bismuth-subsalicylate and bismuth-tripotassium-dicitrate

As one of the most prevalent infections globally, Helicobacter pylori (H. pylori) continues to present diagnostic and therapeutic challenges for clinicians worldwide. Diagnostically, the "test-and-treat" strategy is the recommended approach for healthcare practitioners when managing this potentially curable disease. The choice of testing method should be based on several factors including patient age, presenting symptoms, and medication use, as well as test reliability, availability, and cost. With rising antibiotic resistance, particularly of macrolides, care must be taken to ensure that therapy is selected based on regional resistance patterns and prior antibiotic exposure. In the USA, macrolide antibiotic resistance rates in some areas have reached or exceeded a generally accepted threshold, such that clarithromycin triple therapy may no longer be an appropriate first-line empiric treatment. Instead, bismuth quadruple therapy should be considered, while levofloxacin-based or alternative macrolide-containing therapies are also options. Once treated, it is essential to test for eradication as untreated H. pylori is associated with serious complications including peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. This review article aims to consolidate current knowledge of H. pylori infection with a particular emphasis on diagnostic and treatment strategies.

Topics: Amoxicillin; Anti-Bacterial Agents; Anti-Ulcer Agents; Antigens, Bacterial; Biopsy; Bismuth; Breath Tests; Clarithromycin; Culture Techniques; Doxycycline; Drug Resistance, Bacterial; Drug Therapy, Combination; Dyspepsia; Feces; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Levofloxacin; Lymphoma, B-Cell, Marginal Zone; Metronidazole; Nitro Compounds; Organometallic Compounds; Peptic Ulcer; Polymerase Chain Reaction; Proton Pump Inhibitors; Rifabutin; Salicylates; Salvage Therapy; Serologic Tests; Stomach Neoplasms; Tetracycline; Thiazoles; Treatment Outcome; Urea

Bismuth salts have been used in medicine for over three centuries, particularly in the treatment of dyspepsia. Commonly used agents include colloidal bismuth subcitrate (CBS), bismuth subsalicylate (BSS) and the newer ranitidine bismuth citrate (RBC). These are safe drugs which exert local effects on the gastroduodenal mucosa. Gastric mucosal levels of bismuth exceed the concentrations required to kill Helicobacter pylori in vitro. The mechanisms of actions of bismuth on gastrointestinal pathogens including H. pylori are complex and include inhibition of protein and cell wall synthesis, membrane function and ATP synthesis. Adherence of H. pylori to surface epithelial cells is also impaired. Bismuth monotherapy is effective in vivo to suppress H. pylori but cure rates are low. CBS, BSS and RBC have synergistic activity with one or two antibiotics and are effective in eradicating H. pylori. CBS and RBC also exert other effects on the mucosa including cytoprotective and ulcer healing properties. In addition, RBC is effective in inhibiting gastric acid secretion.

Topics: Anti-Bacterial Agents; Bismuth; Drug Synergism; Duodenum; Gastric Acid; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Histamine H2 Antagonists; Humans; Organometallic Compounds; Ranitidine; Salicylates; Treatment Outcome

Topics: Bismuth; Campylobacter Infections; Chronic Disease; Dose-Response Relationship, Drug; Gastritis; Humans; Organometallic Compounds; Salicylates

In an attempt to increase the efficacy and simplicity of FDA-approved regimens for Helicobacter pylori, we studied (1) addition of an inexpensive antibiotic (amoxicillin) to twice-daily ranitidine bismuth citrate (RBC)-clarithromycin dual therapy, and (2) substitution of RBC for bismuth subsalicylate + H2-receptor antagonist in bismuth-based triple therapy.. Subjects with previously untreated Helicobacter pylori infection documented by 13C-urea breath test plus either endoscopic biopsy or serology were randomly assigned to a 2-wk course of (1) RBC 400 mg b.i.d., amoxicillin 1 g b.i.d., and clarithromycin 500 mg b.i.d. (RAC), or (2) RBC 400 mg b.i.d., metronidazole 250 mg t.i.d., and tetracycline 500 mg t.i.d. (RMT). Repeat breath test was performed 4 wk after the completion of therapy.. Intent-to-treat and per-protocol cure rates for RAC were 46 of 50 patients (92%) and 45 of 47 patients (96%); for RMT they were 40 of 50 patients (80%) and 37 of 42 patients (88%). Study drugs were stopped due to side effects in three patients (6%) taking RAC and six patients (12%) taking RMT.. Twice-daily RBC-based triple therapy with clarithromycin and amoxicillin produces Helicobacter pylori eradication rates over 90%, which is comparable to rates seen with proton pump inhibitor-based triple therapies. RBC also may be substituted for bismuth subsalicylate and an + H2-receptor antagonist in standard bismuth-based triple therapy.

