based on the volunteer data. Individual parameter estimates from this model can then be used to establish covariate relationships. Trough concentrations were influenced by the coadministration of clarithromycin and by creatinine clearance. A simulation study was carried out to check the validity of the estimates obtained from the reduced model. We carry out analysis via Bayesian sampling-based techniques. Throughout, we use predictive distributions for both diagnostic and inference purposes. In particular, we determine predicted distributions for the Cmax, Cmin and AUC characteristics of new individuals.

Background: Ranitidine bismuth citrate is a novel salt of ranitidine and a bismuth citrate complex. It has intrinsic antisecretory and anti-Helicobacter pylori activity, but monotherapy rarely eradicates H. pylori infection in man., Aim: A pilot study to investigate rates of H. pylori eradication achieved by co-prescription of ranitidine bismuth citrate with antibiotics, and to identify several regimens which would merit further investigation., Method: One hundred dyspeptic patients infected with H. pylori were randomly allocated to treatment with ranitidine bismuth citrate 800 mg b.d. plus either amoxycillin, metronidazole, clarithromycin, cefuroxime axetil, tetracycline, tetracycline plus metronidazole or clarithromycin plus tetracycline for 14 days. Eradication of infection was assessed using the 13C-urea breath test 4 weeks after the end of treatment., Results: In a per protocol analysis eradication of H. pylori ranged between 22 and 100%; the intention-to-treat eradication rates ranged between 15 and 92%. No adverse events were specifically attributed to ranitidine bismuth citrate., Conclusion: Co-prescription therapy, using ranitidine bismuth citrate and one or more antibiotics, is suitable for further investigation in large-scale clinical trials in patients infected with H. pylori.

Bismuth preparations are commonly used to treat a variety of gastrointestinal disorders, including peptic ulcers and dyspepsia. The safety profile of currently approved bismuth preparations, such as tripotassium dicitrato bismuthate (De-Nol), bismuth subsalicylate (Pepto-Bismol) and ranitidine bismuth citrate (Pylorid, Tritec), is excellent. Adverse reactions to these agents are mild, transient and infrequent, and reports of serious adverse reactions are rare. This, in part, reflects the low systemic bioavailability of bismuth from these medicines: less than 1% of the bismuth dose administered is absorbed. During repeated dosing with ranitidine bismuth citrate 200, 400 or 800 mg b.d. trough plasma bismuth concentrations remain well below 50 micrograms/L. After 4 weeks of treatment median concentrations of 3.4 micrograms/L or less were reported amongst 1210 duodenal ulcer patients receiving this new chemical entity, while mean concentrations of 5.1 micrograms/L (plasma) and 12.3 micrograms/L (blood) have been reported in two studies of patients receiving tripotassium dicitrato bismuthate 120 mg q.d.s. for 4 weeks. Transient peak plasma bismuth concentrations greater than 50 micrograms/L are observed 30-60 min after dosing with tripotassium dicitrato bismuthate in some patients, but are not associated with any toxic effects. After discontinuation of treatment with bismuth preparations its excretion in urine may continue for up to 3 months, by which time blood bismuth concentrations have declined to pretreatment values.

Background: Ranitidine bismuth citrate (GR122311X) is a new drug which offers potential benefits in healing duodenal ulcers and prevention of relapse., Methods: This randomized, multi-centre double-blind study of 1620 patients compared the effect of 4 weeks of treatment with GR122311X 200 mg b.d. (n = 401), 400 mg b.d. (n = 404) or 800 mg b.d. (n = 404) or ranitidine hydrochloride 150 mg b.d. (n = 411) on the rates of duodenal ulcer healing and of overall success (ulcers healed and remaining ulcer free in the 24-week follow-up phase)., Results: All four treatments were equally effective at ulcer healing (79%, 85%, 84% and 81% of patients, respectively). GR122311X 400 mg b.d. (38%) and 800 mg b.d. (37%) were significantly more effective than ranitidine hydrochloride 150 mg b.d. (32%) with respect to overall success (P = 0.050 and P = 0.030, respectively) but there was no difference with GR122311X 200 mg b.d. (31%). GR122311X caused effective, dose-related suppression of H. pylori (47%, 61% and 74%); H. pylori eradication rates were 18%, 21% and 22%. GR122311X was safe and well tolerated, with an adverse event profile similar to that of ranitidine hydrochloride 150 mg b.d. Median week 4 trough plasma bismuth levels were 1.3 ng/mL, 2.3 ng/mL and 3.3 ng/mL with GR122311X 200 mg b.d., 400 mg b.d. and 800 mg b.d. respectively. No individual plasma bismuth concentrations were of clinical concern., Conclusions: GR122311X is a safe and effective ulcer healing drug, and provides a platform on which anti-H. pylori therapy can be based.

