BISMUTH-CONTAINING DRUGS AS A THERAPY FOR ULCERATIVE COLITIS

Mrakhovski Y.Kh. Republican Specilisation Center of Gatroenterology, Minsk, Belarus

Bismuth-Containing drugs is the classical example of the one of the oldest medication in gastroenterology and  William Brinton in 1857 wrote “Where diarrhoea is present, the compound kino powder is an excellent remedy; with which we may combine what is calculated to allay both the flux and the pain – the trisnitrate of bismuth.” Now, if we search through Medlin, we can find that in period 1989-1994 only 7 publications in all field for “colitis And bismuth” but in 1995-1999 searching results is 16 publications. It points rising of attention to a bismuth-containing drugs for treatment colitis. Moreover, this attention has also experimental backgrounds and explanation to the possible potentially  positive effect of a bismuth-containing drugs as a therapy at a ulcerative colitis.

And  recently it was hypothesized, that ulcerative colitis(UC)  is a disease due to failure of detoxification of sulphide which interacts with 8-oxidation of butyrate /Roediger WEW, Duncan A, Kapaniris 0, Millard S:Sulphide impairment of substrate exidation in rat colonocytes:

a biochemical basis for ulcerative colitis.Clinical Science 85, 623-627 (1993 a/., 33). Moreover, a possible role for faecal mucin sulphatase in the pathogenesis of inflammatory bowel disease has therefore been explored and shown that at ulcerative colitis  fluctuations of faecal mucin sulphatase activity corresponding to clinical disease activity on the one hand and the bismuth salts were found to inhibit faecal mucin sulphatase activity at concentrations achievable therapeutically on the other hand/ Tsai HH,  Dwarakanath AD, Hart CA, Milton JD, Rhodes JM , Increased faecal mucin sulphatase activity in ulcerative colitis: a potential target for treatment.Gut 1995 Apr 36:4 570-6/. Mucous mucinase was investigated in vitro and mucinase activity was reduced by preincubation with  4 g/l bismuth subsalicylate (72.0%) and it was fined that mucinase activity was greater in samples from patients with ulcerative colitis (n = 17, median 52.7, interquartile range 32.9-66.9), than controls (n = 26, 34.4, 26.8-40.4, p < 0.02) / Dwarakanath AD, Campbell BJ, Tsai HH, Sunderland D, Hart CA, Rhodes JM , Faecal mucinase activity assessed in inflammatory bowel disease using 14C threonine labelled mucin substrate. Gut 1995 Jul 37:1 58-62/.  

In experimental animals models of UC  has been show the significant protective effect of topical bismuth colloidal salts, which is accompanied by a reduction of proinflammatory prostaglandins/ Zahavi I, Burg Z, Marcus H, Karmeli F, Nusinovitz M, Dinari G, Therapeutic effect of colloid bismuth subcitrate in experimental colitis in the rat. Digestion 1995 56:3 211-3/.

 Known that generally  salicylate-type drugs such as  sulphasalazine, mesalasine, olsalazine, or systemic corticosteroids such as prednisolone, betamethasone, or methylprednisolone are used in the treatment of patients with ulcerative colitis, depending on the severity of the acute episode (6 Crotty B, Jewell D:

Drug therapy of ulcerative colitis.Br. J. Clin. Pharmacol. 34, 189-198 (1992)., 12, 37 Selby W: Current management of inflammatory bowel disease. J. Gastroenterol. Hepatol. 8, 70-83 (1993).). But, in according some last publications  «Short-chain fatty acids, local anaesthetics and bismuth compounds seem to be the most promising innovations in topical therapy although their equivalence or even superiority to mesalazine has not been established./ Richter F, Scheppach W, Baillieres, Innovations in topical therapy. Clin Gastroenterol 1997 Mar 11:1 97-109/

Bismuth is supposed to act by novel mechanisms and thus could offer a further therapeutic alternative. Possible mechanisms of action could be an antibacterial effect of bismuth (3 Borsch G:

Alte und neue Magentherapie mit Wismutsalzen. Pharmakokinetik, Pharmakodynamik, Toxizitat.

