Bismuth preparations instructions for use. Bismuth preparations - pharmacological basis of clinical effect

Bismuth tripotassium dicitrate(lat. bismuthate tripotassium dicitrate) is a gastroprotective, antiulcer, antibacterial drug. Other name: colloidal bismuth subcitrate.

Chemical compound: bismuth (III) potassium 2-hydroxy-1,2,3-propane tricarboxylate (salt 1:3:2). Empirical formula C 12 H 10 BiK 3 O 14 .

Bismuth tripotassium dicitrate - international generic name (INN) of the medicinal product. According to the pharmacological index of bismuth tripotassium dicitrate belongs to the group "Antacids and adsorbents". According to ATC - to the group "Antiulcer drugs and drugs for the treatment of gastroesophageal reflux" and has the code A02BX05.

Bismuth tripotassium dicitrate (subcitrate) has a pronounced enveloping action . In the acidic environment of the gastrointestinal tract, bismuth subcitrate forms a protective film on the surface of the damaged mucous membrane of the stomach and duodenum, which promotes scarring of ulcers and protects against the effects of hydrochloric acid and pepsin. In addition, bismuth subcitrate stimulates the synthesis of prostaglandin E 2 , which, in turn, stimulates the formation of mucus and the secretion of bicarbonates and leads to the formation and accumulation of epidermal growth factor in the damaged area, which also improves the healing of erosions and ulcers.

Bismuth tripotassium dicitrate can accumulate inside bacteria Helicobacter pylori, resulting in the destruction of the cytoplasmic membranes of the bacterium and its death. That's why bismuth tripotassium dicitrate often used in various Hp eradication schemes . At the same time, bismuth tripotassium dicitrate, unlike other drugs containing bismuth, in particular, bismuth subnitrate and bismuth subsalicylate, is able to dissolve in mucus, which allows bismuth to penetrate under the layer of gastric or duodenal mucus, to the location of the maximum number of Hp bacteria. In addition, bismuth prevents Hp adhesion to the gastric epithelium and duodenum.

Additional inclusion in treatment regimens Helicobacter pylori bismuth tripotassium dicitrate (bismuth subcitrate) increase the frequency of Hp eradication without increasing side effects.

Indications for taking drugs with bismuth tripotassium dicitrate

How to take bismuth tripotassium dicitrate

Preparations with bismuth tripotassium dicitrate are taken half an hour before breakfast, lunch, dinner and bedtime, 120 mg each, with 1-2 sips of water. Duration of treatment - from 4 to 6 weeks. According to indications - up to 8 weeks. After the end of the cycle, a break of 8 weeks is required, during which any drugs containing bismuth must be excluded.

Bismuth tripotassium dicitrate and eradication of Helicobacter pylori

Bismuth tripotassium dicitrate is classified by the World Health Organization as a active drugs in a relationship Helicobacter pylori, along with several antibacterial agents (Podgorbunskikh E.I., Maev I.V., Isakov V.A.).

The very widespread and misuse of common antibacterial agents has led to increased resistance to them. Helicobacter pylori. The choice of eradication scheme depends on the presence of individual intolerance to specific drugs by patients, as well as the sensitivity of strains. Helicobacter pylori to these medicines. Therefore, as a basic drug for eradication Helicobacter pylori Bismuth tripotassium dicitrate has been increasingly used. In recommendations for eradication Helicobacter pylori, set out in the Standards for the diagnosis and treatment of acid-dependent and Helicobacter pylori-associated diseases, adopted by the Scientific Society of Gastroenterologists of Russia in 2010, bismuth tripotassium dicitrate is used both in some first-line and second-line regimens (numbering of options is given in accordance with the mentioned Standards):

Line 1. Option 2. One of the standard dose proton pump inhibitors (PPIs) (omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, esomeprazole 20 mg, rabeprazole 20 mg twice daily) and amoxicillin (500 mg four times daily or 1000 mg twice daily) per day), bismuth tripotassium dicitrate 120 mg 4 times a day or 240 mg 2 times a day in combination with clarithromycin (500 mg 2 times a day), or josamycin (1000 mg 2 times a day), or nifuratel (400 mg 2 times a day). times a day) for 10-14 days.
Line 1. Option 3 (in the presence of atrophy of the gastric mucosa with achlorhydria, confirmed by pH-metry). Amoxicillin (500 mg 4 times a day or 1000 mg 2 times a day) in combination with clarithromycin (500 mg 2 times a day) or josamycin (1000 mg 2 times a day), or nifuratel (400 mg 2 times a day) day), and bismuth tripotassium dicitrate (120 mg 4 times a day or 240 mg 2 times a day) for 10-14 days.

Note. If the ulcer persists, according to the results of control endoscopy on the 10th–14th day from the start of treatment, it is recommended to continue therapy with bismuth tripotassium dicitrate (120 mg 4 times a day or 240 mg 2 times a day) and/or PPI at half the dose for 2– 3 weeks. Prolonged therapy of bismuth tripotassium dicitrate is also indicated in order to improve the quality of the post-ulcer scar and speedy reduction of the inflammatory infiltrate.

Line 1. Option 4 (recommended only for elderly patients in situations in which full-fledged anti-Helicobacter therapy is impossible):

Standard dose PPI plus amoxicillin (500 mg 4 times a day or 1000 mg 2 times a day) and bismuth tripotassium dicitrate (120 mg 4 times a day or 240 mg 2 times a day) for 14 days
bismuth tripotassium dicitrate 120 mg 4 times a day for 28 days. In the presence of pain - a short course of PPI. Performed in the absence of eradication Helicobacter pylori after first line therapy.

Line 2(performed in the absence of eradication Helicobacter pylori after first line therapy ). Option 1. One of the standard dose PPIs, bismuth tripotassium dicitrate 120 mg 4 times a day, metronidazole 500 mg 3 times a day, tetracycline 500 mg 4 times a day for 10–14 days.
Line 2. Option 2. One of the standard dose PPIs, amoxicillin (500 mg 4 times a day or 1000 mg 2 times a day) in combination with a nitrofuran drug: nifuratel (400 mg 2 times a day) or furazolidone (100 mg 4 times a day) and bismuth tripotassium dicitrate (120 mg 4 times a day or 240 mg 2 times a day) for 10–14 days.
Line 2. Option 3. One of the standard dose PPIs, amoxicillin (500 mg 4 times a day or 1000 mg 2 times a day), rifaximin (400 mg 2 times a day), bismuth tripotassium dicitrate (120 mg 4 times a day) for 14 days.

Based on the comparative studies performed on the use of different Hp eradication regimens in pediatrics, data were obtained confirming that the use of bismuth tripotassium dicitrate in these regimens in children is effective, safe and economically justified. The best clinical and economic efficiency, as follows from the economic examination of various schemes, has a scheme: bismuth tripotassium dicitrate + furazolidone + amoxicillin (Belousova Yu.B. and others).

It is important that this bactericidal action of bismuth tripotassium dicitrate, in contrast to the action of most antibacterial agents, is manifested in relation to both vegetative and coccal forms. Helicobacter pylori. The use of bismuth preparations as part of eradication therapy makes it possible to overcome resistance Helicobacter pylori to metronidazole and clarithromycin. An important circumstance is complete absence strains Helicobacter pylori resistant to bismuth salts. Bismuth tripotassium dicitrate also reduces the activity of pepsin and pepsinogen, probably due to the binding of pepsin, and at acidic pH values it is able to bind bile acids, which is most important in the case of duodenogastroesophageal reflux. In addition, bismuth tripotassium dicitrate significantly increases the secretion of prostaglandins and bicarbonates in the stomach and duodenum, the formation of mucus, stimulates the activity of cytoprotective mechanisms and increases the resistance of the mucous membrane to the effects of aggression factors, such as: hydrochloric acid, pepsin, enzymes, salts bile acids(Balukova E.V.).

