Proton pump inhibitors (synonyms: proton pump inhibitors, proton pump inhibitors, proton pump inhibitors; proton pump blockers, blockers H.+/K.+ -Atphase, hydrogen pump blockers, IPP, IPN, etc.) - antisecretory drugs intended for the treatment of acid-dependent diseases of the gastrointestinal tract due to the reduction of hydrochloric acid products due to blocking in the parietal cells of the proton pump stomach mucosa - H.+/K.+ -Atphase.
According to the modern anatomy-therapeutic-chemical classification of medicines (ATC) proton pump inhibitors (IPP) included in the section A.02B. "Anti-sized drugs and preparations for the treatment of gastroesophageal reflux" in the group A.02BC. "Protonic pump inhibitors." It lists international non-specific names of the seven proton pump inhibitors (the first six of them are allowed for use in the USA and in the Russian Federation; seventh, dexrabeprazole, currently no permissions for use):
- A.02BC.01 omeprazole
- A.02BC.02 Pantoprazole
- A.02BC.03 Lansoprazole
- A.02BC.04 Rabeprazole
- A.02BC.05 Ezomeprazole
- A.02BC.06 dexlansoprazole
- A.02BC.07 dexrabeprazole
Proton pump inhibitors in combination with various antibiotics are also posted in the group A.02BD. "Combinations of drugs for eradication Helicobacter pylori.».
The data on a number of new proton pump inhibitors are also published, which are currently at various stages of development and clinical trials (Tenatoprazole, D.-Alsoprazole, Ilaprazole, etc.).
Proton pump inhibitors are currently recognized as the most effective drugs overwhelming hydrochloric acid.
Proton pump inhibitors are widely used in clinical practice in the treatment of acid-dependent diseases of the gastrointestinal tract (including the need for eradication. Helicobacter pylori.), such as:
- gastroesophageal reflux disease (GERD);
- ulcer of the stomach and / or duodenal estate;
- Zollinger-Ellison syndrome;
- damage to the mucous membrane of the stomach caused by the method of non-steroidal anti-inflammatory drugs;
- gastrointestinal bleeding of various origins
- functional dyspeps;
- Quadro- or triple therapy with the use of antibiotics.
The proton pump inhibitors are also shown and for the prevention of the acidic content of the stomach in the respiratory tract during the general anesthesia (Mendelssohn syndrome).
The proton pump inhibitors are produced in the form of such dosage forms as "shell-coated tablets", "capsules", "intestinal capsules" (IPP, except Ezomeprazole, is rather unstable to the effects of acidic content of the stomach), as well as "lyophilisate for the preparation of a solution for Infusions, "" Powder for making a solution for infusions. " Parenteral forms for intravenous administration are particularly shown to treat in cases where the oral administration is difficult.
By chemical structure, all IPSs are benzimidazole derivatives and have a single molecular nucleus.
In essence, they all differ only to chemical radicals on pyridine and benzimidazole rings - which cause their individual properties concerning the duration of the latent period, the duration of the preparation time, features pH-selectivity, interaction with other simultaneous preparations and the like.
Ezomeprazole, dexlansoprazole and DecSarabrazole are optical isomers of omeprazole, Lansoprazole and Rabeprazole, respectively. Due to such a modification, they have higher biological activity.
The mechanism of action of various proton pump inhibitors is the same, and they differ mainly by their pharmacokinetics and pharmacodynamics.
It should be noted that, although, all proton pump inhibitors and have the same mechanism of action, ensuring the similarities of their clinical effects, however, each of them has features of pharmacokinetics (see table), which determines their individual properties and can serve as a choice of choice The appointment and conduct of therapy, although, depending on the genetically deterministic type of metabolism, the pharmacokinetics of the IPP and their concentration in the blood can vary significantly in different patients.
Table. Pharmacokinetics IPP
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Options |
Omeprazole 20 mg |
Ezomeprazole 40 mg |
Lansoprazole 30 mg |
Pantoprazole 40 mg |
Rabeprazole 20 mg |
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Bioavailability,% |
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WITH Mach, mg / a |
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AUC, ICMOL / LHF |
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T. 1/2, Ch |
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T Max, C. |
For example, the minimum inhibitory concentration for omeprazole is 25-50 mg / l, lanzoprazole - 0.78-6.25 mg / l, pantoprazole - 128 mg / l.
According to the results of the comparative studies, it should be paid at that time that omeprazole and esomeprazole, pharmacokinetics indicators are increasing during the first days of reception, after which they reach the plateau, and they do not change pantoprazole and Rabeprazole, remaining stable.
Attention should also be paid to the fact that the main indicator determining the rate of development of the EPP effect is their bioavailability. For example, it was shown that the smallest bioavailability is characterized by omeprazol (after the 1st reception it is 30-40% and increases to 60-65% to the 7th dose). In contrast, the bioavailability of the already initial dose of Lansoprazole is 80-90%, which causes the more rapid beginning of the action of this drug.
Thus, as noted by many researchers, in the early periods of therapy, Lansoprazole has some advantages in the effect of the effect of the effect, which potentially increases the patient's commitment to treatment.
However, it should be noted that the various IPE preparations used in clinical practice differ in the speed of the clinical effect only in the first days of treatment, and the 2-3rd reception week of these differences are lost.
Essential for the practice of applying the moment is, for example, and such a moment that the reception of antacids, like food, does not affect Pantoprazole pharmacokinetics. Sukralfat and food intake can change Lanzoprazole absorption. The pharmacokinetics of omeprazole can be changed by intake, but does not change with liquid antacids. Therefore, Lanzoprazole and omeprazole are taken 30 minutes before meals, and Pantoprazole and Rabeprazole - regardless of meals.
It has been established that in all IPPs the duration of the antisectory effect correlates not with the concentration of the drug in the blood plasma, but with an area under a pharmacokinetic concentration-time concentration ( AUC), reflecting the amount of the drug that has reached the proton pump. Comparative studies have been established that after the 1st reception of all IPPs the largest indicator AUC Pantoprazole was. In Ezomeprazole, she was smaller, but, gradually increasing, to the 7th reception she was somewhat surpassed AUC Pantoprazole. Index AUC omeprazole was the lowest in all compared IPPs.
Therefore, - omeprazole should be prescribed 2 times a day - and the drugs with the greatest indicator AUC (Pantoprazole and Ezomeprazole) most patients are enough to take once. It is noted that for a certain number of patients, the foregoing can be attributed to Lansoprazol and Rabeprazole.
