Colloidal Bismuth Subcitrate

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Abstract
Colloidal bismuth subcitrate (CBS) possesses at least equal efficacy with histamine H2-receptor antagonist drugs in the treatment of peptic ulcer disease. However, CBS has the advantage of slower ulcer relapse rates than those seen after initial healing with the H2-antagonists. It has been postulated that this effect may be partly due to the antibacterial properties of CBS against Campylobacter pylori, a bacterium found in the gastric mucosa and gastric metaplasia within the duodenum of most patients with peptic ulcer and closely associated with gastritis. However, the role of C. pylori in the aetiology of peptic disease is far from clear. The mechanism by which CBS heals ulcers has not been fully elucidated, but several actions may be involved. CBS and mucus form a glycoprotein-bismuth complex in vitro. This provides a diffusion barrier to HCl and may, therefore, provide a protective coating in the ulcer crater which allows healing of the lesion to occur. Prostaglandin E2 production is also stimulated by CBS with subsequent secretion of alkali into the mucus layer. In addition, CBS has a direct inhibitory effect on C. pylori. Administration of CBS results in low levels of bismuth absorption. Most of the ingested bismuth is excreted as bismuth sulphide, causing blackening of the faeces, and the small amount absorbed is excreted in the urine. Bismuth intoxication (encephalopathy) has been reported with prolonged administration of bismuth salts, and there has been 1 report of similar intoxication in a patient receiving unusually high doses of CBS for a prolonged period. However, no such intoxication has been reported with CBS used at its recommended dosage in the acute treatment of peptic ulcer disease, and no other serious adverse effects have been associated with CBS. Tissue accumulation during prolonged therapy seems likely, and the safety of CBS during long term maintenance therapy has not been established. The lack of effect on gastric acid secretion is seen as an added advantage for CBS, since prolonged drug-induced hypochlorhydria has been postulated to have potentially detrimental effects. Thus, while the role of C. pylori in peptic ulceration requires further clarification, CBS would appear to have an important place in the treatment of peptic ulcer disease with the advantage of relatively slow relapse rates after initial healing and treatment discontinuation. CBS is a complex bismuth salt of citric acid which is soluble in water but precipitates at pH less than 5. In gastric juice the optimum pH for precipitation is 3.5. Bismuth is deposited in ulcer craters in preference to the surrounding mucosa, and forms a complex with proteins on the ulcer base which may create a protective layer against digestion by gastric juices. CBS prevents experimental gastric damage in tests conducted in rats, in a dose-dependent manner. Inhibition of such effects by indomethacin suggests prostaglandin involvement. Healing of peptic ulcers in patients occurs over 4 to 8 weeks of treatment. After healing with CBS, the epithelial microvilli in the vicinity of the scar are closer to normal ultrastructure than those in patients whose ulcers were healed with cimetidine. It appears that these effects of CBS also partially involve a prostaglandin mechanism since local prostaglandin E2 production and secretion of alkali are stimulated in CBS-treated patients. CBS also possesses some antipepsin activity but has little effect on gastric acid secretion and, therefore, does not induce prolonged hypochlorhydria. Campylobacter pylori has recently been associated with peptic disease —although its role, if any, in the aetiology of the disease is unclear—and CBS has been proved an effective inhibitory agent against this organism both in vitro and in vivo, in comparison with histamine H2-receptor antagonist drugs which have little or no activity. The formation of an H+ diffusion barrier in the gastroduodenal mucus formed by the glycoprotein-bismuth complex may counteract the ability of C. pylori to decrease mucus viscosity and increase H+ back diffusion. CBS also has a direct effect on the organism, causing vacuolisation within the bacterium resulting in loss of adherence to the epithelium, fragmented cell walls and condensation of cell contents. Following oral administration, low levels of CBS are absorbed from the gastrointestinal tract. Plasma concentrations reach a plateau after about 4 weeks of administration and rarely rise above 50 μg/L. Animal studies have shown that most of the absorbed bismuth is found in the kidneys, with only trace amounts in other organs including the brain. However, the tissue distribution of CBS in man is unknown, and available data from animal studies, particularly with regard to long term administration, is limited. Absorbed bismuth is excreted in the urine and the remainder of the