With eradication Helicobacter pylori monotherapy bismuth preparations are not used . effect can be achieved only when using bismuth preparations as part of a complex scheme of several preparations. "Maastricht-IV" recommends only four-component regimens with bismuth preparations and, in most cases (not always), as second-line regimens (if the first line fails), alternative, etc. (Isakov V.A.).

Professional medical publications concerning the effects of bismuth tripotassium dicitrate on the gastrointestinal tract

Balukova E.V. Possibilities of bismuth preparations in the treatment of gastroesophageal reflux disease // Therapy. - 2017. - No. 7 (17). pp. 102-108.

Belousova Yu.B., Karpov O.I., Belousov D.Yu., Beketov A.S. Pharmacoeconomics of the use of bismuth tripotassium dicitrate in peptic ulcer // Therapeutic archive. - 2007. - No. 2. - T. 79. - p. 1–9.

Khavkin A.I., Zhikhareva N.S., Drozdovskaya N.V. Drug therapy of peptic ulcer in children // Attending physician. - 2006. - No. 1. - With. 26-30.

Grigoriev P.Ya., Yakovenko E.P., Soluyanova I.P., Abdulzhapparova M.L., Talanova E.V., Usankova I.N., Pryanishnikova A.S., Agafonova N.A., Gulyaev P .V., Yakovenko A.V., Vasiliev I.V., Obukhovsky B.I. Modern methods peptic ulcer therapy, their effectiveness and cost // Experimental and clinical gastroenterology. - 2003. - No. 3. - p. 21–25.

Standards for the diagnosis and treatment of acid-dependent and Helicobacter pylori-associated diseases (4th Moscow agreement) adopted by the X Congress of NOGR on March 5, 2010 // Experimental and Clinical Gastroenterology. - 2010. - No. 5. – P. 113–118.

Samsonov A.A., Maev I.V., Ovchinnikova N.I., Shakh Yu.S., Podgorbunskikh E.I. The effectiveness of the use of colloidal bismuth subcitrate in the schemes of eradication therapy for Helicobacter pylori in duodenal ulcer // RJGGK. 2004. No. 4. pp. 30–35.

On the site in the "Literature" section, there are subsections "Gastroprotectors, cytoprotectors, hepatoprotectors, esophagoprotectors" and "Diseases of the stomach and duodenum (DPC)", containing articles for healthcare professionals on relevant topics.

Bismuth tripotassium dicitrate is not absorbed into the blood from the gastrointestinal intestinal tract. However, during the entire period of treatment, a small amount of bismuth can be split off from the colloid and enter the bloodstream. Bismuth, which enters the bloodstream, is excreted in the urine and its plasma concentration rapidly decreases after the end of treatment. Bismuth tripotassium dicitrate is excreted mainly with feces.

Side effects: possible nausea, vomiting, more frequent bowel movements, rarely - skin rash, itching.

Bismuth tripotassium dicitrate (bismuth subcitrate) is not recommended during pregnancy and lactation, as well as with impaired renal function.

Special instructions.

Long-term use of large doses of bismuth tripotassium dicitrate can cause reversible encephalopathy.
Half an hour before and half an hour after taking bismuth tripotassium dicitrate, it is not recommended to drink any drinks, milk, meals and antacids.
Alcoholic beverages during therapy with bismuth tripotassium dicitrate are prohibited.
In the treatment of bismuth tripotassium dicitrate, feces may turn black.

Overdose it is possible to develop reversible renal failure, the symptoms of which may appear after 10 days of taking large doses of bismuth subcitrate and later.

Interaction with other drugs: With the combined use of bismuth tripotassium dicitrate reduces the absorption of tetracycline. With the simultaneous use of bismuth tripotassium dicitrate with other drugs containing bismuth, the risk of increasing the concentration of bismuth in the blood increases.

Medicines with bismuth tripotassium dicitrate

Trade names of medicines active substance bismuth tripotassium dicitrate currently* registered in Russia: Vikanol life, Bismuth tripotassium dicitrate, Vitridinol, De-Nol

Instructions for medical use of the drug Ulcavis

Government Decree Russian Federation dated December 30, 2009 No. 2135-r bismuth tripotassium dicitrate (coated tablets) is included in List of vital and essential medicines.

Bismuth tripotassium dicitrate has contraindications, side effects and application features, consultation with a specialist is necessary.

LP-004536-131117

Trade name of the drug:

Bismuth tripotassium dicitrate

International non-proprietary name:

bismuth tripotassium dicitrate

Dosage form:

film-coated tablets

Compound:

for 1 tablet:
active substance: bismuth tripotassium dicitrate - 304.6 mg, in terms of bismuth oxide - 120.0 mg.
Excipients: corn starch - 71.1 mg; potassium polyacrylate - 23.6 mg; povidone-K25 - 17.7 mg; macrogol-6000 - 6.0 mg; magnesium stearate - 2.0 mg.
Shell composition: hypromellose - 5.5 mg; titanium dioxide - 3.0 mg; macrogol-4000 - 1.5 mg.

Description:

round biconvex tablets, film-coated white or almost white color odorless or with a slight characteristic odor. On the cross section, two layers are visible: the core is white or white with a yellowish tint and the film membrane.

Pharmacotherapeutic group:

antiulcer, antiseptic intestinal and astringent.

ATX code:

А02ВХ05

Pharmacological properties

Pharmacodynamics

Gastroprotective and antiulcer agent with bactericidal activity against Helicobacter pylori. It also has anti-inflammatory and astringent properties.
In the acidic environment of the stomach, insoluble bismuth oxychloride and citrate are precipitated, chelate compounds with a protein substrate are formed in the form of a protective film on the surface of ulcers and erosions. Thus, the drug forms a protective layer, which for a long period of time protects the affected areas of the mucous membrane from the influence of aggressive factors. By increasing the synthesis of prostaglandin E, the formation of mucus and the secretion of bicarbonate, it stimulates the activity of cytoprotective mechanisms, increases the resistance of the gastrointestinal mucosa to the effects of pepsin, hydrochloric acid, enzymes and bile salts. Leads to the accumulation of epidermal growth factor in the area of the defect. Reduces the activity of pepsin and pepsinogen.

Pharmacokinetics
Practically not absorbed from the gastrointestinal tract. It is excreted mainly with feces. A small amount of bismuth that enters the plasma is excreted from the body by the kidneys.

Indications for use

functional dyspepsia not associated with organic diseases gastrointestinal path;
chronic gastritis and gastroduodenitis in the acute phase, including those associated with Helicobacter pylori;
peptic ulcer stomach and duodenum in the acute phase, including those associated with Helicobacter pylori;
irritable bowel syndrome, which occurs mainly with symptoms of diarrhea.

Contraindications

increased individual sensitivity to the components of the drug;
pregnancy;
breastfeeding period;
taking drugs containing bismuth;
chronic kidney failure;
childhood up to 4 years.

Use during pregnancy and during breastfeeding

Bismuth tripotassium dicitrate is contraindicated for use in pregnant women. If necessary, the use of the drug during lactation should be discontinued. breast-feeding.