Topics: Adult; Amoxicillin; Antacids; Anti-Bacterial Agents; Anti-Ulcer Agents; Biopsy; Bismuth; Breath Tests; Carbon Isotopes; Clarithromycin; Drug Combinations; Female; Follow-Up Studies; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Histamine H2 Antagonists; Humans; Male; Metronidazole; Organometallic Compounds; Penicillins; Peptic Ulcer; Proton Pump Inhibitors; Ranitidine; Salicylates; Tetracycline; Urea

Twelve healthy male subjects were dosed with six regimens: ranitidine and De-Noltab (tripotassium dicitrato bismuthate; Gist-Brocades Ltd., Weybridge, England), placebo and De-Noltab, ranitidine and Pepto-Bismol liquid [bismuth salicylate; Procter & Gamble (Health and Beauty Care) Ltd., Egham, England], placebo and Pepto-Bismol, ranitidine and Roter tablets (bismuth subnitrate; Roter Pharma Ltd., Ashford, England), and placebo and Roter. Ranitidine, 300 mg, or placebo was administered at 10 PM (night before) and at 7 AM; at 9 AM, the oral dose of bismuth was either 2 De-Noltabs, 3 30-mL doses of Pepto-Bismol liquid, or 2 Roter tablets. When predosed with placebo, the median integrated 8-hour plasma bismuth concentration was significantly greater after dosing with De-Noltabs than after dosing with either Pepto-Bismol or Roter (61, 8, and 8 ng.h/mL, respectively), with a similar trend for 8-hour median urinary bismuth excretion (213, 40, and 6 micrograms, respectively). When predosed with ranitidine, only after De-Noltab administration were there significant increases in the 8-hour plasma bismuth concentration (147 ng.h/mL), and 8-hour urinary bismuth excretion (686 micrograms). Eliminating intragastric acidity may enhance bismuth absorption after oral dosing with De-Noltabs by maintaining intragastric tripotassium dicitrato bismuthate as a colloidal suspension.

Topics: Adult; Anti-Ulcer Agents; Bismuth; Double-Blind Method; Humans; Intestinal Absorption; Male; Organometallic Compounds; Placebos; Ranitidine; Receptors, Histamine H2; Salicylates

Topics: Anti-Bacterial Agents; Bismuth; Drug Therapy, Combination; Helicobacter Infections; Humans; Organometallic Compounds; Proton Pump Inhibitors; Salicylates

The 2,4,6-trinitrobenzene sulfonic acid (TNBS) -induced model of chronic inflammation of the rat colon was used to determine the efficacy of bismuth subsalicylate (BSS), bismuth subcitrate (CBS), and 5-aminosalicylic acid (5-ASA) administered in enema form. A novel bismuth compound 1, 2-bis[2-(1,3-dithiobismolane)thio]ethane [Bi2(EDT)3] was also tested. On day 1 colitis was induced with 50 mg TNBS/50% ethanol in female Sprague-Dawley rats, while controls received a saline enema. On day 3, twice-daily treatment with enemas of either saline, BSS, CBS, Bi2(EDT)3, or 5-ASA were initiated in the colitis and control rats. All rats were killed on day 14, and the colons excised, weighed, rated macroscopically, and then fixed for hematoxylin and eosin staining. Blinded microscopic scoring was used to determine injury and healing in all groups. Colon mass and macroscopic scores were increased (P < 0.05) in the group of rats treated with TNBS (N = 16) compared to saline controls (N = 12). Colon mass and macroscopic scores in controls treated with BSS (N = 4), CBS (N = 4), Bi2(EDT)3 (N = 4), and 5-ASA (N = 4) alone did not differ from saline control animals. Macroscopic scoring showed a decrease (P < 0.05) in the degree of damage in the group of rats treated with TNBS plus BSS (N = 15), TNBS plus Bi2(EDT)3 (N = 10) and TNBS plus CBS (N = 4) compared to the group of rats treated with TNBS plus saline (N = 16). A decrease (P < 0.05) in injury and an increase (P < 0.05, Kruskal-Wallis) in healing was observed in the groups of rats treated with TNBS plus BSS, TNBS plus CBS, and TNBS plus 5-ASA compared to the group of rats treated with TNBS plus saline. It appeared that Bi2(EDT)3 was not protective against injury at the microscopic level but that the novel Bi2(EDT)3 has an effective healing capacity at the macroscopic level. We conclude that BSS and CBS decrease injury and/or promote healing as effectively as 5-ASA in this model.