administered dose as bismuth sulphide in the faeces. Following oral administration at the recommended dosage urine concentrations show a wide interindividual variation, ranging from 17 to 710 μg/L. The rate of renal elimination drops by 2.6% per day and then reaches a steady-state 2 weeks after the withdrawal of CBS treatment. Urine concentrations are still high at this time (24 to 250 μg/L), which suggests tissue accumulation and slow mobilisation. For this reason a washout period of 8 weeks between CBS courses is recommended. CBS has been studied in clinical trials investigating the treatment of duodenal and gastric ulcer, antral gastritis and non-ulcer dyspepsia. Well-designed trials have established its efficacy in the healing of peptic ulcer. In uncontrolled trials, 58 to 93% of patients with duodenal ulcer were healed after 4 weeks’ treatment and 85 to 94% after 8 weeks. Controlled studies showed similar response rates and statistically significant advantages over placebo. Healing rates seen with CBS (66 to 91% after 4 weeks’ treatment and 73 to 100% after 8 weeks) in comparative trials with H2-antagonists compare favourably with those seen in cimetidine recipients (54 to 83% and 55 to 89%, respectively) and ranitidine recipients (81 to 87% and 94 to 97%, respectively). CBS also appears to be useful in the treatment of patients with duodenal ulcer resistant to standard doses of histamine H2-receptor antagonists. Healing rates of 82 to 85% have been seen with standard doses of CBS versus 39 to 44% with increased doses of cimetidine after 4 weeks’ treatment. Similar results were reported in trials involving patients with gastric ulcer. Healing rates of 55 to 91% after 4 weeks’ treatment and 83 to 87% after 8 weeks’ treatment were seen in uncontrolled trials. In trials comparing CBS with placebo, healing rates of 63 to 90% versus 30 to 42% were observed. Comparative trials with cimetidine demonstrated healing rates in CBS recipients of 61 to 81% after 4 weeks compared with 43 to 74% in cimetidine receipients. The healing rate after 4 to 6 weeks on ranitidine was 63 to 74% compared with 70 to 89% on CBS. The rate of relapse of peptic ulcer is slower after ulcer healing with CBS than with cimetidine or ranitidine. Relapse rates of 39 to 76% have been observed 1 year after healing with CBS compared with 60 to 100% after healing with the H2-antagonists. CBS is effective in the treatment of chronic antral gastritis and non-ulcer dyspepsia in patients with Campylobacter pylori colonisation. CBS alone decreased numbers of C. pylori and improved gastritis temporarily in patients with chronic gastritis. In comparison, cimetidine had no effect and CBS plus an antibacterial drug made the organism undetectable in 82% of patients and improved gastritis with no relapse on follow-up. It appears that relapse is common after healing of gastritis with CBS unless antibacterial treatment is added and C. pylori markedly suppressed. However, it should be pointed out that the cytoprotective properties of CBS could account for its beneficial effects, and other drugs lacking antibacterial activity still improve chronic antral gastritis. Non-ulcer dyspepsia associated with C. pylori gastritis shows consistent improvement after 4 to 8 weeks’ treatment with CBS. Smoking appears to have no appreciable effect on peptic ulcer healing nor on the rate of relapse after healing with CBS. Few adverse effects have been associated with the use of CBS. Faeces are blackened with the excretion of bismuth sulphide and earlier formulations (not the newer coated tablets) have stained the mouth, but other side effects are largely limited to reports of mild dizziness, headache and diarrhoea. High doses of other bismuth salts administered for prolonged periods produced encephalopathy in some patients. There has been 1 report of reversible central nervous system symptoms in a man who received high doses of CBS for 8 weeks followed by intermittent maintenance therapy with low doses for a total of 2 years. No such adverse effects have been reported during or after the use of CBS in the short term for ulcer healing. The safety of CBS as long term maintenance therapy has not been established. CBS should be administered only with caution in patients with renal impairment, and because safety data are lacking CBS should not be administered during pregnancy. The recommended oral adult dose of CBS for duodenal or benign gastric ulcer is 480mg (as Bi2O3) daily for 4 to 8 weeks, given in 2 or 4 divided doses. These 2 regimens have been shown to be equally efficacious. Five ml of the solution formulation is diluted to 20ml with water, and solution or tablets should be taken 30 minutes before each meal and 2 hours after the last meal of the day, or (for the twice daily regimen) 30 minutes before breakfast and the evening meal. Concomitant antacids or milk should not be taken within 30 minutes before or after administration of the drug.