The activity of microsomal hepatocyte enzymes inhibits. Hepatic enzymes. Increase the activity of drugs

When distributing in the body, some l in partially can delay and accumulate in various tissues. This is mainly due to the reversible binding of the LV with proteins, phospholipids and nucleoproteins of cells. This process is called deposit. The concentration of the substance at the place of its deposit (in the depot) can be high enough. The substance is gradually released from the depot and is distributed to other organs and tissues, including reaching the place of its action. Many l in bind to blood plasma proteins. The weakly acidic compounds (nonsteroidal anti-inflammatory agents, sulfonamides) are binding mainly with albumin (the largest fraction of plasma proteins), and weak bases with α1-sour glycoprotein and some other plasma proteins. LV proteins associated with proteins does not show pharmacological activity. But since this binding is reversible, a part of the substance is constantly released from the complex with a protein (this occurs when the concentration of the free substance in the blood plasma decreases) and has a pharmacological effect. Biotransformation (metabolism)- change in the chemical structure of medicinal substances and their physicochemical properties under the action of the enzymes of the body. The main focus of this process is the conversion of whether-pofil substances, which are easily reabsorbed in the renal tubules, into hydrophilic polar compounds that are quickly removed by the kidneys (not rebupported in the renal tubules). In the process of biotransformation, as a rule, the activity (toxicity) of the source substances occurs.

Biotransformation of lipophilic LWs mainly occurs under the influence of liver enzymes localized in the membrane of the endoplasmic reticulum-ma hepatocytes. These enzymes are called microsomal, because they are associated with small subcellular fragments of a smooth endoplasmic reticulum (microsomes), which are formed during homogenization of hepatic tissue or tissues of other organs and can be isolated by centrifugation (deposited in the so-called "microsomal" fraction).

In the plasma of blood, as well as in the liver, intestines, lungs, leather, mucous membranes and other tissues there are nephrosomal enzymes localized in cytozole or mitochondria. These enzymes can participate in hydrophilic metabolism.

The two main types of medicinal metabolism are distinguished:

non-secantic reactions (metabolic transformation);

· Synthetic reactions (conjugation).

Medicinal substances may be subject to either metabolic biotransformation (there are substances called metabolites), or conjugation (conjugates). But the majority of l in first metabolized with the participation of non-content reactions to the formation of reactive metabolites, which then come into the reaction of the conjugation. Metabolic transformation includes the following reactions: oxidation, restoration, hydrolysis. Many lipophilic compounds are subjected to oxidation in the liver under the influence of the microsomal system of enzymes known as oxidases of mixed functions, or monooxygenase. The main components of this system are cytochrome P-450 reductase and cytochrome P-450 - hemoprotein, which binds the molecules of the drug substance and oxygen in its active center. The reaction proceeds with the participation of PDFN. As a result, the addition of one oxygen atom to the substrate (drug substance) occurs to the formation of the hydroxyl group (hydro-xylation reaction). The restoration of medicinal substances can occur with the participation of micro-rosal (chloramphenicol) and non-microscopic enzymes (chlororalhydrate, naloxone). The hydrolysis of medicinal substances is carried out mainly by non-microscopy enzymes (esterasezami, amidazs, phosphatases) in blood plasma and tissues. At the same time, due to the addition of water, the essential, amide and phosphate bonds in the molecules of drugs occur. The hydrolysis is subjected to esters - acetylcholine, suucametonium (hydrolyzed with the participation of cholinesterase), amides (procanamide), acetylsalicylic acid. Metabolites, which are formed as a result of non-secure reactions, may in some cases have higher activity than the initial compounds. An example of an increase in the activity of medicinal substances in the process of metabolism is to use precursors of drugs (prodrugs). The prodrugs are pharmacologically inactive, but in the body they turn into active substances. In the process of biosynthetic reactions (conjugation) to the functional groups of molecules of drugs or their metabolites, residues of endogenous compounds (glucuronic acid, gluta-thion, glycine, sulfates, etc.) or high-polar chemical groups (acetyl, methyl groups) are attached. These reactions proceed with the participation of enzymes (mainly transfers) liver, as well as other tissue enzymes (lungs, kidneys). Localizes enzymes in microscoms or in the cytosolic fraction. Under the action of some medicinal substances (phenobarbital, rifampicin, carbamazepine, griseofulvin), induction may occur (increase the synthesis rate) of microsomal liver enzymes. As a result, while simultaneously appointed with the inductors of microsomal enzymes of other drugs (for example, glucocorticoids, oral contraceptives) increases the speed of metabolism of the latter and their action is reduced. In some cases, the metabolism of the inductor itself may increase, as a result of which its pharmacological effects (carbamazepine) decrease.