However, it should be noted that the clinical significance of this fact is mainly reduced to the multiplicity of reception of various STIs, and the multiplicity of drug intake in turn is associated with the problem of the patient's commitment to treatment.
But, at the same time, it should be taken into account that there is a significant scatter of the duration of the antisecretory effect, both inhibit inhibitors of the proton pump, and individually from 1 to 12 days. Therefore, the definition of individual rhythms of reception and doses of drugs for each patient can be individually controlled by intrabastric pH-Money.
An important distinction of various drugs IPP is their pH-selectivity. It is known that selective accumulation and rapid activation of all IPPs occur only in an acidic environment. The speed of their transformation into the active substance with increasing pH Depends on the value rKa for nitrogen in pyridine structure. It has been established that for pantoprazole rKa is 3.0 for omeprazole, Ezomeprazole and Lansoprazola - 4, for Rabeprazole - 4.9. This means that when pH 1.0-2.0 In the lumen of the secretory tubules, all IPPs there are selectively accumulated, quickly turn into sulfenamide and act equally efficiently. With raising pH Transformation of the IPP slows down: the activation rate of pantoprazole decreases by 2 times pH 3.0 omeprazole, Ezomeprazole and Lanzoprazole - when pH 4.0 Rabeprazole - when pH4.9. Pantoprazole is practically not turning into an active form when pH 4.0 omeprazole, Ezomeprazole and Lanzoprazole - when pH 5.0 When the Rabelrazole activation is still happening. Thus, Pantoprazole is the most pH -selective, and Rabeprazole - the least pH -selective IPP.
In this regard, it is interesting that the authors of Rabeprazole's ability to activate in a wide range pH It is considered as its advantage, since it is associated with a quick antisectory effect. According to others, low pH-selectivity Rabeprazole is its disadvantage. This is explained by the fact that the chemically active forms of IPP (sulfenamide) are potentially able to interact not only with Sh-groups of cysteine \u200b\u200bproton pumps, but also with any Sh-Groups of the body. Currently, in addition to parietal cells, proton pumps ( N. + /TO + - or N. + /Na. + -Atphase) revealed in cells and other organs and tissues: in the intestine epithelium, gallbladder; renal tubules; corneal epitheliums; in muscles; cells of the immune system (neutrophils, macrophages and lymphocytes); osteoclasts, etc. This means that, provided that IPP is activated outside the secretory steamers of the parietal cell, their impact on all these structures is possible. In the cells of the body there are organelles with an acidic medium (lysosomes, neurosecretory granules and endosome), where pH 4.5-5.0, therefore they can be potential targets of the IPP (in particular, Rabeprazole).
From here it was concluded that for selective accumulation in the secretory canals of the parietal cell rThe CA IPP should be optimally below 4.5.
It is the difference pH-Electivity of proton pump inhibitors is also discussed as a pathogenetic mechanism of potential side effects of IPS with prolonged use. So, the possibility of blocking by vacolaolar N. +Ath-phase neutrophils, which can increase the susceptibility of the patient to infection. So, in particular, against the background of the IPP therapy, an increase in the risk of community-hospital pneumonia is described - however, it should be noted that such a complication is most likely not during long-term treatment, but only in the initial period of receiving IPS.
It should also be paid attention to the fact that the therapeutic effect of the IPT significantly depends on the rate of removal of drugs from the body. The metabolism of the proton pump permitted in Russia occurs mainly in the liver with the participation Cyp.2C.9, Cyp.2C.19, Cyp.2D.6 I. Cyp.3A.4, - Cytochrome Isoers R450. Polymorphism of the genes of the cytochrome system Cyp.2WITH19 is a determining factor in the fact that the rate of the offensive and the duration of the antisecretory effect of the IPP in patients differ significantly.
It was found that in the Russian population, the prevalence of the mutation of the gene Cyp.2C.19, encoding the metabolism of the IPP (homozygotes, no mutations - the rapid metabolism of the IPP; heterozygotes, one mutation; two mutations, - slow metabolism), for representatives of the Europeanid race amount to 50.6%, 40.5% and 3.3%, for Mongoloid race - 34.0%, 47.6% and 18.4%, respectively. Thus, it turns out that from 8.3 to 20.5% of patients resistant to a single dose of IPP.
The exception is Rabeprazole, whose metabolism passes without the participation of the isoenzyme Cyp.2C.19 I. Cyp.3A.4, with which is apparently the constant value of its bioavailability after the first application, as well as its smallest interaction with drugs metabolizing through the cytochrome system P.450 and the smallest dependence on polymorphism gene encoding isoform 2 C.19, compared with other proton pump inhibitors. Rabeprazole less than the rest of the drugs affects metabolism (destruction) of other drugs.
The clearance of omeprazole and Ezomeprazole is significantly lower than that of other IPPs, which causes the growth of the bioavailability of omeprazole and its stereoisomer Ezomeprazole.
Such phenomena as "resistance to proton pump inhibitors", "Night acid breakthrough", etc., noted in a number of patients, may be due not only by genetic factors, but also other features of the condition of the body.
Speaking about the treatment of proton pump inhibitors, you should, of course, note the problem of their safety. This problem has two aspects: safety of IPPs as a class and safety of individual drugs.
Side effects from the use of proton pump inhibitors can be divided into two groups: side effects observed with short course of therapy, and arising during long-term reception of these drugs.
The safety profile of proton pump inhibitors with short (up to 3 months) therapy courses are very high. Most often, with short course of therapy, there are side effects on the part of the central nervous system, such as headache, fatigue, dizziness, and from the region of the gastrointestinal tract (diarrhea or constipation). In rare cases, allergic reactions are noted (skin rash, phenomena of bronchospasm). In the intravenous administration of omeprazole, cases of violations of vision and hearing are described.
It was found that with a long-term (especially for several years), the continuous use of proton pump blockers, such as omeprazole, lansoprazole and pantoprazole, - the hyperplasia of enterochromaphine cells of the stomach mucosa or the progression of atrophic gastritis phenomena occurs. It is noted that the risk of developing nodular hyperplasia Ecl.- Blots becomes especially high in cases where the level of serum gastrine exceeds 500 pg / ml.
These changes are usually expressed in the long-term use of high doses of IPP (at least 40 mg of omeprazole, 80 mg of pantoprazole, 60 mg of Lansoprazole). With long-term use of large doses, a decrease in the level of suction level of vitamin was also noted B. 12 .