Topics: Animals; Anti-Ulcer Agents; Bismuth; Colitis; Female; Mesalamine; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Salicylates; Trinitrobenzenesulfonic Acid

Bismuth compounds remain useful for Helicobacter pylori eradication therapy. These include colloidal bismuth subcitrate (CBS), bismuth subsalicylate (BSS) and, most recently, ranitidine bismuth citrate (RBC). CBS appears to prevent the development of imidazole resistance when coadministered with nitroimidazoles. Traditional triple therapy with bismuth, metronidazole and tetracycline or amoxicillin (BMT/A) only partially overcomes metronidazole resistance. However, the addition of a PPI to bismuth triple therapy largely overcomes established metronidazole resistance if treatment is given for at least one week or more. When RBC rather than PPI is used with clarithromycin, this dual regimen appears to be more effective in preventing the development of secondary clarithromycin resistance. The triple combination of RBC, metronidazole and clarithromycin appears to be effective against metronidazole resistant strains of H pylori. Thus, overall, there is some evidence that bismuth compounds may prevent the development of antibiotic resistance and that existing antibiotic resistance may at least be partially overcome in vitro and in vivo. With the growing emergence of H pylori resistance to metronidazole and clarithromycin, further research to clarify the role of bismuth compounds is required.

Topics: Anti-Bacterial Agents; Anti-Ulcer Agents; Bismuth; Clarithromycin; Drug Resistance, Microbial; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Humans; Organometallic Compounds; Ranitidine; Salicylates

The absorption of bismuth from De-Nol (bismuth subcitrate, DN), Pepto-Bismol (bismuth subsalicylate, PB) and bismuth sucrose octasulfate (BISOS) was examined in male Sprague-Dawley rats after a single oral dose of each compound (60mg bismuth). Bismuth was analysed in blood, urine, kidney, brain, liver, and lung using graphite furnace atomic absorption spectrophotometry. Bismuth Cmax averaged 18.4 +/- 11.6 ng mL(-1) for BISOS, 292 +/- 130 ng mL(-1) for DN, and 21.5 +/- 9.63 ng mL(-1 ) for PB. Cmax was significantly lower for BISOS compared to DN (p<0.05) but not significantly different for BISOS compared to PB (p > 0.05). Bismuth AUC was 1356 +/- 474 ng h(-1) mL (-1) for BISOS, 2129 +/- 452 ng h(-l) mL(-1) for DN, and 1824 +/- 919 ng h(-1) for PB, which indicated a lower extent of absorption from BISOS compared to DN. Kidney, liver, and lung levels of bismuth were also significantly lower for BISOS compared to DN (p < 0.05). Bismuth urinary excretion was significantly lower for BISOS (0.04 +/- 0.02%) compared to DN (0.27 +/- 0.15%) but not significantly different compared to PB (0.07 +/- 0.03%). These data suggest that the absorption of bismuth following oral administration of bismuth sucrose octasulfate is significantly lower than that from De-Nol and similar to that from Pepto-Bismo.

Topics: Administration, Oral; Animals; Antacids; Area Under Curve; Bismuth; Intestinal Absorption; Male; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Salicylates; Spectrophotometry, Atomic; Sucrose; Tissue Distribution