Dosage and administration

inside. The duration of the course of treatment and the dose of the drug is determined by the attending physician individually for each patient, depending on the nature of the disease.
Adults and children over 12 years old the drug is prescribed 1 tablet 4 times a day, 30 minutes before meals (breakfast, lunch, dinner) and at night, or 2 tablets 2 times a day 30 minutes before meals (breakfast, dinner).
Children aged 8 to 12 years appoint 1 tablet 2 times a day, 30 minutes before meals (breakfast, dinner).
Children aged 4 to 8 years administered at a dose of 8 mg / kg / day; depending on the body weight of the child, 1-2 tablets are prescribed per day (respectively, 1-2 doses per day).
In this case, the daily dose should be as close as possible to the calculated dose (8 mg/kg/day).
Tablets are taken 30 minutes before meals with a small amount of water. The tablet is recommended to be swallowed whole, without chewing or crushing, drinking plenty of water. It is not recommended to take the tablets with milk.
The duration of the course of treatment is usually 4 to 8 weeks. After the end of taking the drug, it is not recommended to take medicines containing bismuth (for example, Vikalin, Vikair) for 2 months.
For eradication Helicobacter pylori it is advisable to use bismuth tripotassium dicitrate in combination with antibacterial drugs with anti-helicobacter activity.
If there is no improvement during treatment, you should consult a doctor. Use the drug only according to the method of application and in the doses indicated in the instructions. If necessary, please consult your doctor before use. medicinal product.

Side effect

The adverse events listed below, noted with the use of bismuth tripotassium dicitrate, are distributed according to the frequency of occurrence in accordance with the following gradation: very often (> 1/10); often (> 1/100,<1/10); нечасто (> 1/1 000, <1/100); редко (> 1/10 000, <1/1 000); очень редко (<1/10 000).
From the gastrointestinal tract: very often - staining of feces in black; infrequently - nausea, vomiting, diarrhea or constipation.
allergic reactions: infrequently - skin rash, itching; very rarely - anaphylactic reactions.
From the side of the nervous system: very rarely - with prolonged use in high doses - encephalopathy associated with the accumulation of bismuth in the central nervous system.
Side effects are reversible and disappear quickly after discontinuation of the drug.
If any of the side effects listed in the instructions get worse, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

When using the drug in doses ten times higher than recommended, or with prolonged use of excessive doses of the drug, bismuth poisoning may develop.
Symptoms: dyspepsia, rash, inflammation of the oral mucosa, characteristic darkening in the form of blue lines on the gums; with prolonged use in doses exceeding those recommended, kidney function may be impaired.
These symptoms are completely reversible when the drug is discontinued.
Treatment: There is no specific antidote. In case of an overdose of the drug, gastric lavage, intake of enterosorbents and symptomatic therapy aimed at maintaining the function of the nights are indicated. In case of an overdose, the appointment of saline laxatives is also indicated. Further treatment should be symptomatic. In case of impaired renal function, accompanied by a high level of bismuth in the blood plasma, it is possible to introduce complexing agents - dimercaptosuccinic and dimercaptopropanesulfonic acids. With the development of severe renal impairment, hemodialysis is indicated.

Interaction with other drugs

Within half an hour before and half an hour after taking the drug, it is not recommended to use other medicines orally, as well as the intake of food and liquids, in particular antacids, milk, fruits and fruit juices. This is due to the fact that they, when taken orally, can affect the effectiveness of bismuth tripotassium dicitrate.
The drug reduces the absorption of tetracyclines.
The drug is not used simultaneously with other drugs containing bismuth, since the simultaneous use of several bismuth drugs increases the risk of side effects, including the risk of developing encephalopathy.

special instructions

The drug should not be used for more than 8 weeks. It is not recommended to exceed the established daily doses for adults and children during treatment. During the period of drug treatment, other drugs containing bismuth should not be used (see the section "Interaction with other drugs"). At the end of the course treatment with the drug in recommended doses, the concentration of the active active substance in the blood plasma does not exceed 3-58 μg / l, and intoxication is observed only at a concentration above 100 μg / l.
When using bismuth tripotassium dicitrate, feces may be stained dark due to the formation of bismuth sulfide.
Sometimes there is a slight darkening of the tongue.
During therapy, alcohol intake is not recommended.

Influence on the ability to drive vehicles and mechanisms

There are no data on the effect of Bismuth tripotassium dicitrate on the ability to drive vehicles and mechanisms.

Release form

Film-coated tablets 120 mg.
7, 10, 14, 28, 30 tablets in a blister pack made of PVC film and printed lacquered aluminum foil.
7, 10, 14, 20, 28, 30, 50, 56, 60, 100, 112, 160 or 240 tablets in polyethylene terephthalate jars for drugs or polypropylene jars for drugs, sealed with high pressure polyethylene lids with first opening control , or polypropylene lids with a "push-turn" system or low-pressure polyethylene lids with first opening control.
One jar or 1, 2, 3, 4, 5, 6, 7, 8, 10 or 16 blister packs together with instructions for use are placed in a carton (pack).

Storage conditions

At a temperature not higher than 25°C.
Keep out of the reach of children.

Best before date

3 years. Do not use after the expiration date.

Holiday conditions

Released without a prescription.

Manufacturer

LLC "Ozon Pharm"

Address of the place of production, including for correspondence and receipt of claims:
445143, Russia, Samara region, Stavropol district, s. Podstepki, the territory of the SEZ PPT, Highway No. 3, section No. 11, building No. 1.

Bismuth tripotassium dicitrate (bismuthate, tripotassium dicitrato)

Composition and form of release of the drug

◊ Film-coated tablets white or almost white, round, biconvex, odorless or with a slight characteristic odor, two layers are visible on the cross section: the core is white or white with a yellowish tint and the film membrane.

Excipients: corn starch - 71.1 mg, potassium polyacrylate - 23.6 mg, K25 - 17.7 mg, macrogol 6000 - 6 mg, magnesium stearate - 2 mg.

The composition of the film shell: hypromellose - 5.5 mg; titanium dioxide - 3 mg; macrogol-4000 - 1.5 mg.

7 pcs. - cellular cardboard packaging (1) - cardboard packs.
7 pcs. - cellular cardboard packaging (2) - cardboard packs.
7 pcs. - cellular cardboard packaging (3) - cardboard packs.
7 pcs. - cellular cardboard packaging (4) - cardboard packs.
7 pcs. - cellular cardboard packaging (5) - cardboard packs.
7 pcs. - cellular cardboard packaging (6) - cardboard packs.
7 pcs. - cellular contour packings (7) - packs of cardboard.
7 pcs. - cellular contour packings (8) - packs of cardboard.
7 pcs. - cellular contour packings (10) - packs of cardboard.
7 pcs. - cellular contour packings (16) - packs of cardboard.
10 pieces. - cellular contour packings (1) - packs of cardboard.
10 pieces. - cellular contour packings (2) - packs of cardboard.
10 pieces. - cellular contour packings (3) - packs of cardboard.
10 pieces. - cellular contour packings (4) - packs of cardboard.
10 pieces. - cellular contour packings (5) - packs of cardboard.
10 pieces. - cellular contour packings (6) - packs of cardboard.
10 pieces. - cellular contour packings (7) - packs of cardboard.
10 pieces. - cellular contour packings (8) - packs of cardboard.
10 pieces. - cellular contour packings (10) - packs of cardboard.
10 pieces. - cellular contour packings (16) - packs of cardboard.
14 pcs. - cellular contour packings (1) - packs of cardboard.
14 pcs. - cellular contour packings (2) - packs of cardboard.
14 pcs. - cellular contour packings (3) - packs of cardboard.
14 pcs. - cellular contour packings (4) - packs of cardboard.
14 pcs. - cellular contour packings (5) - packs of cardboard.
14 pcs. - cellular contour packings (6) - packs of cardboard.
14 pcs. - cellular contour packings (7) - packs of cardboard.
14 pcs. - cellular contour packings (8) - packs of cardboard.
14 pcs. - cellular contour packings (10) - packs of cardboard.
14 pcs. - cellular contour packings (16) - packs of cardboard.
28 pcs. - cellular contour packings (1) - packs of cardboard.
28 pcs. - cellular contour packings (2) - packs of cardboard.
28 pcs. - cellular contour packings (3) - packs of cardboard.
28 pcs. - cellular contour packings (4) - packs of cardboard.
28 pcs. - cellular contour packings (5) - packs of cardboard.
28 pcs. - cellular contour packings (6) - packs of cardboard.
28 pcs. - cellular contour packings (7) - packs of cardboard.
28 pcs. - cellular contour packings (8) - packs of cardboard.
28 pcs. - cellular contour packings (10) - packs of cardboard.
28 pcs. - cellular contour packings (16) - packs of cardboard.
30 pcs. - cellular contour packings (1) - packs of cardboard.
30 pcs. - cellular contour packings (2) - packs of cardboard.
30 pcs. - cellular contour packings (3) - packs of cardboard.
30 pcs. - cellular contour packings (4) - packs of cardboard.
30 pcs. - cellular contour packings (5) - packs of cardboard.
30 pcs. - cellular contour packings (6) - packs of cardboard.
30 pcs. - cellular contour packings (7) - packs of cardboard.
30 pcs. - cellular contour packings (8) - packs of cardboard.
30 pcs. - cellular contour packings (10) - packs of cardboard.
30 pcs. - cellular contour packings (16) - packs of cardboard.
7 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
10 pieces. - polyethylene terephthalate cans (1) - cardboard packs.
14 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
20 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
28 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
30 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
50 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
56 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
60 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
100 pieces. - polyethylene terephthalate cans (1) - cardboard packs.
112 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
160 pcs. - polyethylene terephthalate cans (1) - cardboard packs.
240 pcs. - polyethylene terephthalate cans (1) - cardboard packs.