For example, it should be noted that in practice, the need for a long-term supportive reception of such high doses of proton pump inhibitors is usually available only in patients with Zolinger-Ellison syndrome and in patients with severe erosive-ulcer esophagitis. At the conclusion of the Medicinal Committee in Gastroenterology FDA (Food and Drag Administration, USA), "... There is no reliable increase in the risk of atrophic gastritis, intestinal metaplasia or stomach adenocarcinoma with prolonged use of IPS." Therefore, it can be safely argued that, in general, these drugs have a good security profile.
An important problem of treatment of treatment is the ability to change the effects of drugs with a joint admission with IPS. It has been established that among IPP Pantoprazole has the lowest affinity to the cytochrome system P.450, since after initial metabolism in this system, further biotransformation occurs under the influence of cytosol sulfontransferase. This explains the smaller potential of Pantoprazole's interprehensive interactions than other IPPs. Therefore, it is believed that if necessary, the reception of several drugs for the simultaneous treatment of other diseases is the use of pantoprazole most safely.
An individual effect should be noted and unwanted effects during the cessation of the treatment of proton pump inhibitors. For example, in a number of studies, it was emphasized that after the discontinuation of Rabeprazole, there is no "Ricochlet" syndrome (cancellation), i.e. It does not arise a compensatory sharp increase in the level of acidity in the stomach, - the secretion of hydrochloric acid after treatment with this IPP is restored slowly (within 5-7 days). "Cancellation syndrome" is more pronounced in the abolition of Ezomeprazole, prescribed by patients at a dose of 40 mg.
Taking into account the above listed features of various proton pump inhibitors (features of metabolism associated with genetics, reasons for resistance, the possibility of night "acid breakthroughs", etc.) It can be concluded that any single "best" drug for acid-dependent diseases. does not exist. Therefore, in order to eliminate failures under therapy of the IPA, the selection and purpose of the proton pump inhibitors should be individually and in a timely manner, taking into account the reaction to the treatment carried out and, if necessary, must be accompanied by an individual selection of drugs and doses of their reception under control pH-Money (daily pH-thry) or gastroscopy.
Against the background of long-term treatment with various proton pump inhibitors, the acquired (secondary) resistance to one or another IPP is possible. Such resistance becomes noticeable after long-term treatment with the same drug when the effectiveness of it against the background of continuous use during the year and is more significantly reduced, but the translation of patients for treatment by other IPS improves their condition.
Omeprazole (omise, losk), lansoprazole
Antisecretory tools
Divided into the following groups:
Gistamine Blockers H 2 -receptors
Cimetidine, Ranitidine, Famotidin
Blocators H + K + -ATFase (proton pump inhibitors)
M-cholinoblocators
a) non-selective M-cholinoblocators
Atropine, Metacin, Platifillain
b) selective M-cholinoblocators
Pyrenspin (Gastretepin)
Since histamine is a direct stimulator of the secretion of gastric juice, histamine H 2-receptor blockers are one of the most efficient and frequently used groups of anti-rich agents. They have a pronounced antisecretory effect - reduce basal (alone, outside meal) secretion of hydrochloric acid, reduce the selection of acid at night, slow down the production of pepsin.
Cimetidine is the histamine H 2-receptor of the I generation. Effective with a duodenal ulcer and a stomach ulcer with increased acidity; During the period of exacerbation 3 times a day and at night (duration of treatment 4-8 weeks), it is rarely applied.
Side effects: Galactere (in women), impotence and gynecomastia (in men), diarrhea, disorders of the liver and kidney function. Cimetidine is an inhibitor of microsomal oxidation, inhibits the activity of cytochrome P-450. The sharp abolition of the drug leads to the "cancellation syndrome" - recuridation of ulcerative disease.
Ranitidine - Gistamine H 2-receptor II Blocator II; As an antisectory agent is more effective than cimetidine, it acts longer (10-12 hours), therefore it is accepted 2 times a day. Practically does not cause side effects (the headache, constipation is possible), does not oppress the microsomal liver enzymes.
Indications: ulcerative ulcerative disease of the stomach and duodenal intestine (including due to the intake of the NSAID), the tumor of the secreting stomach cells (Zollinger-Ellison syndrome), hyperacid states, reflux esophagitis.
Contraindications: hypersensitivity.
Available in the form of a tablet of 150mg, 300mg, a solution for injection 1% 5ml and 10% 2ml.
Apply 150-300mg 2 times a day inside.
For injections, 50mg intramuscularly introduced or intravenously slowly (for 2 minutes) in 20 ml sodium sodium solution every 6 hours.
Famotidine - histamine H 2-receptor of the III of generation. When aggravating ulcerative diseases can be assigned 1 time per day before bedtime at a dose of 40 mg. The drug is well tolerated, less often causes side effects. Contraindicated in pregnancy, lactation, in childhood.
Release form: Tablets at 20mg and 40mg.
Inside 20mg 2 times a day or 40mg 1 time per day.
Blocators H, K + -ATFase (proton pump inhibitors)
H + / K + -ATPAZ (proton pump) is the main enzyme that ensures the secretion of hydrochloric acid by the stomach parietal cells.
The blockade of this enzyme leads to an effective oppression of the synthesis of hydrochloric acid by parietal cells.
Currently used proton pump blockers inhibit the enzyme irreversible, the secretion of acid is restored only after the synthesis of the enzyme de novo.This group of drugs oppresses the secretion of hydrochloric acid most effectively.
Omeprazole - a single reception of the drug leads to the oppression of secretion by more than 90% over 24 hours. The effect occurs within 1 hour, maximum - after 2 hours.
Side effects: nausea, headache, activation of cytochrome P-450, the possibility of the development of atrophy of the mucous membrane of the stomach.
Since when akhlorohydria, the secretion of gastrin is increased against the background of the appointment of omeprazole, the hyperplasia of enterochromaffofofod-like stomach cells (in 10-20% of patients), i.e., polypo-shaped grows on the gastric mucosa. These increases give reverse development after canceling the drug.
Forms of release: Capsules of 10, 20, 40mg, powder for infusion bottles of 40mg.
Inside are taken by 20mg 1-23 times a day, with reflux at 40mg 1-2 times a day.
Omeprazole is quickly decomposed in an acidic environment - take on an empty stomach in the morning or 2 hours after dinner in the evening, it is not possible to cheat capsules, it is advisable to wash with alkaline water.