Drug removal pathways, their value for pharmacotherapeutic and side effects of drugs. Medication of drugs with salivary glands in the oral cavity.

The interactions that reduce the concentration of medicinal substances include:

Reduced suction in the gastrointestinal tract.

Induction of hepatic enzymes.

Reduced cell capture.

I. I am absorption in the gastrointestinal tract.

II.induccination of hepatic enzymes.

If the main path of elimination of the drug is metabolism, the acceleration of metabolism leads to a decrease in the concentration of the drug in the target organs. Most of the medicinal substances are metabolized in the liver - an organ with a large cell mass, high blood flow and enzyme content. The first reaction in the metabolism of many drugs is catalyzed by microsomal liver enzymes associated with cytochrome P450 and contained in the endoplasmic reticulum. These enzymes oxidize drug molecules using various mechanisms - hydroxylation of aromatic ring, n-demethylation, o-demethylation and sulfoculation. The molecules of these reactions are usually more polar, than the molecules of their predecessors, and therefore are easier to be removed by the kidneys.

The expression of some isoenzymes of cytochrome P450 is regulated, and their content in the liver may increase under the action of some drugs.

A typical substance causing the induction of microsomal liver enzymes is phenobarbital. Other barbiturates also operate. The inducing effect of phenobarbital is already manifested in a dose of 60 mg / day.

The induction of microsomal liver enzymes is also caused by rifampicin, carbamazepine, phenytoin, glatemide; It is observed in smokers, when exposed to chlorine-containing insecticides of the type DDT and constant alcohol consumption.

Phenobarbital, rifampicin and other inductors of microsomal liver enzymes cause a decrease in the serum concentration of many drugs, and including warfarin, quinidine, mexyleletina, verapamil, ketoconazole, itraconazole, cyclosporine, dexamethasone, methylprednisolone, prednisone (active prednis metabolite), steroid oral contraceptives , methadone, metronidazole and metrapon. These interactions have a great clinical value. So, if a patient, against the background of indirect anticoagulants, achieves a proper level of blood clotting, but at the same time he accepts any inductor of microsomal liver enzymes, then when canceling the latter (for example, when discharge), the serum concentration of the anticoagulant will increase. As a result, bleeding may occur.

There are significant individual differences in the indexability of drug metabolism enzymes. In some patients, phenobarbital sharply increases this metabolism, others - almost does not affect.

Phenobarbital not only causes the induction of some isoenzymes of cytochrome P450, but also enhances the hepatic blood flow, stimulates the secretion of the bile and transport of organic anions in hepatocytes.

Some medicinal substances can also increase the conjugation of other substances with bilirubin.

III. Cell seizure.

The derivatives of guanidine used to treat arterial hypertension (Guanethidine and Guadadrell) are transferred to adrenergic neurons due to the active transport of biogenic amines. The physiological role of this transport is the reverse seizure of adrenergic mediators, but it can be transferred to the concentration gradient and many other similar compound structures, including guanidine derivatives.