pharmachologic effect

Antiulcer agent with bactericidal activity against Helicobacter pylori. It also has anti-inflammatory and astringent properties. In the acidic environment of the stomach, it forms insoluble bismuth oxychloride and citrate, and also forms chelate compounds with a protein substrate in the form of a protective film on the surface of ulcers and erosions. By increasing the synthesis of prostaglandin E, the formation of mucus and the secretion of bicarbonate, it stimulates the activity of cytoprotective mechanisms, increases the resistance of the gastrointestinal mucosa to the effects of pepsin, hydrochloric (hydrochloric) acid, enzymes and bile salts. Leads to the accumulation of epidermal growth factor in the area of the defect. Reduces the activity of pepsin and pepsinogen.

Pharmacokinetics

Bismuth tripotassium dicitrate is practically not absorbed from the gastrointestinal tract. However, a small amount of bismuth can enter the systemic circulation. It is excreted mainly with feces. A small amount of bismuth, received in, is excreted by the kidneys.

Indications

Peptic ulcer of the stomach and duodenum in the acute phase (including those associated with Helicobacter pylori); chronic gastritis and gastroduodenitis in the acute phase (including those associated with Helicobacter pylori); irritable bowel syndrome, occurring predominantly with symptoms; functional dyspepsia, not associated with organic diseases of the gastrointestinal tract.

Contraindications

Severe renal dysfunction, pregnancy, lactation, hypersensitivity to bismuth tripotassium dicitrate.

Dosage

Adults and children over 4 years old - inside 2-4 times / day 30 minutes before meals. The dose depends on the age of the patient.

The course of treatment is 4-8 weeks. For the next 8 weeks, you should not take drugs containing bismuth.

For eradication Helicobacter pylori, it is advisable to use bismuth tripotassium dicitrate in combination with antibacterial drugs with anti-Helicobacter pylori activity.

Salt of bismuth (III) potassium 2-hydroxy-1,2,3-propane tricarboxylate

Chemical properties

Colloidal bismuth subcitrate belong to the group antacids and adsorbents . The substance is usually found in film-coated tablets. Its molecular weight is 704 g per mole.

pharmachologic effect

Enveloping, antibacterial, gastroprotective, antiulcer.

Pharmacodynamics and pharmacokinetics

The substance has a pronounced astringent and anti-inflammatory effect. Getting into the acidic environment of the stomach bismuth oxychloride and bismuth citrate precipitate and form chelate complexes in the form of a protective film on the surface of the damaged mucosa. The agent stimulates the synthesis PgE2 , selection bicarbonate and mucus, activates the protective properties of the gastric mucosa, thereby protecting gastrointestinal tract from the effects of aggressive acids, salts and enzymes. In the area where the damage to the mucous membrane occurred, accumulates epidermal growth factor . Activity pepsin and pepsinogen starts to decline.

Bismuth Dicitrate Accumulates Inside Bacteria Helicobacter and leads to their destruction. cytoplasmic membrane and death. Due to the ability of the substance to penetrate under the layer duodenal mucus , where the concentration Helicobacter pylori the greatest, its effectiveness in the eradication of bacteria Helicobacter significantly higher than similar products.

The medicine is not absorbed by the walls gastrointestinal tract and does not enter the systemic circulation. The unchanged substance is excreted in the feces. A small amount of the drug that enters the bloodstream is metabolized and excreted in the urine.

Indications for use

The drug Bismuth Tripotassium Dicitrate is used:

with, accompanied by seizures;
for treatment, including those caused by bacteria Helicobacter ;
during exacerbation chronic and gastroduodenitis ;
in patients with, which is not caused by organic lesions gastrointestinal tract .

Contraindications

The drug can not be prescribed:

during breastfeeding;
pregnant women;
for this substance;
patients with renal insufficiency.

Side effects

During treatment with the drug may occur:

vomiting, constipation or nausea;
skin rashes, itching, other allergic reactions.

With prolonged use of this substance in the central nervous system may accumulate bismuth , which leads to development.

Bismuth Tripotassium Dicitrate, instructions for use (Method and dosage)

Depending on the disease, it is advisable to use different treatment regimens.

Bismuth Tripotassium Dicitrate tablets are taken orally with water.

As a rule, adults are prescribed 480 mg per day, divided into 4 doses, half an hour before meals or at bedtime. You can also take 240 mg, 2 times a day.

Children from 4 to 8 years old are prescribed 8 mg per kg of body weight per day, the daily dosage should be divided into 2 doses. The course of treatment is prescribed by the attending physician and, as a rule, it is 1-2 months.

Within 2 months after the course, you can not take drugs bismuth .

Bismuth Tripotassium Dicitrate is used in various treatment regimens Helicobacter pylori . The drug is combined with inhibitors proton pump ( , or ) and antibiotics ( , , ).

Overdose

With prolonged use of overdoses of the drug, there are: violations in the work of the kidneys,.

The treatment is: gastric lavage, enterosorbents and saline laxatives means, symptomatic therapy.

In case of violations in the work of the kidneys, which are accompanied by a high level of bismuth in the blood, are shown: complexing agents — dimercapto-propanesulfonic acid and dimercapto-succinic acid, .

Interaction

Before starting treatment with this drug, it is recommended that you tell your doctor if you are taking other drugs.

Also, the effectiveness of the drug can be affected by: antacids , fruit juices and fruits, milk.

Terms of sale

With a prescription.

Storage conditions

Store tablets in a cool place, out of reach of children, at a temperature not exceeding 25 degrees.

Best before date

special instructions

During therapy, the feces may turn black, and a change in the color of the tongue is rarely observed.

Medicines containing (Analogues of Bismuth Tripotassium Dicitrate)

Coincidence in the ATX code of the 4th level:

The substance is part of the drugs: , .