Med. Klinik. 83, 605-610 (1988)., 16 Goodwin CS, Blake P, Blincow E: The minimum inhibitory and bactericidal concentrations of antibiotics and anti-ulcer agents against Campylobacter pyloridis. J. Antimicrob. Chemoth. 17, 309-314 (1986)., 21), its mucus-protecting effects (20 Hughes S, Rhodes JM:

Tripotassium di-citrato bismuthate (Denol) inhibits enzymatic degradation of colonic mucus by faecal enzymes. Clin. Science 72 (suppl.), 80P Abstr. No. 228 (1987).) and its detoxifying effect by forming sulphide salts.

 Bismuth salts have been in common use for a long time for the treatment of diarrhoea. Its efficacy and safety for this indication have been assessed through several controlled clinical trials (10 Du Pont HL, Ericsson CD, Johnson PC, de la Cabada FJ:Use of bismuth subsalicylate for the prevention of travelers' diarrhea. Rev. Infect. Dis 12 (Suppl. 1), 564-567 (1990)., 13 Figueroa-Quintanilla D, Salazar-Lindo E, Sack RB, Leon-Barua R, Sarabia-Arce S, Campos-Sanchez M, Eyzaguirre-Maccan E: A controlled trial of bismuth subsalicylate in infants with acute watery diarrheal disease. New England Journal of Medicine 328, 1653-1658 (1993)., 18 Grysboski JD, Kocoshis S:Effect of bismuth subsalicylate on chronic diarrhea in childhood: A pre-liminary report.Rev. Infect. Dis. 12 (Suppl. 1), S.36-S40 (1990)., 38 Soriano-Brucher H, Avendano P, O'Ryan M, Braun SD, Manhardt MD, Balm TK, Soriano HA: Bismuth subsalicylate in the treatment of acute diarrhea in children: A clinical study. Pediatrics 87, 18-27 (1991)., 40 Steffen R: Worldwide efficacy of bismuth subsalicylate in the treatment of travelers' diarrhea. Rev. Infect. Dis. 12 (Suppl. 1), S-SO-S86 (1990)., 41 Steinhoff MC, Douglas RGJr., Greenberg HB, Callahan DR: Bismuth subsalicylate therapy of viral gastroenteritis. Gastroenterology 78, 1495-1499 (1980).). In addition several studies indicate that bismuth salts represent also an effective and safe therapy for ulcerative colitis. In a prospective open study, 15 patients with ulcerative colitis which was unresponsive to conventional therapy were treated with enemas containing bismuth subsalicylate (700 or 800 mg b.d.). Nine out of 15 patients showed a significant clinical response, and 6 had gone into complete remission after 8 weeks treatment. Furthermore the sigmoidoscopic appearance of the rectal mucosa was clearly improved (35 Ryder SD, Walker RJ, Jones H, Rhodes JM: Rectal bismuth subsalicylate as therapy for ulcerative colitis. Aliment. Pharmacol. Therap. 4, 333-338 (1990).). A further pilot study including 11 patients with active proctitis and proctosigmoiditis revealed similar positive results for treatment with bismuth-containing enemas (39 rivastava ED, Swift GL, Wilkinson S, Williams GT, Evans BK,Rhodes JR: Tripotassium dicitrato bismuthate enemas in the treatment of ulcerative proctitis. Aliment. Pharmacol. Therap. 4, 577-581 (1990).). Encouraged by these data a controlled trial comparing bismuth enemas with 5-ASA enemas was performed in 63 patients with distal ulcerative colitis (29 Pullan RD, Ganesh S, Mani V, Morris J, Evans BK, Williams GT, Rhodes J: Comparison of bismuth citrate and 5-aminosalicylic acid enemas in distal ulcerative colitis: a controlled trial. Gut 34, 676-679 (1993).).

That multicentre trial was randomized and double-blind with enemas given over four weeks; clinical sigmoidoscopic and histological assessments were made. Clinical remission was seen in 18 of 32 patients treated with 5-ASA and 12 of 31 patients with bismuth. Improvement of rectal biopsy histology was seen in 16 of 32 patients in the 5-ASA group and 14 of 31 patients with bismuth. Comparable findings were reported concerning sigmoidoscopic remission. The observed differences between both groups were not statistically significant.