The aim of this work was to investigate whether the normal use of colloidal bismuth subcitrate (CBS) and bismuth subnitrate (BSN) exhibits neurotoxic side-effects. A randomised, single-blind controlled study was carried out in 66 patients with H. pylori associated gastritis. Patients were randomised to receive either amoxicillin (control group) for 4 weeks or BSN for 8 weeks or CBS for 8 weeks. Clinical and neurophysiological tests including electroneurography (ENG) and spectral electroencephalography (EEG) were performed before and after therapy. No clinically relevant changes were observed with clinical tests as well as with ENG and spectral EEG recordings within each group and between the groups. It was concluded that the normal use of CBS and BSN does not exhibit clinical neurotoxicity.

Evaluation of the amount of bismuth (Bi) absorbed from the gastrointestinal tract is important for assessment of the possible risks associated with the use of Bi compounds in the treatment of gastrointestinal disorders. We compared the absorption of Bi from media containing the equivalent of 1 g of elemental Bi from either Bi subnitrate (BSN), Bi subsalicylate (BSS), colloidal Bi subcitrate (CBS), Bi chloride (BiCl3), or Bi citrate (BCit) by an in vivo perfusion system of rat small intestine. The intestinal absorption was < 1% for all compounds, but higher from BCit and CBS than from BSN, BSS, and BiCl3. The dose dependency of Bi absorption from both CBS and BiCl3 in citrate buffer showed a nonlinear relationship between the concentration of Bi in perfusate and the concentration of Bi in blood after 60 min.

The effect of liver disease on total body handling of bismuth was studied in normal and cirrhotic rats to test the hypothesis that hepatic function can be a significant determinant of heavy metal handling. Excretion and tissue distribution of bismuth were investigated in animals administered bismuth subcitrate by the intramuscular route for 70 d. Plasma bismuth in control rats reached an apparent steady state of 31.89 +/- 4.15 micrograms l-1 (mean +/- standard error of mean, n = 12) by day 28-35. The plasma profile in cirrhotic rats resembled that of controls until day 42 after which bismuth concentrations became significantly elevated. At day 70 of dosing the mean plasma bismuth concentration was 63.68 +/- 9.68 micrograms l-1 (n = 11) in cirrhotic rats compared with 32.68 +/- 4.24 micrograms l-1 (n = 12) in control rats (p < 0.05). Total urinary excretion of cirrhotic animals closely paralleled that of controls; however, urinary bismuth clearance was significantly reduced beyond 42 d, as was faecal excretion. Bismuth tissue distribution was analysed in a randomly selected sub-set of control and cirrhotic animals. There was a significantly higher concentration of bismuth in the liver, bone, spleen, lungs and heart of the cirrhotic rats, with no change in the kidney. There was minimal accumulation of bismuth in the central nervous system of either normal or cirrhotic animals. Bismuth accumulation in cirrhotic rats suggests that patients with cirrhosis could be at risk from similar accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

The bismuth concentration was measured in the blood and urine of 21 children from 8 to 17 years old (13.12 +/- 2.67) treated with Ventrisol (Polfa)-tripotassium dicitrato bismuthate (TDB). One tablet of TDB-equivalent to 120 mg Bi2O3. One tablet was given orally to the patients four times a day. Blood and urine was taken for measurement of bismuth concentration in the morning, on fasting, before the administration of Ventrisol on the 6-8 days, the 27-28 days of the therapy and in the 4-5, 8-9 weeks after TDB therapy. The reason for TDB treatment was chronic gastritis and/or duodenal ulcers, which were diagnosed by endoscopic examination. No bismuth in the blood and a very low concentration in the urine were determined in 19 children before TDB treatment. After 6-8 days of TDB treatment the bismuth concentration in the blood was 40.85 +/- 31.05 micrograms/L and 75.11 +/- 82.07 micrograms/L in the urine. In the 27-28 days of the treatment the bismuth concentration in the blood was 37.67 +/- 25.06 micrograms/L, and 163.56 +/- 181.86 micrograms/L in the urine. In the 4-5 weeks after the TDB treatment the bismuth concentration in the blood was 7.77 +/- 10.56 micrograms/L, and 15.72 +/- 9.87 micrograms/L in the urine. The bismuth concentration level in the urine rose together with the rise of the bismuth concentration level in the blood, the correlation factor was r = 0.68. No symptoms of side effects caused by the TDB treatment were observed. Before the treatment a high bismuth concentration was found in the blood of two patients. These cases are discussed later.