Bismuth (Bi) is a relatively rare element that has not only metallic properties, but also characteristics close to semiconductors and insulators, therefore it is sometimes classified as a semimetal or metalloid.

Bi(III) is easily hydrolyzed in aqueous solutions and has a high affinity for oxygen, nitrogen and sulfur-containing ligands, Bi(V) is a powerful oxidizing agent in aqueous solution and is unstable in biological systems.

Bismuth preparations

Bismuth compounds have entered medical practice since the Middle Ages, and the first scientific report on a preparation containing bismuth for the treatment of dyspepsia was made in 1786. To date, the most widely used bismuth compounds have been found in gastroenterology, and the most commonly used among them are bismuth subsalicylate and colloidal subcitrate (bismuth tripotassium dicitrate, VTD) (Table 1).

Bismuth subsalicylate is used in many countries as an over-the-counter drug for the rapid relief of heartburn, nausea, and diarrhea.

Colloidal bismuth subcitrate has found application primarily for the treatment of diseases associated with Helicobacter pylori infection, and also as a film-forming gastroprotector. It is this drug that is of greatest interest in terms of pharmacological properties and clinical use.

The use of bismuth radionuclides (for example, 213 Bi) seems promising for the diagnosis and treatment of various tumors - lymphomas, leukemia.

Bismuth tripotassium dicitrate

Mucosal interaction

On the surface of the mucosa, VTD forms glycoprotein-bismuth complexes, which in fact represent a diffusion barrier for HCl, which is enhanced by an additional increase in the viscosity of the parietal mucus. This process is pH dependent and weakens as pH increases. If at neutral pH, VTD is predominantly in a colloidal state, forming structures 6- and 12-, then at pH< 5 он быстро образует трехмерные полимерные преципитаты окси-хлорида и цитрата висмута, оптимум образования которых наблюдается при рН ≈ 3,5 .

The distribution of VTD along the gastric mucosa is uneven - a significant part of it is found in the bottom of the ulcer, and the rest is distributed over the intact mucosa. In the area of damaged mucosa, the precipitates are much larger and form a kind of "polymer film", which, as expected, provides a more pronounced protective effect. It is believed that due to the negative charge, bismuth microprecipitates are especially actively deposited on the affected areas of the mucosa, which have a positive charge due to the large amount of proteins. The resulting microprecipitates can penetrate the microvilli and enter the epithelial cells by endocytosis.

At the same time, under the influence of VTD, a redistribution of mucin production occurs - the level of acidic mucins, increased in the affected epithelium, decreases with a simultaneous increase in the number of neutral mucins.

Effect on pepsin activity

Research in vitro showed that VTD has antipepsin activity. At a concentration of 25 and 50 g/l, the drug (after preincubation with gastric juice at pH = 4) inhibited the proteolytic activity of pepsin (at pH = 2) by 29% and 39%, respectively. In patients with duodenal ulcer, VTD (120 mg 4 times / day) reduced both basal and stimulated pepsin production by more than 30%.

It is assumed that these effects are mediated both by direct inactivation of pepsin due to the formation of complexes with bismuth and by a decrease in chief cell activity.

Binding of bile acids

The phenomenon of bile acid binding of VTD was described after studies in vitro, and its clinical significance has not yet been fully determined. However, at pH = 2, VTD binds various bile acids, especially glycochenodeoxycholic (up to 50%), losing this activity sharply at pH = 4.

Influence on the production of prostaglandins and bicarbonate

This component of the mechanism of action is considered important in the implementation of the gastroprotective action of the VTD and in accelerating the healing of the ulcer. A dose - dependent increase in prostaglandin E 2 production has been shown in experimental and clinical studies . So, in patients with ulcerative lesions of the gastric mucosa after three weeks of VTD therapy, the concentration of prostaglandin E 2 in the antral mucosa of the stomach increased by 54%, and in the duodenal mucosa by 47%.

Simultaneously with the secretion of prostaglandins, prostaglandin-dependent bicarbonate production also increases, which increases the buffering capacity of mucus. This effect is significantly reduced under the influence of non-steroidal anti-inflammatory drugs.

Influence on the ultrastructure of the mucosa

In a study by M. G. Moshal et al. (1979) in patients with duodenal ulcer, the use of VTD for six weeks led to the epithelialization of the defect with the formation of normal epithelium without changing the structure of microvilli (unlike cimetidine). It is assumed that along with the action of the classically described pharmacological effects of bismuth, which provide protection and restoration of the mucosa, the acceleration of the repair of the epithelium in the area of the ulcer is facilitated by the protection of the epidermal growth factor from hydrolytic destruction by bismuth.

Along with this, the ability of VTD to stimulate the membrane Ca 2+ -sensitive receptor (CaSR), which is normally activated by extracellular Ca 2+ and provides an increase in intracellular Ca 2+ , MAP kinase activity and, as a result, proliferation of epithelial cells of the gastric mucosa, is discussed.

In experimental studies on the mucosa of the colon of mice, the ability of Bi (III) ions, due to antagonism with Fe (III) ions, to suppress the activity of non-amidated gastrin and, thus, the possibility of reducing excessive gastrin-mediated cell proliferation was shown.

Antihelicobacter activity

The bactericidal effect of VTD is very important. Under the influence of bismuth ions H. pylori loses the ability to adhere, the mobility of the microorganism decreases, vacuolization and fragmentation of the cell wall occurs, suppression of the enzyme system of bacteria, i.e., a bactericidal effect is achieved (in relation to both vegetative and coccal forms H. pylori) . This effect in VTD monotherapy, although insignificant (in the range of 14-40%), is not susceptible to the development of resistance and sharply potentiates when administered simultaneously with antibiotics.

Bismuth penetrates into H. pylori, predominantly localized in the area of the cell wall of the microorganism. It actively interacts with nucleotides and amino acids, peptides and proteins H. pylori. Although the molecular mechanisms of the anti-Helicobacter action of bismuth compounds are not fully understood, it is clear that the main targets in the microorganism are still protein molecules (including enzymes). Expression of approximately eight proteins is subject to up- or down- regulation under the action of bismuth ions.

J. R. Lambert and R. Midolo formulated the main molecular mechanisms of the anti-Helicobacter action of bismuth drugs, subsequently supplemented by other researchers:

1) blockade of adhesion H. pylori to the surface of epithelial cells;
2) suppression of various enzymes produced H. pylori(urease, catalase, lipase/phospholipase, alkyl hydroperoxide reductase, etc.), and translational factor (Ef-Tu);
3) direct interaction with heat shock proteins (HspA, HspB), neutrophil-activating protein (NapA), disruption of the structure and function of other proteins;
4) violation of the synthesis of ATP and other macroergs;
5) violation of the synthesis, structure and function of the cell wall and membrane function;
6) induction of free radical processes.

One of the mechanisms of the antibacterial action of bismuth ions is their interaction with the cell wall / glycocalyx complex present in some microorganisms (including H. pylori), with the displacement of the divalent cations Mg 2+ and Ca 2+ necessary for the construction of polysaccharide chains. In this case, local weakening of glycocalyx sites and bulging of the cell wall/membrane through the formed “windows” occur, which leads to disruption of the functioning of the microorganism and can activate autolytic processes leading to its death.

It is assumed that the entry of bismuth into H. pylori mediated through iron transport pathways, and having penetrated, it interacts with the binding sites of Zn (II), Ni (II) and Fe (III) proteins and enzymes, disrupting their function. For example, the binding of bismuth ions to small cytoplasmic proteins Hpn and Hpnl leads to a sharp violation of their detoxifying and accumulating function of "storage" for Ni ions.