Oxygen free radicals (OFR) are implicated in the pathogenesis of stress, chemically induced gastric lesions, and gastrointestinal injury. The concentration-dependent scavenging abilities of bismuth subsalicylate (SBS), colloidal bismuth subcitrate (CBS), and selected OFR scavengers, including superoxide dismutase (SOD), catalase, mannitol, and allopurinol were examined against biochemically or chemically generated superoxide anion, hydroxyl radical, and hypochlorite radical plus hypochlorous acid based on a chemiluminescence assay. Furthermore, both gastric (GM) and intestinal mucosa (IM) were individually exposed in vitro to these free radical generating systems, and the concentration-dependent protective abilities of SBS and CBS against lipid peroxidation (LP) were compared with selected OFR scavengers. In addition, 24-hr fasted rats were orally treated with the necrotizing agents 0.6 M HCl, 0.2 M NaOH, 80% ethanol, and aspirin (200 mg/kg). The extent of tissue injury in the GM and IM was determined by assessing LP, DNA fragmentation, and membrane microviscosity. Dose- and time-dependent in vivo protective abilities of CBS (100 mg/kg) and SBS (15 mg/kg) were also assessed. Following incubations with superoxide anion and hydroxyl radical generating systems in the presence of 125 mg SBS/liter, approximately 47% and 61% inhibitions were observed in the chemiluminescence response, respectively, while 48% and 46% inhibitions were observed with 125 mg CBS/liter. SBS and CBS exerted similar abilities towards hypochlorite radical plus hypochlorous acid. Approx. 3.1- and 3.7-fold increases in LP were observed in the GM and IM of rats following oral administration of 0.6 M HCl. Pretreatment of the rats with SBS and CBS decreased 0.6 M HCl-induced LP in the GM by approx. 39% and 27%, respectively, with similar decreases in LP in the IM. SBS exhibited better protective abilities towards 0.6 M HCl and 0.2 m NaOH-induced GM and IM injury as compared to CBS. SBS and CBS provided similar protection towards 80% ethanol-induced gastric injury, while CBS exerted a superior protective ability towards aspirin-induced gastric injury. The results demonstrate that both SBS and CBS can scavenge reactive oxygen species and prevent tissue damage produced by OFR.

Topics: Animals; Anti-Ulcer Agents; Bismuth; Female; Gastric Mucosa; Intestinal Mucosa; Lipid Peroxidation; Luminescent Measurements; Organometallic Compounds; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Salicylates

Colonic mucin is heavily sulphated and it has been shown that enzymatic desulphation by faecal bacterial sulphatases greatly increases its susceptibility to degradation by faecal glycosidases. A possible role for faecal mucin sulphatase in the pathogenesis of inflammatory bowel disease has therefore been explored. Faecal mucin sulphatase activity assayed using 35S mucin as substrate was increased in ulcerative colitis (median 80.2 units/g pellet weight (range 6.9-1063; 95% confidence intervals (CI): 45.2 to 293.8, n = 22) compared with 11.3 units/g (range 3.0-53.5; 95% CI: 8.7 to 29.8, n = 17) in healthy controls (p < 0.01), where one unit released 1000 dpm free sulphate/hour from 35S mucin (1680 dpm/microgram). Patients with active ulcerative colitis had higher sulphatase activity (median 146; 95% CI: 98 to 253 units/g, n = 10) than those with inactive ulcerative colitis (median 42.2; CI: 22.5 to 81.6 units/g, n = 12) (p < 0.05). Longitudinal studies in patients with ulcerative colitis show fluctuations of faecal mucin sulphatase activity corresponding to clinical disease activity in six of seven patients. Faecal mucin sulphatase activity was not significantly increased in Crohn's disease (median 36.6, range 5.7-106.6; 95% CI: 22.9 to 65.3 units/g, n = 14). The bismuth salts, bismuth subcitrate and bismuth subsalicylate were found to inhibit faecal mucin sulphatase activity at concentrations achievable therapeutically. The increased faecal mucin sulphatase activity in ulcerative colitis could be the result of greater intraluminal substrate (mucin) availability leading to bacterial enzyme induction, but would probably result in more rapid degradation of secreted mucin and represents a potential target for treatment.

Topics: Adult; Aged; alpha-Glucosidases; Bismuth; Colitis, Ulcerative; Crohn Disease; Feces; Female; Humans; Longitudinal Studies; Male; Middle Aged; Organometallic Compounds; Salicylates; Sulfatases

We have recently shown that colloidal bismuth subcitrate inhibits cytosolic alcohol dehydrogenase of Helicobacter pylori as well as acetaldehyde production from excess ethanol. We now extend our studies to bismuth subsalicylate and nitecapone, a novel antiulcer agent.. Cytosol of H. pylori was incubated with 0.1% or 1% ethanol in the presence of different drug concentrations for 2 h, whereafter acetaldehyde formed was analyzed by head space gas chromatography. In addition, we incubated a culture solution containing intact bacteria with the drugs at 1% ethanol.. Bismuth subsalicylate and nitecapone inhibit acetaldehyde formation from 0.1% ethanol by H. pylori cytosol at drug concentrations theoretically achievable in the stomach after intake of therapeutic doses of these drugs. Furthermore, colloidal bismuth subcitrate, bismuth subsalicylate, and nitecapone also inhibit acetaldehyde production by intact H. pylori, although rather high drug concentrations are required for this to occur.. Inhibition of H. pylori acetaldehyde formation may be one of the mechanisms by which bismuth and nitecapone exert their effect in the treatment of H. pylori-related disorders.