Lansoprazole has similar properties with omeprazole. But, unlike omeprazole, it is distinguished by the liver (omeprazol - kidneys), so preference is given for the diseases of the liver.
The form of the release of the capsule is 30mg.
It is accepted 30-60mg 1-2 times a day.
Ezomeprazole (Nexium) is an active metabolite of omeprazole - the action and action is faster and the action is longer and strong.
The form of release - capsules 20 and 40mg.
Pantoprazole (Controls, Pantasan, Pantap, Nalpaz) combines the properties of IPP and antibacterial activity in relation to Helicobacter pylori.
Form of release of tablets 20 and 40mg.
Rabeprazole (Pariet, Rabelol, Once) on the action close to omeprazol.
Form of the release of Tablet 10 and 20mg.
The proton pump inhibitors are drugs intended for the treatment of acid-dependent diseases of the gastrointestinal tract due to a decrease in hydrochloric acid products by blocking in parietal cells of the mucous membrane of the proton pump - H + / K + -ATPhase. Belong to antisecretory drugs.|
Omeprazole - historically the first proton pump inhibitor |
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Ezomeprazole - omeprazole s-isomer |
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Pantoprazole |
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Lansoprazole |
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Rabeprazole |
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Dextelasoprazole - Optical isomer Lansoprazola |
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Tenatoprazole. |
By chemical structure, all proton pump inhibitors are benzimidazole derivatives and have a single molecular kernel. The proton pump inhibitors only differ in chemical radicals, which give them individual properties relating to the duration of the latent period, the duration of the action of the drug, the features of pH-selectivity, interacting with other simultaneous preparations and so on.
1.4.1. Mechanism of action
For the products of acid in the stomach correspond to the parietal cells of the foundal glands. The central link in the secretion of hydrochloric acid is hydrogen-potassium adenosyntrifyosphatase (H + / K + -ATFAZ), which, being embedded in the apical (directed in the lumen of the stomach) of the parietal cell membrane, performs the role of a proton pump that ensures the transfer of hydrogen ions H + through the membrane In the space of the stomach in exchange for potassium ions K + in directions opposed to the electrochemical gradient for both ions, using the hydrolysis energy of the adenosine trifosphoric acid molecule (ATP). After that, the ion of potassium K + is already transported by an electrochemical gradient back, causing a joint transfer to it into the gastric lumen of the chlorine ion CL -.
The molecules of the proton pump inhibitors, accumulating in the intracellular tubules of parietal cells in the immediate vicinity of the H + / K +-cat molecules, after some transformations are transformed into tetracyclic sulfenamide, which is covalently turns on to Cistein groups H + / K + -ATPAZ, making, thereby making it , the last unable to participate in the process of transporting ions.
1.4.2. Lansoprazole (Lansoprazole)
Structural formula:
Composition and form of release. Lansoprazole. Capsules (30 mg).
Pharmachologic effect. Anti-sized. A specific inhibitor H + -K + -atphase. Acting in the final phase of secretion of hydrochloric acid in the stomach, the drug reduces acid production, regardless of the nature of the stimulating factor.
Indications. Ulceal duodenal ulcer or stomach in the aggravation phase, reflux-esophagitis.
Application. The daily dose is 30 mg in one reception. The course of treatment is 4 weeks, if necessary, treatment can be continued 2-4 weeks. Patients receiving theophylline, Lansoprazole appointed with caution and under the strict observation of the doctor. The drug may cause the induction of various ferment systems of cytochrome P 450. Antacids containing aluminum and magnesium hydroxide should be taken 2 hours after receiving Lansoprazole.
Side effect. Rarely - diarrhea, constipation; In isolated cases - skin rash.
1.4.3. Pantoprazole (Pantoprazole)
Structural formula:
Composition and form of release. Pantoprazole. Capsules (40 mg).
Pharmachologic effect. Inhibitor H + -K + -atphase. Reduces the level of basal and stimulated (regardless of the type of irritant) secretion of hydrochloric acid in the stomach. With a duodenal ulcer, associated with Helicobacter Pylori, such a decrease in gastric secretion increases the sensitivity of the microorganism to antibiotics. Pantoprazole has its own antimicrobial activity against H. pylori.
Indications. Ulcerative ulcer of the stomach or duodenal in the exacerbation phase, Zolinger-Ellison syndrome, Helicobacter Pylori Eradication (in combination with antibacterial therapy), reflux-esophagitis.
Application. The average therapeutic dose is 40 mg / day. Maximum dose - 80 mg / day. The duration of the course of therapy is established depending on the testimony, but it should not exceed 8 weeks. Prior to the start of therapy, the possibility of malignant neoplasm in the stomach and the esophagus should be excluded, since the use of pantoprazole reduces the severity of symptoms and can delay the establishment of the correct diagnosis.
Side effect. Diarrhea, headache; rarely - nausea, pain in the top of the abdomen, meteorism, rash, itching, weakness, dizziness; In isolated cases, the edema, an increase in body temperature, initial manifestations of depressive states, violation of vision.
Interaction with other medicines. With simultaneous use, Pantoprazole can change the absorption of drugs, the absorption of which depends on the pH of the gastric content (ketocanazole). Due to the fact that Pantoprazole is metabolized in the liver of the trimmed system of cytochrome P 450, it is impossible to exclude the possibility of drug interaction with drugs, metabolizing the same enzyme system. 1.4.4. Omeprazole (omeprazole)
Structural formula:
Composition and form of release. Omeprazole. Tablets (20 mg); capsules (10 mg, 20 mg); Lyophilized dry substance for infusion (in 1 vial - 40 mg).
Pharmachologic effect. Inhibitor H + -K + -atphase. It slows down the activity of H + -K + -atfase in parietal eczrinocytes of the stomach and blocks the final stage of the secretion of hydrochloric acid. This leads to a decrease in basal and stimulated secretion, regardless of the nature of the stimulus. The effect of the drug occurs quickly depends on the value of the adopted dose and is maintained for 24 hours and more after a single reception of 20 mg of omeprazole.
Indications. The ulcer of the stomach and duodenalist in the exacerbation phase, reflux-esophagitis, Zolinger - Ellison syndrome.