Biotransformation (metabolism) is a change in the chemical structure of medicinal substances and their physicochemical properties under the action of the organism enzymes. The main orientation of this process is the conversion of lipophilic substances that are easily reabsorbed in the renal tubules, into hydrophilic polar compounds that are quickly removed by the kidneys (not reasurable in the renal tubules). In the process of biotransformation, as a rule, the activity (toxicity) of the source substances occurs.
Biotransformation of lipophilic LV mainly occurs under the influence of liver enzymes localized in the membrane of the endoplasmic reticulum of hepatocytes. These enzymes are called microsomal because
they are connected with small subcellular fragments of a smooth endoplasmic reticulum (microsomes), which are formed during the homogenization of hepatic tissue or tissues of other organs and can be highlighted by centrifugation (precipitated by the so-called "microsomal" fraction).
In the plasma of blood, as well as in the liver, intestines, lungs, leather, mucous membranes and other tissues there are nephrosomal enzymes localized in cytozole or mitochondria. These enzymes can participate in hydrophilic metabolism.
The two main types of medicinal metabolism (stages) are distinguished:
non-secantic reactions (metabolic transformation);
Synthetic reactions (conjugation).

biotransformation (metabolism reaction of the 1st phase), occurs under the action of enzymes - oxidation, restoration, hydrolysis.

conjugation (reaction of metabolism of the 2nd phase), in which the substance of the residues of other molecules (glucroy, sulfuric acids, alkyl radicals) is connected to the molecule, to form an inactive complex, easily derived from the body with urine or feces.

Under the action of some medicinal substances (phenobarbital, rifampicin, carbamazepine, griseofulvin), induction may occur (increase the synthesis rate) of microsomal liver enzymes. As a result, while simultaneously appointed with the inductors of microsomal enzymes of other drugs (for example, glucocorticoids, oral contraceptives) increases the speed of metabolism of the latter and their action is reduced. In some cases, the metabolism of the inductor itself may increase, as a result of which its pharmacological effects (carbamazepine) decrease.
Some medicinal substances (cimetidine, chloramphenicol, ketoconazole, ethanol) reduce the activity (inhibitors) of metabolizing enzymes. For example, cimetidine is an inhibitor of microsomal oxidation and, slowing the metabolism of warfarin, can increase its anticoagulant effect and provoke bleeding. There are known substances (furanocumarines) contained in grapefruit juice, which inhibit the metabolism of drugs such as cyclosporine, Midazolas, Alprazolam and, therefore, enhance their effect. With the simultaneous use of medicinal substances with inductors or metabolic inhibitors, it is necessary to adjust the prescribed doses of these substances.

12. Ways of removal of medicinal substances from the body, meaning, notion of the quota of elimination, half-life (t 1/2) and the total plasma clearance. The dependence of the action of medicinal substances from the path of removal, examples.

The elimination of an unchanged drug substance or its metabolites is carried out by all excretory bodies (kidneys, intestines, light, dairy, salivary, sweat glands, etc.).

The main organ of removal of drugs from the body is kidneys. Drug removal by the kidneys occurs by filtration and with the help of active or passive transport. Lipoid-soluble substances are easily filtered in the glomers, but in the tubules they are passively absorbed. Preparations, weakly soluble in lipoids, are faster with urine, since they are poorly reabonorbing in the renal tubules. The acidic urine reaction contributes to the removal of alkaline compounds and makes it difficult to excrete acidic. Therefore, at intoxication of acidic medications (for example, barbiturates), sodium hydrocarbonate or other alkaline compounds are used, and at intoxicating alkaloids having an alkaline character, ammonium chloride is used. You can accelerate the removal of drugs from the body and the appointment of potent diuretics, such as osmotic diuretics or furosemide, on the background of introducing a large amount of liquid to the body (forced diuresis). The excretion from the body bases and acids occurs by active transport. This process comes with energy consideration and using certain enzyme-carriers. Creating competition for the carrier by any substance, it is possible to slow down the removal of the drug (for example, it is secreted with the same enzyme systems, therefore, it is the eminent rejecting of penicillin).