H. pylori characterized by an unusual version of the GroES chaperonin (i.e., HpGroES) that has a unique C-terminus rich in histidine, cysteine, and three metal-binding residues (with Zn(II)), which allows polypeptide chains to fold to form a quaternary protein structure. Bismuth-containing preparations attach strongly at this site, displacing bound zinc and hence causing a dramatic disruption of HpGroES chaperonin function.

Bismuth preparations, penetrating into H. pylori, are able to induce powerful oxidative stress in the microorganism, which leads to inhibition of the activity of many enzymes in general. The prooxidant action is potentiated by suppressing the activity of thioredoxin and alkyl hydroperoxide reductase (TsaA) of the microorganism.

Inhibition of enzymes important for the microorganism, such as protease and urease, is a proven fact in the development of the anti-Helicobacter effect of VTD. At the minimum inhibitory concentration, VTD suppresses the total protease activity of the microorganism by approximately 87%.

Much attention is drawn to the interaction of bismuth with the enzymes of the tricarboxylic acid cycle of the microorganism (fumarate reductase, fumarase), which provides the formation of a number of biochemical precursors (α-ketoglutarate, succinyl-CoA, oxaloacetate) and works as a source of ATP formation. As a result, the production of macroergs decreases and many energy-dependent processes (including reparative, motor) are suppressed, which is reflected, for example, in the rate of colonization of various parts of the stomach by the microorganism. This effect is potentiated by the blockade of the Na + /K + -ATPase dithiol enzyme localized in the microbial wall/membrane, with which Bi ions form a stable complex.

As another enzymatic target of bismuth preparations, alcohol dehydrogenase is considered, which is involved in the production of acetaldehyde, which, secreted by a microorganism, has a suppressive effect on local protective factors of the mucosa, inhibiting protein secretion and disrupting the binding of pyridoxal phosphate to dependent enzymes.

The suppression of the activity of phospholipases C and A 2 by bismuth is also important. H. pylori. S-adenosylmethionine synthase, aldolase, fructose bisphosphate, and protein S6 of the 30S ribosome subunit are discussed as new targets for the anti-Helicobacter pylori action of VTD.

Pharmacokinetics of VTD

After oral administration of VTD, the concentration of bismuth in the gastric mucus and mucosa remains within three hours, after which it drops sharply due to normal mucus renewal. Despite the fact that a small part of VTD microprecipitates can penetrate into microvilli and enter epithelial cells by endocytosis, the exact mechanisms of bismuth transport into the systemic circulation are still unknown. However, it is clear that this process occurs predominantly in the upper small intestine.

The bioavailability of bismuth preparations is low and in VTD is 0.2-0.5% of the administered dose. H 2 -histamine blockers and proton pump inhibitors can increase this figure. After entering the blood, the drug is more than 90% bound to plasma proteins.

Measurement of the concentration of bismuth in the blood and urine after a course of application of VTD at a dose of 360 mg/day for 4-6 weeks showed a large variability of this indicator. Thus, the concentration of bismuth in the blood varied from 9.3 to 17.7 µg/l and reached a plateau approximately by the 4th week of the drug use. In separate studies, higher blood levels of the drug (33-51 µg / l) were recorded, but this was not accompanied by the development of side effects. The concentration of bismuth in the blood, as well as the area under the pharmacokinetic curve, is higher if the drug is taken in the morning, compared with the early evening intake.

Animal studies have shown that the predominant accumulation of the drug occurs in the kidneys and in much lower concentrations it is found in the lungs, liver, brain, heart and skeletal muscles.

Features of metabolism and elimination of bismuth have not been studied enough. The half-life of bismuth from blood and urine in patients with intoxication is 5.2 and 4.5 days, respectively. In healthy volunteers and patients with gastritis, clearance is approximately 22-102 ml / min (median 55 ml / min) and T1 / 2 about 5 days (T1 / 2 β up to 21 days), which indicates tissue deposition of the drug and its slow mobilization from there. The elimination of the drug is influenced by renal function, and if it worsens, the renal clearance of the drug may decrease. Some pharmacokinetic indicators of VTD are given in table. 2.

Clinical efficacy of VTD

VTD is an important component of clinical regimens of anti-Helicobacter pylori therapy, either as part of traditional quadruple therapy or as an additional component of first-line triple therapy, which gives an increase in eradication efficiency by 15-20%. First of all, this is due to the ability of the VTD to overcome the resistance H. pylori to antibiotics (especially clarithromycin), and not to the inherent bactericidal activity of the bismuth drug. Also of interest is the inclusion of VTD in sequential anti-Helicobacter therapy regimens.

VTD safety

Despite its status as a heavy metal, bismuth and its compounds are considered non-toxic, unlike arsenic, antimony, lead and tin located next to each other in the periodic table. The non-toxicity of bismuth compounds is mainly due to their insolubility in neutral aqueous solutions and biological fluids and extremely low bioavailability. Most bismuth compounds are even less toxic than sodium chloride.

A. C. Ford et al. in a meta-analysis conducted on MEDLINE and EMBASE publications, including 35 randomized controlled trials and 4763 patients, concluded that bismuth therapy for gastric ulcers was safe and well tolerated. The most commonly reported side effect is darkening of the stool due to the formation of bismuth sulfide.

In a very small proportion of patients, a mild transient increase in transaminase levels may occur, but it disappears after the end of the course of therapy. High doses of VTD used for a long time can theoretically cause the development of encephalopathy, but a very small number of such lesions of the central nervous system have been recorded. The most pronounced but reversible manifestation of bismuth encephalopathy has been described in a man who received two 28-day courses of VTD with 600 mg of the drug 4 times a day and took 240 mg / day intermittently for two years.

Conclusion

The uniqueness of VTD is that it combines the properties of a gastroprotective and antibacterial drug. Its multicomponent mechanism of action provides protection of the mucosa from the effects of various damaging factors, and anti-Helicobacter pylori activity allows you to overcome resistance. H. pylori to antibiotics, increasing the effectiveness of pharmacotherapy. In a general view, the combination of individual components of the mechanism of action of the drug is shown in Fig.

New directions in the creation of bismuth preparations for the treatment of gastroenterological diseases include the development of bismuth-containing nanostructures (bismuth-containing nanoparticles, Bi NPs). Thus, the created preparation of bismuth subcarbonate nanotubes has a powerful effect on H. pylori(50% inhibition at 10 µg/mL) and Bi NPs are potentially active against Gram-negative organisms including P. aeruginosa .

Bismuth nanoparticles at MIC 0.5 mmol/l are able to completely suppress biofilm formation S. mutans, which is comparable to the effect of chlorhexidine. In the work of the same authors, an aqueous colloid of Bi 2 O 3 nanoparticles with an average size of 77 nm effectively inhibited the growth and formation of biofilms. C. albicans without showing cytotoxicity. Attempts are being made to synthesize bismuth-fluoroquinolone complexes active against fluoroquinolone-resistant strains of microorganisms.

Comprehensive information on modern areas of medical chemistry of bismuth compounds can be found in the review by J. A. Salvador et al. .