Application. One-time dose is 20-40 mg. The daily dose is 20-40 mg, the multiplicity of application is 1-2 times / day. In case of severe the course of the disease, 40 mg of the drug is introduced 1 time / day. The climbness of treatment is 2-8 weeks. Before starting therapy, it is necessary to eliminate the presence of a malignant process (especially in patients with a stomach ulcer), since the treatment of the drug can mask symptoms and delay the correct diagnosis. With the exacerbation of the ulcer of the stomach and duodenum, the drug is prescribed in a dose of 20 mg 1 time / day in the morning on an empty stomach. Patients with poor healing of duodenal ulcers are recommended to be administered omeprazole at a dose of 40 mg 1 time / day, which makes it possible to achieve healing for 4 weeks. To prevent the recurrences of the duodenal ulceneous disease, 10 mg 1 time / day are prescribed. If necessary, the dose can be increased to 20-40 mg 1 time / day. To prevent the recurrences of the peptic ulcer of the stomach in patients with bad healing, it is recommended to assign 20 mg 1 time / day. Patients with poor healing of stomach ulcers are recommended to assign omeprazole at 40 mg / day, which will provide a scarring for 8 weeks. With a peptic ulcer associated with Helicobacter Pylori, omeprazole is prescribed at a dose of 40 mg / day in combination with amoxicillin (1.5-3 g of 2 reception) for 2 weeks.
Side effect. On the nervous system: rarely - dizziness, headache, excitement, drowsiness, insomnia; paresthesia; In some cases, depression and hallucinations. On the digestive system: rarely - dry mouth, violation of taste, diarrhea or constipation, stomatitis, abdominal pain; Improving the activity of liver enzymes in blood plasma. On the respiratory system: rarely - bronchospasm. On the musculoskeletal system: arthralgia, muscle weakness, Malgy. On the blood formation system: rarely leukopenia, thrombocytopenia. Skin reactions: rash, urticaria, itching, multiform erythema. Others: impairment of vision, peripheral edema, strengthening, fever.
Interaction with other medicines. Omeprazole can slow down the elimination of drugs, metabolized by oxidation in the liver (in particular, warfarin, diazepama and phenyotine).
Atmospheric corrosion inhibitor « N-M-1 »
Atmospheric corrosion inhibitor "N-M-1" is intended to protect products from atmospheric and microbiological corrosion during operation, storage, conservation and transportation in various climatic conditions (continental, marine, tropical, arctic). It is also used to protect equipment from parking corrosion and inter-operational conservation of thermal power equipment.
"H-M-1" is an analogue of the M-1 inhibitor. For its manufacture, instead of the synthetic fatty acids of fraction C 10 -C 13 used fatty acids C 10 -C 18.
Protects products from biological structures due to the increase in the growth of the most common types of mold fungi.
To obtain inhibited anticorrosive primers with enhanced protective properties and an increased service life of the paint coating.
Joint research and development works of Notech NTPP LLC with the developer of inhibitors M-1 and "N-M-1" - the laboratory of corrosion inhibitors of JSC VNIINFTEKHIM (St. Petersburg) under the leadership of the Honored Scientist of the Russian Federation, Professor A. AND. Altzieva - ensured the maximum approximation of the technological and protective properties of the "n-M-1" inhibitor to the properties of the inhibitor M-1..
The "N-M-1" inhibitor is not a precursor.
Specifications:
Appearance - pasty substance
Colour - Brown
It is a high molecular weight adduct of fatty acids fraction C 10 -C 18 and cyclic amine.
Solubility(% of mass at +25 o c):
In water up to 3;
In gasoline to 80;
In industrial oils - at least 20;
In organic solvents up to 50%.
Protects steel, cast iron, zinc, nickel, chromium, aluminum, copper and its alloys.
Packing: Euroved 18 kg.
The technological and protective properties of the "N-M-1" inhibitor are similar to the properties and composition of the M-1 inhibitor. Inhibitor "N-M-1" is included in GOST 9.014-78 "Temporary anti-corrosion protection of products. General requirements".
Preparation of inhibited conservation oils and solutions, production of anti-corrosion LKM.
Atmospheric corrosion inhibitor "N-M-1" applies:
- in the form of 5 ... 10% solutions in volatile solvents (gasoline, ethanol, etc.);
- in the form of 1 ... 3% solutions in water (condensate);
- in the form of additives to mineral oils and fuels (diesel, reactive, kerosene), rust transducers, detergents in the amount of 0.1 ... 3% of the mass;
- in the form of 0.2 ... 3% of the mass. aqueous solutions when combining hydro-testing and preservation with additional use of volatile corrosion inhibitors;
- by administering to anti-corrosion epoxy, vinyl, vinyl epoxy, etc. primers in an amount of up to 2.5% by weight of the LX at the stage of their manufacture.
The preparation of inhibitor oils and solutions can be carried out by administering an inhibitor without heating or when heated (avoid open fire sources) to 40-50 ° C, depending on the consistency of the inhibitor and inhibitor oil, with a thorough mixing, until a homogeneous mixture is obtained. If necessary, before use, it is allowed to warm up to + 80 ° C in the mass of the inhibitor. Condensate is used for the preparation of aqueous solutions. Solutions on tap water, as a rule, muddy.
Warranty period of storage: 24 months from the date of manufacture.
Specifications:
Solubility (% of mass at + 25 ° C):
In water at least 3%;
In gasoline 82.9%;
In industrial oils at least 50%.
Surface preparation
Products must come to preservation clean. Preparation for preservation is carried out in accordance with sections 4.5 GOST 9.014 ESSKS.
Conducting conservation
Preservation of products (parts, nodes, mechanisms, etc.) with inhibited oils, fuels, as well as solutions "H-M-1" in volatile solvents carried out by applying them to the surface of metal with dipping, brush, spraying or in any other way So that there are no places in the products are not left. After applying the solution (oil) on the surface of the equipment, it is necessary to spend the excess of oil or evaporate the solvent. Preservation of internal cavities of mechanisms (fuel systems, etc.) without their disassembly is carried out by short-term overlap (pumping) at a temperature not higher than 70 ° C or filling the mechanism in inhibited oil (fuel, mortar).
The rate of consumption of inhibitated materials (oils, solutions, etc.) are established depending on the design of products, the method of application, conditions and storage terms.
Conducted for long term storage with solutions "N-M-1" in oils and volatile solvents, knots and parts of the equipment are wrapped in paraffinated or wrapped paper.