Under the dosage used in this clinical trial no bismuth accumulation occurred. Long term intake of high doses of bismuth can induce encephalopathy. Blood levels of bismuth > 100 hg/I are regarded as potentially neurotoxic (3), whereas concentrations up to 50 kg/I are in a safe level. Extended dosing of bismuth (3.14 g of bismuth subsalicylate per day) for up to 6 weeks produced a mean plasma concentration of bismuth in blood of 16.1 + 7.9 ng/g, considerably below the concentrations in blood that have been reported to cause neurotoxicity.

In a recent clinical trial a lack of evidence of neurotoxicity following 8 weeks of treatment with tripotassium dicitrato bismuthate was reported. Bismuth encephalopathy occurred in France as an epidemic of toxicity and was associated with the intake of inorganic salts including bismuth subnitrate, subcarbonate and subgallate at high doses in 80% more than 3 g/day . But safety bismuth compounds was assessment in infant with watery diarrhoea diseases and shown that the  treatment with bismuth subsalicylate decreases the duration of diarrhoea and is a safe and effective adjunct to oral dehydration therapy for infants and young children with acute watery diarrhoea / Figueroa-Quintanilla-D; Salazar-Lindo-E; Sack-RB; Leon-Barua-R; Sarabia-Arce-S; Campos-Sanchez-M; Eyzaguirre-Maccan-E., A controlled trial of bismuth subsalicylate in infants with acute watery diarrheal disease. N-Engl-J-Med. 1993 Jun 10; 328(23): 1653-8; Soriano-Brucher-H; Avendano-P; O'Ryan-M; Braun-SD; Manhart-MD; Balm-TK; Soriano-HA,  Bismuth subsalicylate in the treatment of acute diarrhea in children: a clinical study. Pediatrics. 1991 Jan; 87(1): 18-27/

We pefomed special study and the major aim of our study was to show the efficacy and safety of an oral bismuth formulation compared to placebo in patients with mildly to moderately active ulcerative colitis. The primary objective of this study was the evaluation of the efficacy of an oral bismuth preparation(BISMOFALKÒ)[Bi] for therapy of patients(n=44) with mildly to moderately active ulcerative colitis regarding the improvement of Clinical Activity Index (CAI) values over a 6-week study period compared to placebo.  Secondary objectives: treatment failure assessment, course of Endoscopic(El) and Histological(HI)  Index during the 6-week study period, comparison of the number of stools using a weekly mean at baseline and  at the  final examination or the individual endpoint, laboratory parameters of inflammation, time-to-response, subgroup analyses with regard to the severity of the disease at baseline, documentation of adverse events with causality as well as measures taken by using the general questionnaire, laboratory parameters, and bismuth serum concentration after 6 weeks of treatment

Results.  In according primary objective Bi overall responders were 72,7% in Bi group and 31,8% in placebo(p<0.05)

Table 1. Bismofalk efficacy in according primary objective analysis

Note: criterion 1 - Overall responders were defined as patients with a reduction of the CAI

of more than 4 points; criterion 2 - with an absolute CAI-score < 3 points  at the individual final study visit compared to the baseline value.

The rate of overall responders was significantly different between the groups at the prespecified level of a = 0.05.

Table 2.   Total assessment response rate

 Unexpected or clinically relevant pathologic developments in the safety profile (adverse events, vital signs, laboratory evaluations) could not be detected. The mean El decreased from 5,4 to 3,5 in the Bismofalk group and only from 5,6 to 5,5 in the placebo group. Corresponding changes were found for the Hl: The HI improved in 16 of 22 patients (= 73 %) in the Bismofalk, but only in 6 of 22 patients (27%) in the placebo group. The number of adverse events was low and comparable in both groups.

In conclusions: Clear positive effects of an oral 6-week bismuth therapy with BismofalkÒ tablets on the course of the underlying disease ulcerative colitis could be demonstrated, regarding predominantly the development of seven single CAI-items, as well as histological and endoscopical findings. The differences between the groups in terms of the CAI-results were statistically significant in favour of BismofalkÒ. Therefore, bismuth containing tablets can be classified as an effective,  and well tolerable treatment of a mildly or moderately active ulcerative colitis.

Additional publications in query "colitis and bismuth" 

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