Literature

Yang N., Sun H. Biological chemistry of antimony and bismuth / Biological chemistry of arsenic, antimony and bismuth / Sun H. (Ed.). Singapore: John Wiley & Sons Ltd., 2011. 400 rubles.
Li W., Jin L., Zhu N. et al. Structure of colloidal bismuth subcitrate (CBS) in dilute HCl: unique assembly of bismuth citrate dinuclear units (2-) // J Am Chem Soc. 2003 Vol. 125, No. 4. P. 2408-12409.
Andrews P. C., Deacon G. B., Forsyth C. M. et al. Towards a structural understanding of the anti-ulcer and anti-gastritis drug bismuth subsalicylate // Angew Chem Int Ed Engl. 2006 Vol. 45, No. 34. P. 5638-5642.
Mendis A. H. W., Marshall B. J. Helicobacter pylori and bismuth / Biological chemistry of arsenic, antimony and bismuth / Sun H (Ed.). Singapore: John Wiley & Sons Ltd., 2011. 400 rubles.
Morgenstern A., Bruchertseifer F., Apostolidis C. Bismuth-213 and Actinium-225 — generator performance and evolving therapeutic applications of two generator-derived alpha-emitting radioisotopes // Current Radiopharmaceuticals. 2012. Vol. 5, No. 3. P. 221-227.
Lee S.P. A potential mechanism of action of colloidal bismuth subcitrate; barrier to hydrochloric acid // Scand J Gastroenterol. 1982 Vol. 17, Suppl. 80. P. 17-21.
Turner N.C., Martin G.P., Marriott C. The influence of native porcine gastric mucus gel on hydrogen ion diffusion: the effect of potentially ulcerogenic agents // J Pharm Pharmacol. 1985 Vol. 37, No. 11. P. 776-780.
Tasman-Jones C., Maher C., Thomsen L. et al. Mucosal defenses and gastroduodenal disease // Digestion. 1987 Vol. 37, Suppl. 2. P. 1-7.
Williams D.R. Analytical and computer simulation studies of a colloidal bismuth citrate system used as an ulcer treatment // J Inorg Nucl Chem. 1977 Vol. 39, No. 4. P. 711-714.
Soutar R. L, Coghill S. B. Interaction of tripotassium dicitrato bismuthate with macrophages in the rat and in vitro // Gastroenterology. 1986 Vol. 91, No. 1. P. 84-93.
The ultrastructural localization of De-Nol (colloidal tripotassium dicitrato-bismuthate — TDB) in the upper gastrointestinal tract of man and rodents following oral and instrumental administration // J Pathol. 1983 Vol. 139, No. 2. P. 105-114.
Hollanders D., Morrissey S. M., Mehta J. Mucus secretion in gastric ulcer patients treated with tripotassium dicitrato bismuthate (De-Nol) // Br J Clin Pract. 1983 Vol. 37, No. 3. P. 112-114.
Roberts N. B., Taylor W. H., Westcott C. Effect of cyclo-alkyl lactamimides upon amylase, lipase, trypsin and chymotrypsin // J Pharm Pharmacol. 1982 Vol. 34, No. 6. P. 397-400.
Baron J. H., Barr J., Batten J. et al. Acid, pepsin, and mucus secretion in patients with gastric and duodenal ulcer before and after colloidal bismuth subcitrate (De-Nol) // Gut. 1986 Vol. 27, No. 5. P. 486-490.
Wieriks J., Hespe W., Jaitly K. D. et al. Pharmacological properties of colloidal bismuth subcitrate (CBS, De-Nol) // Scand J Gastroenterol. 1982 Vol. 17, Suppl. 80. P. 11-16.
Stiel D., Murray D. J., Peters T. J. Uptake and subcellular localization of bismuth in the gastrointestinal mucosa of rats after short term administration of colloidal bismuth subcitrate // Gut. 1985 Vol. 26, No. 4. P. 364-368.
Hall D.W.R., van de Hoven W.E. Protective properties of colloidal bismuth subcitrate on the gastric mucosa // Scand J Gastroenterol. 1986 Vol. 21, Suppl. 122. P. 11-13.
Estela R., Feller A., Backhouse C. et al. Effects of colloidal bismuth subcitrate and aluminum hydroxide on gastric and duodenal levels of prostaglandin E2 // Rev Med Chil. 1984 Vol. 112, No. 10. P. 975-981.
Konturek S. J., Bilski J., Kwiecien N. et al. De-Nol stimulates gastric and duodenal alkaline secretion through prostaglandin dependent mechanism // Gut. 1987 Vol. 28, No. 12. P. 1557-1563.
Crampton J. R., Gibbons L. C., Rees W. D. Effect of certain ulcer-healing agents on amphibian gastroduodenal bicarbonate secretion // Scand J Gastroenterol. 1986 Vol. 21, Suppl. 125. P. 113-118.
Moshal M. G., Gregory M. A., Pillay C., Spitaels J. M. Does the duodenal cell ever return to normal? A comparison between treatment with cimetidine and denol // Scand J Gastroenterol. 1979 Vol. 14, Suppl. 54. P. 48-51.
Gilster J., Bacon K., Marlink K. et al. Bismuth subsalicylate increases intracellular Ca2+, MAP-kinase activity, and cell proliferation in normal human gastric mucous epithelial cells // Dig Dis Sci. 2004 Vol. 49, No. 3. P. 370-378.
Kovac S., Loh S. W., Lachal S. et al. Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo // Biochem Pharmacol. 2012. Vol. 83, No. 4. P. 524-530.
Beil W., Bierbaum S., Sewing K. F. Studies on the mechanism of action of colloidal bismuth subcitrate. I. Interaction with sulfhydryls // Pharmacology. 1993 Vol. 47, No. 2. P. 135-140.
Wagner S., Beil W., Mai U. E. et al. Interaction between Helicobacter pylori and human gastric epithelial cells in culture: effect of antiulcer drugs // Pharmacology. 1994 Vol. 49, No. 4. P. 226-237.
Ge R. G., Sun H. Z. Bioinorganic chemistry of bismuth and antimony: target sites of metallodrugs // Acc Chem Res. 2007 Vol. 40, No. 4. P. 267-274.
Ge R. G., Sun X, Gu Q. et al. A proteomic approach for the identification of bismuth-binding proteins in Helicobacter pylori // J Biol Inorg Chem. 2007 Vol. 12, No. 6. P. 831-842.
Lambert J. R., Midolo P. The actions of bismuth in the treatment of Helicobacter pylori infection // Aliment Pharmacol Ther. 1997 Vol. 11, Suppl. 1. P. 27-33.
Stratton C. W., Warner R. R., Coudron P. E., Lilly N. A. Bismuth-mediated disruption of the glycocalyx-cell wall of Helicobacter pylori: ultrastructural evidence for a mechanism of action for bismuth salts // J Antimicrob Chemother. 1999 Vol. 43, No. 5. P. 659-666.
Tsang C. N., Ho K. S., Sun H., Chan W. T. Tracking Bismuth anti-ulcer drug uptake in single Helicobacter pylori cells // J Am Chem Soc. 2011 Vol. 133, No. 19. P. 7355-7357.
Xia W., Li H., Sun H. Functional disruption of HypB, a GTPase of Helicobacter pylori, by bismuth // Chem Commun (Camb). 2014. Vol. 50, No. 13. P. 1611-1614.
Li H., Sun H. Recent advances in bioinorganic chemistry of bismuth // Curr Opin Chem Biol. 2012. Vol. 16, no. 1-2. P. 74-83.
Cun S, Sun H. A zinc-binding site by negative selection induces metallodrug susceptibility in an essential chaperonin // Proc Natl Acad Sci USA. 2010 Vol. 107, No. 11. P. 4943-4948.
Baer W., Koopmann H., Wagner S. Effects of substances inhibiting or uncoupling respiratory-chain phosphorylation of Helicobacter pylori // Zentralbl Bakteriol. 1993 Vol. 280, No. 1. P. 253-258.