Precautionary measures: Atmospheric corrosion inhibitor "N-M-1" - a small substance. When working with the "N-M-1" inhibitor, it is necessary to use specialobuvi personnel, workwear, safety devices in accordance with typical sectoral norms. When working with solutions of an inhibitor in oils, fuels and volatile solvents, it is necessary to comply with general rules for working with fire or explosive substances. If you get on the skin or mucous membranes, rinse with warm water or weak soda solution.
The use of corrosion inhibitor "N-M-1"
Without reliable protection against corrosion, the equipment quickly fails. Especially important anti-corrosion protection in those situations where the operation of metal structures or mechanisms is carried out in an aggressive chemical environment, and they are constantly under the influence of vapors and high temperatures.
We take part in the reconstruction of the water supply system of fountains of the State Museum-Reserve "Peterhof", which has no analogues in the world. The corrosion inhibitor "N-M-1" preserves pipes and water-fitting devices for the winter. The rust converter "Notech" is used when painting metal structures and external protection of the joints of pipes.
Corrosion inhibitors "FMT" and "N-M-1" are used to conservate the weapon collection of the State Hermitage.
Application for the purchase of corrosion inhibitor "N-M-1" You can send by email :. We look forward to collaborating.
Application for the purchase xyou can send an imical rust converter "Notech" by email:. We look forward to collaborating.
(Also called: proton pump inhibitors, proton pump inhibitors, proton pump blockers, N + / K + -AT phase blockers, hydrogen pump blockers, etc.) - antisecretory drugs intended for the treatment of acid-dependent stomach and duodenum and esophagus blocking proton pumps (H + / K + -ATPAZ) of shelling (parietal) cells of the gastric mucosa and thus reducing the secretion of hydrochloric acid. The abbreviation of IPP is most often used, less often IPN.
Proton pump inhibitors are the most efficient and modern drugs in the treatment of ulcerative lesions of the stomach, duodenum (including those associated with the infection of Helicobacter Pylori) and esophagus providing a decrease in acidity and, as a result, the aggressiveness of the gastric juice.
All proton pump inhibitors are benzimidazole derivatives and have a close chemical structure. The IPP differs only by the structure of radicals on pyridine and benzimidazole rings. The mechanism of action of various proton pump inhibitors is the same, they differ mainly by their pharmacokinetics and pharmacodynamics.
The mechanism of action of the proton pump inhibitor
The proton pump inhibitors, after passing the stomach, fall into the small intestine, where they dissolve, after which the blood flow comes first to the liver, and then penetrate through the membrane into parietal cells of the stomach mucosa, where they are concentrated in secretory tubules. Here, with an acidic pH value, proton pump inhibitors are activated and turn into tetracyclic
 |
| The mechanism of action of inhibitors proton pump (Maev I.V. et al.) |
Types of proton pump inhibitors
Anatomy-therapeutic-chemical classification (ATC) in the section A02B "Anti-sized preparations for the treatment of gastroesophageal reflux" contains two groups with proton pump inhibitors. In the A02BC group "Proton pump inhibitors" lists international non-specific names (MNN) seven IPPs (the first six types of them are allowed for use in the United States and in the Russian Federation, seventh, dexrabeprazole, no permissions for use):
Ezomeprazole, dexlansoprazole and Decsarazole are optical isomers of omeprazole, Lansoprazole and Rabeprazole, respectively, having greater biological activity. Also in this group included combinations: A02BC53 Lansoprazole in combination with other drugsIn group A02BD "Combination of drugs for eradication Helicobacter pylori.»The proton pump inhibitors are listed in combination with various antibiotics intended for treatment Helicobacter pylori.-Soed diseases of the digestive tract:
A02BC54 Rabeprazole in combination with other drugs
A02BD01 omeprazole, amoxicillin and metronidazoleThere are a number of new proton pump inhibitors located at various stages of development and clinical trials. The most famous from them is close to the completion of Tenatoprazole test. However, some clinicians believe that it does not have obvious pharmacodynamic advantages over its predecessors and that the differences concern only the pharmacokinetics of the active substance (Zakharova N.V.). Among the advantages of Ilaprazole, they call the fact that it is less dependent on the polymorphism of the Gena Syr2C19 and that the period of its semi-life (T 1/2) is 3.6 hours (Maev I.V., etc.)
A02BD02 Lansoprazole, Tetracycline and Metronidazole
A02BD03 Lansoprazole, Amoxicillin and Metronidazole
A02BD04 Pantoprazole in combination with amoxicillin and clarithromycin
A02BD05 omeprazole, amoxicillin and clarithromycin
A02BD06 Ezomeprazole, Amoxicillin and Clarithromycin
A02BD07 Lansoprazole, Amoxicillin and Clarithromycin
A02BD09 Lansoprazole, Clarithromycin and Tinidazole
A02BD10 Lansoprazole, Amoxicillin and Levofloxacin
The USA control and medicine control (FDA) in January 2009 made it possible to use in the treatment of GERD the sixth proton pump inhibitor - dexlaxoprazole, which is an optical isomer of Lansoprazole, in May 2014 he received permission in Russia.
In the pharmacological index in the Gastrointestinal Facilities section there is a group of "proton pump inhibitors".
Order of the Government of the Russian Federation of December 30, 2009 No. 2135-p One of the proton pump inhibitors - omeprazole (capsules; lyophilisate for the preparation of a solution for intravenous administration; lyophilisate for the preparation of the solution for infusions; shell-coated tablets) is included in the list of vital and necessary and Major medicines.
Currently, in Europe, it is licensed to treat GERB 5 standard doses of proton pump inhibitors (Ezomeprazole 40 mg, Lansoprazole 30 mg, omeprazole 20 mg, Rabeprazole 20 mg, 
pantoprazole 40 mg) and one double (omeprazole 40 mg). The standard doses of proton pump inhibitors are licensed for the treatment of erosive esophagitis for 4-8 weeks, and a double dose - for the treatment of refractory patients, which have already been previously treated with standard doses appointed for up to 8 weeks. Standard doses are assigned once a day, double dose - twice a day (V.D. Pomes, etc.).