Preparations, poorly absorbed from the gastrointestinal tract are derived from the intestines and are used in gastritis, enteritis and colitis (for example, binders, nosenetibiotics used in intestinal infections). In addition, the hepatic cells of the drug and their metabolites fall into bile and do not enter the intestines, from which it is either re-absorbed, delivered to the liver, and then with bile in the intestine (intestinal circulation), or are removed from the body with wheel masses. The direct secretion of a number of drugs and their metabolites of the intestinal wall is not eliminated.

Through the lungs are volatile and gases (ether, nitrogen, camphor, etc.). To accelerate their emission, it is necessary to increase the volume of pulmonary ventilation.

Many drugs can be excreted with milk, especially weak grounds and non-electrolytes, which should be considered when treating nursing mothers.

Some medicinal substances are partially removed by the glazers of the oral mucosa, having a local (for example, annoying) action on the paths of removal. So, heavy metals (mercury, lead, iron, bismuth), released by salivary glands, cause irritation of the mucous membrane of the oral sheath, arise stomatitis and gingivitis. In addition, they cause the appearance of a dark border along the gantry edge, especially in the region of carious teeth, due to the interaction of heavy metals with hydrogen sulfide in the oral cavity and the formation of practically insoluble sulfides. Such "Kaima" is a diagnostic sign of chronic poisoning with heavy metals.

With prolonged use of diphenine and sodium valproate (anticonposts) irritation of the gum mucosa may cause hypertrophic gingivitis ("diphenin gingivit"). The level of elimination of any medicinal substance is evaluated using two main tests:

first, the time determines during which half of the administered dose of the chemotherapy is eliminated, that is, they find a half-period of the life of the latter (T 1/2);
secondly, the percentage of that part of the single dose of the drug, which eliminates throughout the day (coefficient, or quota, elimination) has been calculated.

These two criteria elimination of any medicinal substance are not stable, for the conditions of the conditions depend on the complex. Among the latter, a significant role is assigned to the properties of the drug itself and the condition of the body. They depend on the metabolism rate of the medicinal substance in the tissues and liquid media of the body, the intensity of its excretion, the functional state of the liver and the kidneys, the way of administering the chemotherapy, duration and conditions of storage, lipoid solvent, chemical structure, etc.
The elimination of fat-soluble, ionized drugs associated with proteins is carried out slower "than drugs of water-soluble, ionized, non-protein-related drugs. With the introduction of high doses of drugs, elimination is lengthened, which is due to the intensification of all processes involved in transport, distribution, metabolism and isolating chemotherapy.
Elimination of most medicines in children is significantly lower than adults. She is particularly slowed down by the premature first months of life. The elimination of congenital and acquired enzymopathy (deficiency of glucose-6-phosphate dehydrogenase, N-acetyltransferase in others), diseases of the liver and kidneys flowing with the insufficiency of their functions occurble sharply.
Other factors affect the rate of elimination: The patient's floor, body temperature, physiological biorhythms, a child's stay in bed, etc. Data on the half-period of the life of drugs allows the doctor to more reasonably prescribe a one-time and daily dose of this or that drug, the multiplicity of introducing it.

a source

Enzymes (enzymes) are specific proteins that participate in biochemical reactions, can accelerate or slow down. A large number of such compounds are produced in the liver due to its important role in the exchange of fats, proteins and carbohydrates. Their activity is determined by the results of biochemical blood test. Such studies are important to assess the condition of the liver and for the diagnosis of many diseases.

The liver enzymes are a group of biologically active proteins that can be produced exclusively by cells of this organ. They can be on the inner or outer membrane, inside cells or blood. Depending on the role of enzymes, they are divided into several categories:

hydrolase - accelerate the splitting of complex compounds on the molecules;
synthetases participate in the reactions of the synthesis of complex biological compounds from simple substances;
transferases - participate in the transport of molecules through membranes;
oxy subcatases - are the main condition for the normal flow of oxidative reducing reactions at the cellular level;
isomerase - necessary for the processes change configuration of simple molecules;
liazes are formed additional chemical bonds between molecules.