A case of bismuth intoxication following the intraoral use of BIPP-impregnated gauze packs is presented. This report illustrates the need for caution when using potentially toxic compounds in the oral cavity where significant quantities can be absorbed to produce symptoms of poisoning.

Bismuth iodoform paraffin paste (BIPP) is used in dressings in ear, nose, and throat, dental, and neurosurgical practice. Neurotoxicity due to absorption of bismuth from the BIPP pack is rare. It is preventable and reversible but likely to be fatal if unrecognised. A case of relapsing but reversible toxic encephalopathy due to a large extradural BIPP pack is reported in a 57 year old Caucasian woman, operated on for a huge basal cell carcinoma of the vertex invading the skull and extradural space. Clinical, neuroradiological (CT and MRI), and biochemical studies are presented and discussed in the light of the available literature.

The content of bismuth in blood serum, kidneys and brain of rabbits was determined after Ventrisol and its foreign analogue administration. The results indicate the lock of essential differences between Bi (III) content in biological material under the study.

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 Cmax 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 tau) 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 tau) were 97 micrograms, 227 micrograms and 309 micrograms, 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 Cmax for GR122311X 500 mg was 35% that of TDB, while for GR122311X 1.0 g the Cmax was 42% that of TDB. Similar differences were observed for Ae tau. In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Ae tau and Cmax, with a much narrower Cmax range than those observed for TDB.

Pb(p, xn) thick target excitation functions were measured in the energy range 10-38 MeV in order to optimize the production of isotopically pure radiobismuth from natPb, 206Pb, and 207Pb. Additionally, the decay of Po-isotopes from deuteron irradiation of natural bismuth (209Bi) was exploited for radiobismuth production. 205Bi was produced from 206Pb at 20 MeV with only 2% of 206Bi at 4 weeks post irradiation. Bismuth compounds as used in the treatment of peptic ulcer were labeled with 205Bi for absorption studies in animals and subjects.

A sensitive method for the determination of the bismuth concentration in human serum is described. Analyses were carried out by inductively coupled plasma-mass spectrometry (ICP-MS), after a simple dilution of the samples with nitric acid. The detection limit of the applied method is 0.007 microgram/l whereas relative standard deviations varied from 5.7 to 13.6%. Determination of reference values in human serum of healthy adults gave a range from < 0.007 to 0.067 microgram/l (19 persons). Bismuth concentrations in serum were also measured before, during and after the intake of therapeutic doses of colloidal bismuth subcitrate (CBS). About 1.5-2 h after the intake of one tablet of CBS, the bismuth concentration in serum was found to have increased 51-1483 times (two apparently healthy volunteers and six hospitalized patients), showing that the serum bismuth concentrations can increase by several orders of magnitude during the intake of CBS. During the intake of four tablets of CBS per day by two apparently healthy volunteers, bismuth concentrations in serum after an overnight fast were found to be, respectively, 5.56 and 8.1 micrograms/l on day 15 and 4.28 and 13.6 micrograms/l on day 29. After stopping the therapy, the concentration of bismuth in serum slowly returned towards normal over a period of months.

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.

A convenient and accurate analytical procedure has been developed for the trace determination of bismuth(III) in natural waters and biological fluids. Bismuth gives a well-defined, diffusion-controlled cathodic wave in 1 M HCl with a half wave potential of -0.21 V with reference to a saturated calomel electrode. Trace amounts of Bi(III) have been determined by normal pulse and differential pulse polarographic techniques in a 1 M HCl supporting electrolyte with linear calibration plots. The determination of Bi(III) has been achieved in the presence of metals with which it is commonly associated. This is illustrated with bismuth measurements in the presence of copper and zinc. Suitable methods of preparing the samples for analysis have also been suggested. The method may also be used for the determination of Bi(III) in different natural water samples and biological materials such as blood and urine samples with lowest detection limit of 0.02 microgram/L.