Topics: Acetaldehyde; Anti-Ulcer Agents; Bismuth; Catechols; Colloids; Depression, Chemical; Ethanol; Helicobacter pylori; Organometallic Compounds; Pentanones; Salicylates

Topics: Administration, Oral; Bismuth; Campylobacter Infections; Dose-Response Relationship, Drug; Gastritis; Humans; Organometallic Compounds; Salicylates; Stomach Ulcer

The minimum inhibitory concentrations of five bismuth salts (bismuth subcitrate, bismuth subgallate, bismuth subnitrate, bismuth subsalicylate and tripotassium dicitrato bismuthate, a water soluble compound of bismuth subcitrate) were assayed against 48 strains of Campylobacter pylori employing the agar dilution method. Tripotassium dicitrato bismuthate was most effective (MIC50 8 mg/l), the other bismuth salts exhibited somewhat lower inhibitory activities. It is concluded that bismuth salts are suitable agents for inhibiting growth of Campylobacter pylori.

Topics: Antacids; Anti-Bacterial Agents; Anti-Ulcer Agents; Bismuth; Campylobacter; Gallic Acid; Humans; Molecular Structure; Organometallic Compounds; Salicylates

Colloidal bismuth subcitrate (CBS) precipitates in an acid environment, adheres to mucus, blocks pepsin activity, retards hydrogen-ion back diffusion and stimulates prostaglandin synthesis. The average healing rate after 4 weeks' treatment with CBS is 78% in duodenal ulcer versus 67% with cimetidine. A direct comparison with ranitidine gives healing rates of 78% (CBS) as opposed to 78% with ranitidine. The corresponding figures in gastric ulcer are 68% (CBS) and 54% (cimetidine). The percentage of relapse-free patients is substantially higher after CBS ulcer healing than after H2-blockers. Bismuth subsalicylate eliminates Campylobacter pylori in 71% after 4-weeks' therapy. Parallel to this elimination a decrease and normalization of the acute inflammatory process can be seen in antral mucosa.

Topics: Anti-Ulcer Agents; Bismuth; Campylobacter Infections; Chronic Disease; Duodenal Ulcer; Gastritis; Humans; Organometallic Compounds; Peptic Ulcer; Salicylates; Stomach Ulcer

An investigation was done on the action in vitro of two pharmaceutical preparations containing Bi, De Nol and Pepto Bismol, on the fermentative capacity of intestinal bacteria. For the purpose, using an instrument and a technique previously described, fecal fermentation (FF) was measured in 21 stool samples, to which lactose was added to assure appreciable levels of fermentation. In 11 of the samples, FF was measured without and with addition of De Nol; and in the 10 remaining samples, without and with addition of Pepto Bismol. In 7 of the samples with which the action of De Nol was studied, this preparation significantly reduced FF from 10.9 not equal to 4.3 (mean not equal to s. d.) to 4.9 not equal to 5.0 ml of gas/24 h (p less than 0.02); on the contrary, in the 4 remaining samples, it increased FF, although not significantly, from 8.7 not equal to 4.8 to 16.7 not equal to 8.8 ml of gas/24 h (N.S.). Pepto Bismol significantly reduced FF, in all the 10 samples with which the action of that pharmaceutical - preparation was investigated, from 11.7 not equal to 6.1 to 3.0 not equal to 2.1 ml of gas/24 L (p less than 0.0001). A discussion was done on the possible mechanisms of the antifermentative action of Bi, as well as on the probable usefulness of De Nol and Pepto Bismol for the control of exaggerated intestinal fermentation and the flatulence it frequently causes.

Topics: Antacids; Bacteria; Bismuth; Feces; Fermentation; Humans; In Vitro Techniques; Intestines; Lactose; Organometallic Compounds; Salicylates