Non-legal inhibitors of proton pump
In the first decades, after their appearance, antisecretory drugs are generally inhibitors of proton pumps in the United States, Russia, and many other countries have been prescription. In 1995, the FDA resolved the non-receptible (over-the-coutne r) for the sale of the Zantac 75 H2-blocker, in 2003 - the first non-receptible IPP Prilosec OTC (omeprazole magnesium). Later in the United States registered non-pressed IPPs: omeprazole (omeprazole), Prevacid 24hr (Lansoprazole),
Nexium 24HR (Ezomeprazole Magnesium), Zegerid OTC (omeprazole + sodium bicarbonate). All non-receptible forms are characterized by a reduced content of the active substance and have the purpose "for the treatment of frequent heartburn." Pantoprazole 20 mg is allowed for a non-receptible vacation in the European Union (EU) 12.6.2009, in Australia - in 2008, Ezomeprazole 20 mg - in the EU 26.8.2013, Lansoprazole - in Sweden since 2004, later allowed in a number other EU countries, Australia and New Zealand. Omeprazole - in Sweden since 1999, later in Australia and New Zealand, other EU countries, Canada, a number of Latin America countries. Rabeprazole - in Australia since 2010, later - in the UK (Boardman HF, Heeley G. The Role of the Pharmacist In The Selection and Use of Over-the-Counter Proton-Pump Inhibitors. INT J Clin Pharm (2015) 37: 709-716. DOI 10.1007 / S11096-015-0150-Z).
In Russia, the following dosage forms of IPP are admitted to non-receptible sale 
:
- Gastroin, omise, orethanol, omeprazole-teva, ultra, capsules containing 10 mg of omeprazole
- Berth, Noflux, Pariet, Rabbats, Capsules, containing 10 mg Rabeprazole Sodium (or Rabeprazole)
- Controls, capsules containing 20 mg pantoprazole
Proton pump inhibitors in the treatment of gastrointestinal diseases
Proton pump inhibitors are the most efficiently overwhelming hydrochloric acid products by drugs, although not deprived of some drawbacks. In this capacity, they found wide use in the treatment of acid-dependent diseases of the gastrointestinal tract, including, if necessary, the eradication of Helicobacter Pylori. Diseases and conditions, in the treatment of which the use of proton pump inhibitors (Lapina T.L.) is shown:
- gastroesophageal Reflux disease (GERD)
- gastric ulcer and / or duodenal
- syndrome Zlinger Ellison
- damage to the mucous membrane of the stomach caused by the method of non-steroidal anti-inflammatory preparations (NPSV)
- diseases and conditions in which the Eradication of Helicobacter Pylori is shown.
Numerous studies showed a direct relationship between the duration of maintaining the acidity of the stomach with pH\u003e 4.0 and the speed of curing the ulcers and erosions in the esophagus, the stomach ulcers and the duodenum, the eradication frequency of Helicobacter Pylori, a decrease in the symptoms characteristic of the extrapiosal manifestations of gastroesophageal reflux. The smaller the acidity of the contents of the stomach (i.e., the greater the pH value), the earlier the effect of treatment is achieved. In general, it can be said that for most acid-dependent diseases, it is important that the pH level in the stomach was more than 4.0 for at least 16 hours a day. For more detailed studies, it was established that each of the acid-dependent diseases corresponds to its critical level of acidity, which must be kept within at least 16 hours a day (Isakov V.A.): | Acid-dependent diseases | Necessary for healing the level of acidity, pH, not less |
| Gastrointestinal bleeding | 6 |
| GERB, complicated by the extravagated manifestations | 6 |
| Quadro- or triple therapy with antibiotics | 5 |
| Erosive GERB | 4 |
| Damage to the mucous membrane of the stomach caused by the intake of non-steroidal anti-inflammatory drugs | 4 |
| Functional dyspepsia | 3 |
| Supporting therapy GERB | 3 |
In the pathogenesis of the ulcers of the stomach and / or duodenum, the crucifier is an imbalance between aggression factors and the protection factors of the mucous membrane. Currently among aggression factors, in addition to hypersection of hydrochloric acid, isolated: hyperproduction of pepsin, Helicobacter Piylori, a violation of gastroduodenal motility, effect on the mucous membrane of the stomach and duodenal of bile acids and lysolicisetin, pancreatic enzymes in the presence of duodenogastral reflux, and ischemia of the mucous membrane, Smoking, consumption of strong alcoholic beverages, the reception of some drugs, such as non-steroidal anti-inflammatory funds.
The protection factors include: secretion of gastric mucus, bicarbonate products that contribute to the neutralization of intragastric acidity at the surface of the gastric mucosa to 7 units. PH, the ability of the latter to regeneration, synthesis of prostaglandins, which have a protective effect and participate in ensuring adequate blood flow in the mucous membrane of the stomach and duodenum. It is important that many of these aggression factors and protection are genetically determined, and the balance between them is maintained by the coordinated interaction of the neuroendocrine system, including the bark of the brain, hypothalamus, peripheral endocrine glands and gastrointestinal hormones and polypeptides. The most important role of hyperacidity in the genesis of ulcerative disease is confirmed by the high clinical efficacy of antisecretory drugs, which have been widespread use in modern therapy of ulcerative disease, among which the inhibitors of proton pump (Maev I.V.) play a leading role. Proton Pump Inhibitors in Eradication Schemes Helicobacter pylori.
Eradication Helicobacter pylori. It does not always achieve the goal. Very wide and improper use of common antibacterial agents led to an increase in resistance to them Helicobacter pylori..
It is recognized that in different countries of the world (different regions) it is advisable to apply different schemes. In the absolute majority of circuits, one of the proton pump inhibitors in the so-called standard dosage (omeprazole 20 mg, Lansoprazole is 30 mg, Pantoprazole 40 mg, Ezomeprazole 20 mg, Rabeprazole 20 mg 2 times a day). The presence in the circuit of the proton pump inhibitor significantly increases the efficiency of antibiotics and sharply increases the percentage of successful eradications. An exception when proton pump inhibitors do not apply - atrophy of the gastric mucosa with akhlorhydria, confirmed by pH-metry. The selection of a proton pump inhibitor affects the likelihood of eradication, however, the replacement of other drugs (antibiotics, cytoprotectors) has a much greater influence than IPS. Specific recommendations for the Eradication of Helicobacter Pylori are given in the standards of diagnostics and treatment of acid-dependent and associated with Helicobacter Pylori diseases taken by the scientific society of gastroenterologists of Russia in 2010 Proton pump inhibitors increase the risk of fractures may cause Clostridium Difficile.-Soed diarrhea and may be the cause of hypomantee and dementia in old age, and also probably increase the risk of pneumonia in the elderly
USA control and medicine control (FDA) issued a number of reports of possible hazards with prolonged or in large doses receiving proton pump inhibitors: - in May 2010, the FDA warning on the increased risk of fractures of the thigh, wrists and spine with long-term admission or reception in large doses of proton pump inhibitors ("FDA warns")
- in February 2012, a FDA message was released, in which patients and doctors are warned that the therapy of proton pump inhibitors is possible increases the risk of Clostridium difficile-soluble diarrhea (FDA message from 8.2.2012).