Their function in cell metabolism processes depend on the localization of hepatic enzymes. So, mitochondria is involved in the exchange of energy, the granular endoplasmic network synthesizes proteins, smooth - fats and carbohydrates, and hydrolase proteins are located on lysosomes. All enzymes that produce liver can be found in the blood.

Depending on which functions are performed by enzymes and where they are in the body, they are divided into 3 large groups:

secretory - after secretion of liver cells enter the blood and are here in the maximum concentration (blood coagulation factors, cholinesterase);
indicator - normally contained inside the cells and are released into blood only when they are damaged, therefore they can serve as indicators of the degree of liver damage during its diseases (ALT, AST and others);
excretory - removed from the liver with bile, and the increase in their blood level indicates a violation of these processes.

To diagnose the liver condition, each of the enzymes is important. Their activity is determined by suspected the main pathology of the liver and to assess the degree of damage to the hepatic tissue. To obtain a more complete picture, the diagnosis of digestive enzymes, the enzymes of the gastrointestinal tract, the pancreas and biliary tract may also be required.

Blood biochemistry is an important stage of diagnosing liver disease. All pathological processes in this organ can occur with cholestasis or cytolysis. The first process is a violation of bile outflow, which hepatocytes is distinguished. With other disorders, there is a destruction of healthy cellular elements with the release of their content in blood. According to the presence and quantity of enzymes of the liver in the blood, it is possible to determine the stage of the disease and the nature of pathological changes in the organs of the hepatobiliary tract.

The cholestasis syndrome (the difficulty of the bile) accompanies inflammatory liver diseases, violation of the secretion of the bile and pathology of biliary tract. These phenomena cause the following changes in biochemical analysis:

excretory enzymes are increased;
components of bile, including bilirubin, bile acids, cholesterol and phospholipids, are also increased.

The outflow of bile may be impaired under mechanical pressure on the bile ducts (inflamed cloth, neoplasms, stones), the narrowing of their lumen and other phenomena. The complex of characteristic changes of blood indicators becomes the basis for a more detailed study of the state of the gallbladder and biliary tract.

Citolism (the destruction of hepatocytes) can occur in infectious and unsuccessful hepatitis or in poisoning. In this case, the contents of the cells are released, and the indicator enzymes appear in the blood. These include Alt (Alaninotransferase), AST (Aspartataminotransferase), LDH (lactate dehydrogenase) and aldolaza. The higher the indicators of these compounds in the blood, the extensive degree of degradation of the passage of the organ.

Alkaline phosphatase, which is found in the blood, may have not only liver origins. A small amount of this enzyme is produced by a bone marrow. We can say about the diseases of the liver if there is a simultaneous increase in the level of the SFF and GAMMA-GGT. Additionally, an increase in the indicators of bilirubin can be detected, which indicates the pathologies of the gallbladder.

GGT is usually rising with alkaline phosphatase. These indicators indicate the development of cholestasis and on possible diseases of the biliary system. If this enzyme rises insulated, there is a risk of minor damage to the hepatic tissue at the initial stages of alcoholism or other poisoning. With more serious pathologies, there is a simultaneous increase in hepatic enzymes.

Alt (Alaninotransferase) is the most specific liver enzyme. It is in the cytoplasm and other organs (kidneys, hearts), but it is in the hepatic parenchyma that it is present in the greatest concentration. Its increase in blood may indicate various diseases:

hepatitis, intoxication with damage to the liver, cirrhosis;
myocardial infarction;
chronic diseases of the cardiovascular system, which manifest themselves necrosis of the functional fabric;
injuries, damage or bruises of muscles;
heavy degree of pancreatitis - inflammation of the pancreas.