A sensitive and precise electrothermal atomic absorption spectrophotometric method for determining bismuth concentration is described. Protein precipitation and the use of a palladium modifier reduce the problems of foaming and permit the use of a higher ashing temperature. The detection limit of the assay is 0.9 nmol/L. Total CVs (intra- and interassay) for serum ranged from 3.5% to 15.1% and for urine from 4.8% to 14.5% at concentrations of 60.0 and 6.0 nmol/L, respectively. Analytical recoveries of bismuth added to serum and urine were 102% and 103% over the same range. The method is robust and reproducible and can be accurately calibrated with aqueous standards.

Bismuth-containing medicines have been used for years, but there is a lack of clinically applicable methods for measuring bismuth in body fluids. We describe a sensitive, accurate and precise method for analysis of bismuth in blood and serum, which is suitable both for monitoring purposes and for further investigations into the biokinetics and safety of bismuth. Bismuth was quantitated with electrothermal atomic absorption spectrometry with Zeeman background correction. In the furnace programme a cool-down step was introduced and platinum was used as a matrix modifier. Recovery for 40 micrograms/l is 93.7 +/- 4.6% (mean +/- SD) from serum and 92.8 +/- 5.4% from blood; within-day precision (n = 10) at 40 micrograms/l is 3.2% for serum and 4.2% for blood. Day-to-day precision at 40 micrograms/l (n = 10) was 4.5% for serum and 4.0% for blood. The detection limit is 0.7 microgram/l for serum and 1.0 microgram/l for blood. Blood samples have to be collected in glass tubes and stored at -20 degrees C.

The extent to which bismuth is absorbed following single and multiple oral administration of basic bismuth nitrate was investigated in healthy male subjects. The blood concentration of bismuth and the amounts excreted in urine and feces were determined. The results show that only a small fraction of the administered bismuth dose given in this form is absorbed. Existing differences in the absorption kinetics between this relatively insoluble bismuth salt and colloidal bismuth citrate are discussed.

Bismuth subsalicylate (BSS) and placebo were evaluated in a double-blind, placebo-controlled study as adjunct to rehydration therapy in 123 children, aged 4 to 28 months, hospitalized with acute diarrhea. The dosing regimen was 20 mg/kg five times daily for 5 days. Significant benefits were noted in the BSS group compared with placebo as manifested by decreases in stool frequency and stool weights and an improvement in stool consistency, significant improvement in clinical well-being, and shortening of the disease duration. Patients treated with BSS had a significant reduction in duration of hospital stay (6.9 days) compared with placebo-treated patients (8.5 days). Also, intravenous fluid requirements decreased significantly more rapidly and to a greater degree in the BSS-treated group. Bismuth subsalicylate was associated with clearance of pathogenic Escherichia coli from the stools in 100% of cases but was not different from placebo in rotavirus elimination. Bismuth subsalicylate was well tolerated with no reported adverse effects. Blood bismuth and serum salicylate levels were well below levels considered toxic. In this study, BSS provided effective adjunctive therapy for acute diarrhea, allowing children to get well sooner with less demand on the nursing and hospital staff.

Bismuth encephalopathies appeared in the mid-seventies in France and concerned about 1,000 people and led to a fatal outcome in 70 cases. Responsibility of Bi was clearly confirmed by the disappearance of the intoxication after prescription of drugs containing Bi had been more tightly regulated. Since the implication of a substance increasing the intestinal absorption of Bi has been suspected, we studied the concentrations of Bi in the tissues of rats who had been treated with bismuth nitrate basic 400 mg/kg per d for one month with and without an intake of a chelating agent added to the drinking water at a concentration of 10 mmol/l. The chelating agents tested were ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA) and tripolyphosphate (TPP), cysteine and diethyldithiocarbamate (DEDTC). Cysteine and DEDTC gave the highest increase of Bi in tissues but with a wide dispersion of levels. However, even in the rats with the highest levels of Bi, there were no behavioral problems. EDTA induced an increase of Bi in kidney, brain and bone and NTA in kidney but there was no obvious sign of toxicity. We did not succeed in reproducing in rats the Bi toxicity observed in patients some years ago.

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.