Pitson S. M., Mendz G. L., Srinivasan S., Hazell S. L. The tricarboxylic acid cycle of Helicobacter pylori // Eur J Biochem. 1999 Vol. 260, No. 1. P. 258-267.
Jin L., Szeto K. Y., Zhang L. et al. Inhibition of alcohol dehydrogenase by bismuth // J Inorg Biochem. 2004 Vol. 98, No. 8. P. 1331-1337.
Ottlecz A., Romero J. J., Lichtenberger L. M. Effect of ranitidine bismuth citrate on the phospholipase A2 activity of Naja naja venom and Helicobacter pylori: a biochemical analysis // Aliment Pharmacol Ther. 1999 Vol. 13, No. 7. P. 875-881.
Tsang C. N., Bianga J., Sun H. et al. Probing of bismuth antiulcer drug targets in H. pylori by laser ablation-inductively coupled plasma mass spectrometry // Metallomics. 2012. Vol. 4, no. 3. 277-283.
Lambert J. R., Yeomans N. D. Campylobacter pylori — gastroduodenal pathogen or opportunistic bystander? // Aust N Z J Med. 1988 Vol. 18, No. 4. P. 555-556.
Coghill S. B., Hopwood D., McPherson S., Hislop S. The ultrastructural localization of De-Nol (colloidal tripotassium dicitrato-bismuthate-TDB) in the upper gastrointestinal tract of man and rodents following oral and instrumental administration // J Pathol. 1983 Vol. 139, No. 2. P. 105-114.
Treiber G., Gladziwa U., Ittel T. H. et al. Tripotassium dicitrato bismuthate: absorption and urinary excretion of bismuth in patients with normal and renal impaired function // Aliment Pharmacol Ther. 1991 Vol. 5, No. 5. 491-502.
Phillips R. H., Whitehead M. W., Lacey S. et al. Solubility, absorption, and anti-Helicobacter pylori activity of bismuth subnitrate and colloidal bismuth subcitrate: In vitro data do not predict In vivo efficacy // Helicobacter. 2000 Vol. 5, No. 3. P. 176-182.
Nwokolo C. U., Prewett E. J., Sawyerr A. M. et al. The effect of histamine H2-receptor blockade on bismuth absorption from three ulcer-healing compounds // Gastroenterology. 1991 Vol. 101, No. 4. P. 889-894.
Lee S.P. Studies on the absorption and excretion of tripotassium dicitrato-bismuthate in man // Res Commun Chem Pathol Pharmacol. 1981 Vol. 34, No. 2. 359-364.
Hamilton I., Worsley B. W., O'Connor H. J., Axon A. T. R. Effects of tripotassium dicitrato bismuthate (TDB) tablets or cimetidine in the treatment of duodenal ulcer // Gut. 1983 Vol. 24, No. 12. P. 1148-1151.
Dekker W., Dal Monte P. R., Bianchi Porro G. et al. An international multi-clinic study comparing the therapeutic efficacy of colloidal bismuth subcitrate coated tablets with chewing tablets in the treatment of duodenal ulceration // Scand J Gastroenterol. 1986 Vol. 21, Suppl.122. P. 46-50.
Nwokolo C. U., Gavey C. J., Smith J. T. et al. The absorption of bismuth from oral doses of tripotassium dicitrato bismuthate // Aliment Pharmacol Ther. 1989 Vol. 3, No. 1. P. 29-39.
Wieriks J., Hespe W., Jaitly K. et al. Pharmacological properties of colloidal bismuth subcitrate (CBS, DE-NOL) // Scand J Gastroenterol. 1982 Vol. 17, Suppl. 80. P. 11-16.
Allain P., Chaleil D., Emile J. L'elevation des concentrations de bismuth dans les tissus des malades intoxiques // Therapie. 1980 Vol. 35, No. 3. P. 303-304.
Froomes P. R., Wan A. T., Keech A. C. et al. Absorption and eliminationof bismuth from oral doses of tripotassium dicitratobismuthate // Eur J Clin Pharmacol. 1989 Vol. 37, No. 5. P. 533-536.
Ivashkin V. T., Maev I. V., Lapina T. L. and other Recommendations of the Russian Gastroenterological Association for the diagnosis and treatment of Helicobacter pylori infection in adults // Ros. magazine gastroenterolia, hepatology, coloproctology. 2012. No. 1. C. 87-89.
Standards for the diagnosis and treatment of acid-dependent and Helicobacter pylori-associated diseases (Fifth Moscow Agreement) // Experiment. wedge. gastroenterol. 2013. No. 5. S. 3-11.
Maev I. V., Samsonov A. A., Korovina T. I. Bismuth tripotassium dicitrate increases the effectiveness of first-line anti-Helicobacter therapy // Experiment. wedge. gastroenterol. 2012. No. 8. C. 92-97.
Williamson R., Pipkin G. A. Does bismuth prevent antimicrobial resistance of Helicobacter pylori?/Helicobacter pylori. Basic Mechanisms to Clinical Cure 1998/Ed. by R. H. Hunt, G. N. J. Tytgat. Dordrecht; Boston; London: Kluwer Acad. Publ., 1998. P. 416-425.
Yoon J. H., Baik G. H., Kim Y. S. et al. Comparison of the eradication rate between 1-nd 2-week bismuth-containing quadruple rescue therapies for Helicobacter pylori eradication // Gut Liver. 2012. Vol. 6, No. 4. P. 434-439.
Sun Q., Liang X., Zheng Q. et al. High efficacy of 14-day triple therapy-based, bismuth-containing quadruple therapy for initial Helicobacter pylori eradication // Helicobacter. 2010 Vol. 15, No. 3. P. 233-238.
Uygun A., Ozel A. M., Sivri B. et al. Efficacy of a modified sequential therapy including bismuth subcitrate as first-line therapy to eradicate Helicobacter pylori in a Turkish population // Helicobacter. 2012. Vol. 17, No. 6. P. 486-490.
Ford A.C., Malfertheiner P., Giguere M. et al. Adverse events with bismuth salts for Helicobacter pylori eradication: systematic review and meta-analysis // World J Gastroenterol. 2008 Vol. 14, No. 48. 7361-7370.
Weller M.P.I. Neuropsychiatric symptoms following bismuth intoxication // Postgraduate Medical Journal. 1988 Vol. 64, No. 750. P. 308-310.
Chen R., So M. H., Yang J. et al. Fabrication of bismuth subcarbonate nanotube arrays from bismuth citrate // Chem Commun. 2006 Vol. 21. P. 2265-2267.
Pelgrift R. Y., Friedman A. J. Nanotechnology as a therapeutic tool to combat microbial resistance // Adv Drug Deliv Rev. 2013. Vol. 65, No. 13-14. P. 1803-1815.
Hernandez-Delgadillo R., Velasco-Arias D., Diaz D. et al. Zerovalent bismuth nanoparticles inhibit Streptococcus mutans growth and formation of biofilm // Int J Nanomedicine. 2012. Vol. 7. P. 2109-2113.
Hernandez-Delgadillo R., Velasco-Arias D., Martinez-Sanmiguel J. J. et al. Bismuth oxide aqueous colloidal nanoparticles inhibit Candida albicans growth and biofilm formation // Int J Nanomedicine. 2013. Vol. 8. P. 1645-1652.
Shaikh A. R., Giridhar R., Megraud F., Yadav M. R. Metalloantibiotics: synthesis, characterization and antimicrobial evaluation of bismuth-fluoroquinolone complexes against Helicobacter pylori. 2009 Acta Pharm. 59, 259-271.
Salvador J. A., Figueiredo S. A., Pinto R. M., Silvestre S. M. Bismuth compounds in medicinal chemistry // Future Med Chem. 2012. Vol. 4, No. 11. P. 1495-1523.

S. V. Okovity 1 , doctor of medical sciences, professor
D. Yu. Ivkin, candidate of biological sciences