A drug that increases the activity of microsomal human liver oxidases is proposed, it can be used in the treatment and prevention of various intoxication by substances, the biotransformation of which depends on the activity of the oxidation system enzymes. As such a tool, Xmedon (N-aoxyethyl) -4,6-dimethyl-1,2-dihydro-2-oxopyrimidine was proposed, which was previously known as a preparation with a wide range of biological action and low toxicity. Xmedon increases the activity of microsomal human liver oxidases, and its inducing effect is comparable to the induction of phenobarbital. 2 table.

The invention relates to medicine, in particular to drugs that increase the activity of microsomal human liver oxidases, and can be used in the treatment and prevention of various diseases and intoxication by substances, the biotransformation of which depends on the activity of the oxidation system enzymes.

As is known, the rate of elimination from the body of medicinal substances undergoing biotransformation depends on the activity of enzyme systems responsible for this type of metabolism. One of the main enzyme systems localized in the liver is the system of microsomal oxidases. As a test preparation, antipirin is often used to determine oxidation speed.

Currently, a large number of inductors of the oxidation process [Khalilov E.M. Modern ideas about the metabolism of medicinal substances in the body, a short course of molecular pharmacology ed. Sergeeva P.V., Moscow Medical Institute. N.I.Pirogov, Moscow, 1975, 340 p.; Bolshev V.N., Inductors and Inhibitors of Metabolism Enzymes of Drugs, Pharmacology and Toxicology, 1980, No. 3], increasing the activity of biotransformation of drugs by induction of microsomal oxidase synthesis.

Among them, substances that increase the activity of biotransformation of drugs by induction of microsomal oxidase synthesis:

a) a group of phenobarbital, rifampicin, diphenine, diazepits, diphenin, nitroglycerin (autoinductor);

b) polycyclic (carcinogenic) hydrocarbons;

c) steroid hormones;

and substances that reduce the activity of biotransformation of drugs in the endoplasmic liver reticulum:

a) monoaminoxidase inhibitors;

b) Ethasol, cobalt chloride, H2 histamine blockers, chloramphenicol, -Adrenoblays, erythromycin, amidaron, lidocaine.

It is known that the inductors used (for example, phenobarbital) can have a negative impact on the human body, causing drowsiness, addiction, etc. [Mashkovsky MD Medicines. T.2. - M.: New Wave, 2000. - 648 s]

The task of the claimed invention is a new drug to increase the activity of human liver oxidase, expanding the arsenal of well-known inductor drugs.

The technical result is to increase the activity of the microsomal oxidases of the liver of the person when taking the drug xymedon.

Xmedon is N- (-oxethyl) -4,6-dimethyl-1,2-dihydro-2-oxopyrimidine formula:

and it is one of the most simple black-eyed pyrimidinucleoside analogues. The drug has a wide range of biological action, xymedon toxicity is extremely low LD 50 - from 6500 to 20,000 mg / kg for different animals with different ways of administration [Izmailov S.G. And Dr. Xiedon in clinical practice. Nizhny Novgorod: Publishing House of NGMA 2001]. Order of the Ministry of Health No. 287 dated December 7, 1993, Xmedon was allowed for use in medicine and entered into the register of medicines.

The technical result of the proposed solution is achieved by the use of the drug xiedon in a daily dose of 1.5 grams with a 7-day course for induction of oxidation processes, which makes it promising as a drug that can increase the activity of microsomal human liver oxidases. Side effects when using Xmedon was not detected.

The oxidation rate was evaluated by the authors previously developed by the method - with the help of a modified antipyrin test, during which the antipyrin concentration was determined in saliva. Test-preparation of oxidation - Antipirin - prescribed patients once orally at a dose of 0.6 g. [Evgeniev M.I., Harmonov S.Yu., Shitova N.S., Pogoreltsev V.I. Biopharmaceutical analysis of the enzymatic activity of organism metabolic systems // Bulletin of the Kazan State Technological University. - 2004. - № 1-2. - p.74-81; Harmonov S.Yu., Kiseleva TA, Salikhov I.G., Evgeniev M.I., Shitova N.S., Polyshina V.I., Pogoreltsev V.I. Assessment of acetylation and oxidation phenotypes in patients with diabetes mellitus 2 // Nizhny Novgorod Medical Journal. - 2005. - № 3. - C.29-35.]