It described several cases of the threatening life of the hypomagnation (lack of magnesium in the blood) associated with the admission of proton pump inhibitors (Yang Y.-x., Metz D.C.). Inhibitors of proton pumps, when they admit the elderly patients together with diuretics, to a small extent increase the risk of hospitalizations about the hypomagnemiology. However, this fact should not affect the reasonable appointment of proton pump inhibitors, and a small amount of risk does not require screening of magnesium level in the blood (Zipursky J El Al. Proton Pump Inhibitors and Hospitalization with Hypomagnesemia: A Population-based Case-Control Study / Plos Medicine - SEP 30, 2014).
According to research conducted in Germany (German Center for Neurodegenerative Diseases, Bonn), the prolonged reception of proton pump inhibitors increases the risk of dementia in old age by 44% (Gomm W. et al. Association of Proton Pump Inhibitors with Risk of Dementia. A Pharmacoepidemiological Claims Data Analysis. Jama Neurol. Published Online February 15, 2016. DOI: 10.1001 / JamaneuroL.2015.4791).
Scientists from the UK found that the elderly who received IPPs during a biennium, a higher risk of pneumonia. The logic of the authors of the study is the following: Acid in the stomach creates a barrier for the pathogenic for light intestinal microbiotes. Therefore, if acid production is reduced thanks to the reception of the IPP, then due to high refluxs, more pathogens can fall into the respiratory tract (J. Zirk-Sadowski, et al. Proton-pump inhibitors and Long-Term Risk of Community-Acquired Pneumonia in Older Adults. Journal of the American Geriatrics Society, 2018; DOI: 10.1111 / JGS.15385).
Acceptance of proton pump inhibitors during pregnancy
Different proton pump inhibitors have different risk categories for FDA fetal:
The reception of the proton pump inhibitors for the treatment of gastroesophageal reflux disease during the first trimester of pregnancy increases the risk of a child with heart defects more than twice (GI & HEPATOLOGY NEWS, August 2010). There are also studies proving that the admission of proton pump inhibitors during pregnancy increases the risk of asthma at the future child of 1.34 times (reception of H2-blockers - 1.45 times). Source: Lai T., et al. Acid-Suppressive Drug Use During Pregnancy And The Risk of Childhood Asthma: A Meta-Analysis. Pediatrics. Jan 2018.
Selection of proton pump inhibitors
The acid-blowing effect of the effect of proton pump inhibitors is strictly individual with each patient. A number of patients have such phenomena as "resistance to proton pump inhibitors", "Night acid breakthrough", etc. This is due to both genetic factors and the condition of the body. Therefore, in the treatment of acid-dependent diseases, the purpose of the proton pump inhibitors should be individually and in a timely manner taking into account the reaction to the treatment carried out. Determination of individual rhythms of reception and doses of drugs for each patient should be carried out under the control of intragastric pH-metry (Bredichina N.A., Kovanova L.A.; Belmer S.V.).
Daily pH gram of the stomach after receiving IPP
Comparison of proton pump inhibitors
It is generally recognized that proton pump inhibitors are the most effective means for the treatment of acid-dependent diseases. The class of antisecretory agents that appeared before the IEP - H2-blockers of histamine receptors are gradually displaced from clinical practice and IPP competes only among themselves. Among the gastroenterologists there are different points of view on the comparative effectiveness of specific types of proton pump inhibitors. Some of them claim that, despite some differences that exist between the STIs, today there are no convincing data that allows you to talk about greater efficiency of any IPA compared to the rest (Vasilyev Yu.V. et al.) Or that when eradication HP Type of IPP, including the composition of triple (quadruple therapy) does not matter (Nikonov E.K., Alekseenko S.A.). Others write that, for example, Ezomeprazole is fundamentally different from the other four IPPs: omeprazole, Pantoprazole, Lansoprazola and Rabeprazole (Lapina T.L., Demyanenko D., etc.). Third believe that Rabeprazole is most effective (Ivanashkin V.T., and others, Maev I.V. et al.).
A group of scientists from Germany (Kirchheiner J. et al.) Made a metaanalysis of the dose-effect dependence for the average level of the 24-hour intragastric pH and the percentage of time with pH\u003e 4 for 24 hours for various IPSs. They obtained the following values \u200b\u200bof the efficiency of various IPPs to achieve the average value of the intragastric pH \u003d 4:
The cost of generics omeprazole, Pantoprazole and Lansoprazole is much lower than the original preparations of Ezomeprazole and Rabeprazole, which is important for the patient and often determines the choice of the drug based on financial capabilities, especially for long-term reception (Alekseenko S.A.).
Trade Names of Drugs - Proton Pump Inhibitors
The domestic pharmaceutical market presents a wide range of various drugs from a group of proton pump inhibitors:
- active substance omeprazole: biofrazole, faith-omeprazole, gastroin, demo-omeprazole, gastroyt, zerozide, clerk, chrismel, lomak, losek, omezol, omekaps, omepara, omeprazole, omeprazole pellets, omeprazole-acos, omeprazol Acry, omeprazole-ek -20, Proma and Risk, Romyshek, Soparla, Ulzol, Ultra, Helicid, Helol, Cisagast
- the active substance omeprazole, except for which the medicine contains a noticeable amount of sodium bicarbonate: instant omez
- active substance omeprazole + Domperidon: Omez d
- active substance Pantoprazole: Zipantola, Controls, Crosside, Nalpaz, Panum, Peptazol, Panzum Sanovel, Puloref, Sanmpraz, Ulter
- active substance Lansoprazole: Acrimianz, Helicol, Lanzabel, Lanzoptol, Lansoprazole, Lansoprazole Pellets, Lansoprazole Stada, Lancefied, Lancide, Loensar Sanovel, Epicur
- active substance Rabeprazole: Berth, Zolyspan, Zulbex, Noflyux (previously called Zolyspan), Otaym, Noflyux, Pariet, Rabelok, Rabeprazole-Obl, Rabeprazole-SZ, Rabitet, OTOMO, Hailaise
- active substance
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