Introduction

Bismuth subnitrate (Figure 1), also referred to as bismuth oxynitrate or bismuthyl nitrate, is a highly water-soluble crystalline compound that has been used as a treatment for duodenal ulcers and anti-diarrheic agent. Bismuth subnitrate is a commercially available bismuth(III) compound that bears significant medical uses (e.g., as an antidiarrheic agent). It can readily be prepared by the controlled thermal decomposition of Bi(NO₃)₃·5H₂O, and it is practically insoluble in most typical organic solvents.[1]The composition of bismuth subnitrate is highly variable, as is the composition of other bismuthsalts; Both light and heavy forms were available. The light form was a mixture of bismuth subnitrate and subcarbonate in a ratio of either 20:80 or 80:20 and contained 73 to 80% bismuth,whereas the heavy form consisted of the subnitrate only and contained 72% bismuth.Colloidal bismuth subcitrate forms a colloidal solution with particles consisting of bismuth,citrate and hydroxy groups [Bi_x(OH)_y(C₆H₅O₇)_z];the exact structure remains to be elucidated and is probably dependent on the acidity of the solution.At low pH the complex precipitated as bismuth oxychloride and citrate, but no precipitate was formed in the presence of the sulfhydryl-containing compounds cysteine and glutathione.[2]Bismuth compounds have in vivo and in vitro activity against H. pylori by mechanisms including inhibition of protein and cell wall synthesis, membrane function and ATP synthesis. It may also prevent the development of resistance to antibiotics. Moreover, bismuth compounds are described as having cytoprotective properties.[3]

Alleviation of cisplatin toxicity

Twelve patients with several malignant neoplasms, including lung and gastrointestinal carcinoma were treated with high-dose Cisplatin and high-dose Bismuth Subnitrate. Therapeutic efficacy and protective effect of high-dose Bismuth Subnitrate on toxicity of Cisplatin were evaluated in twenty-five courses of treatment. The Pharmacokinetics of Bismuth Subnitrate and Cisplatin were also studied in several courses. Bismuth Subnitrate was administered orally at a dose of 150 mg/kg/day for 10 days and a dose of 80-150 (Mean 108) mg/m2 of Cisplatin was administered intravenously on the day six of Bismuth Subnitrate administration. Toxicities of high-dose Cisplatin were minimal under administration of high-dose Bismuth Subnitrate and therapeutic efficacy was observed in several patients. The pharmacokinetics of Bismuth Subnitrate in plasma and urine demonstrated that 10 days administration of high-dose Bismuth Subnitrate was appropriate to maintain adequate concentration of Bismuth for preinduction of Metallothionein in organs. The pharmacokinetics of Cisplatin in plasma and urine demonstrated that deposition of total and ultrafilterable (free) platinum in blood were well described by a biphasic manner with a very rapid first phase and a very prolonged second phase, and that urine excretion of platinum was similar to the conventional manner. This study demonstrated that concurrent administration of high-dose Bismuth Subnitrate can permit the administration of high-dose Cisplatin with minimal toxicity and appropriate antitumor effect.[4]

Improve eradication of Helicobacter pylori

To evaluate whether the addition of bismuth subnitrate to a dual oral therapy regimen with omeprazole plus amoxycillin could improve Helicobacter pylori eradication. Fifty consecutive Helicobacter pylori-positive patients were randomly enrolled to receive either (A) bismuth subnitrate (300 mg q.d.s.), omeprazole (20 mg b.d.) and amoxycillin (500 mg q.d.s.), or (B) omeprazole (20 mg b.d.) and amoxycillin (500 mg q.d.s.). Both groups (n=25 each) received the medication for 14 days. H. pylori status was reassessed 30 days after completion of the therapy in order to evaluate eradication rates. RESULTS: Six patients were lost to follow-up and therefore excluded from the study (three patients from each group). One patient from Group B withdrew from the study because of side-effects. The addition of bismuth subnitrate to omeprazole and amoxycillin significantly improved its efficacy in eradicating H. pylori, with 72% (18/25) eradication in Group A and 52% (13/25) in Group B (P=0.027). The addition of bismuth subnitrate to dual oral therapy was also capable of improving the healing of peptic ulcers when compared with dual oral therapy alone (100%, 8/8 vs. 58%, 4/7; P=0.021).These results demonstrate that the addition of bismuth subnitrate to dual oral therapy enhances H. pylori eradication, and improves healing of peptic ulcers.[3]

Prevent intramammary infections

The mode of action of bismuth subnitrate in teat sealant formulations as a preventative for intramammary infections during the dry period is unknown. Although previous studies proposed an action mechanism—creating a physical barrier in the teat canal to prevent bacterial invasion—it has not been proven experimentally. Authors hypothesized that bismuth subnitrate has an inhibitory effect on bacterial growth, in addition to its barrier effect. The objective of this study was to assess the effect of bismuth subnitrate on bacterial growth of major mastitis-causing agents. A strain of Streptococcus uberis (SR115), 2 strains of Staphylococcus aureus (SA3971/59 and SA1), and a strain of Escherichia coli (P17.14291) were tested in vitro for their ability to grow in the presence or absence of bismuth subnitrate. Disk diffusion testing, impedance measurement, and evaluation of bacterial growth in shaking conditions were the methods used to test this hypothesis. A reduction of growth in the presence of bismuth subnitrate occurred for all the strains tested. However, they observed strain and species variations in the extent of growth inhibition. These results suggest that an inhibitory effect on bacterial growth by bismuth subnitrate could partially explain the efficacy of bismuth-based formulations for preventing intramammary infections over the dry period. Further research is required to test the effect of teat sealant formulations on bacterial growth.[5]

References

[1]Szécsényi Z, Fül?p F, ?tv?s SB. Bismuth Subnitrate-Catalyzed Markovnikov-Type Alkyne Hydrations under Batch and Continuous Flow Conditions. Molecules. 2021;26(10):2864. Published 2021 May 12. doi:10.3390/molecules26102864

[2]Slikkerveer A, de Wolff FA. Pharmacokinetics and toxicity of bismuth compounds. Med Toxicol Adverse Drug Exp. 1989;4(5):303-323. doi:10.1007/BF03259915

[3]Carvalho AF, Fiorelli LA, Jorge VN, et al. Addition of bismuth subnitrate to omeprazole plus amoxycillin improves eradication of Helicobacter pylori. Aliment Pharmacol Ther. 1998;12(6):557-561. doi:10.1046/j.1365-2036.1998.00344.x

[4]Morikawa T, Kawamura E, Komiyama T, Imura N.Alleviation of cisplatin toxicity by high-dose bismuth subnitrate and pharmacokinetics of bismuth subnitrate and cisplatin. Nihon Gan Chiryo Gakkai Shi. 1990 Jun 20;25(6):1138-45.

[5]Notcovich S, Williamson NB, Flint S, Yapura J, Schukken YH, Heuer C. Effect of bismuth subnitrate on in vitro growth of major mastitis pathogens. J Dairy Sci. 2020;103(8):7249-7259. doi:10.3168/jds.2019-17830