The induction of the microsomal human liver oxidases was expressed as a percentage of the cumulative amount of antipyrin derived from saliva within 12 hours after the administration of the test preparation before and after the course reception of the xymedon inductor in a daily dose of 1.5 g for 7 days.

Studies were conducted in a group of 8 healthy volunteers.

Methods for determining the activity of microsomal oxidases of the human liver.

Antipirin introduces a volunteer once orally at a dose of 0.6 g on an empty stomach. Saliva is collected every 3 hours within 12 hours after taking a test preparation. In the hourly samples of saliva determine the content of the anti-view spectrophotometric method. According to the data obtained, kinetic curves are built, the cumulative amount of antipyrin derived from saliva in 12 hours is calculated, the amount of antipirin contained in the saliva is determined by gradual graphics.

Xmedon is adopted in a daily dose of 1.5 g (3 times a day of 0.5 g) for 7 days before repeated determination of the amount of antipyrin in saliva. After 7 days, the determination of the output of the antipirin described above is determined by the method (anti-view).

With total.1 - the cumulative amount of antipyrin (μg) derived from saliva within 12 hours before receiving the inductor;

C general. 2 is the cumulative amount of antipyrin (μg) derived from saliva within 12 hours after receiving the inductor.

The method of the method is illustrated by the following examples of a particular execution.

Patient Kayumova is a healthy volunteer.

Antipyrin once is orally administered to a patient at a dose of 0.6 g. Salyu is collected every three hours within 12 hours after taking a test preparation. To precipitate solid particles, saliva is centrifuged for 10 minutes. The tubes are introduced in 2 ml of supernatant, 2 ml of distilled water, 2 ml of zinc reagent, 2 ml of 0.75 H potassium hydroxide (dropwise). Shake the solution for 30 seconds. Next, the centrifugation is carried out for 15 minutes. A 3 ml of pure supernatant of each sample is transferred to test tubes and placed in a thermostat for 5 minutes at a temperature of 25 ° C. Then, not removing the samples from the thermostat, add 0.05 ml of 4 n sulfuric acid and 0.1 ml of 0.2% sodium nitrite solution. Incubation continues for 20 minutes. Next, the optical density is measured on the spectrophotometer at a wavelength of 350 nm. The amount of antipyrin derived is determined by graduation graphics. A solution of comparison is a solution prepared with a salivary, taken in a patient before taking the test preparation, according to the sample described above.

The next day, the patient is prescribed the drug Xiedon in a dose of 0.5 g 3 times a day. The course is 7 days. After 7 days, the determination of the output of the anti-view described above is determined.

The calculation of induction (%) is made according to Formula 1:

With total.1 - the cumulative amount of antipyrin (μg) derived from saliva within 12 hours before receiving xymedon;

C general. 2 is a cumulative amount of antipyrin (μg) derived from saliva within 12 hours after receiving xymedon.

The results are shown in Table 1.

The activity of microsomal oxidases of the liver of patients 2-8 was performed similarly to example 1. The results are shown in Table 1.

Patient Ibragimov is a healthy volunteer.

Patient Meadhova - a healthy volunteer.

Patient Mothallina is a healthy volunteer.

Patient Yarullina is a healthy volunteer.

Patient Yakovleva - a healthy volunteer

Patient Sultanbekov is a healthy volunteer.

Calaibasheva's patient is a healthy volunteer.

To compare the increase in the activity of oxidative enzymes when receiving the xymedon, an influence on the pharmacokinetics of the well-known inductor of the oxidation process of phenobarbital was checked. Phenobarbital was administered orally at a dose of 0.03 g 3 times a day for three days, which corresponds to a standard pharmacological dose used in medicine for antispasmodic and soothing effect [Mashkovsky MD. Medicines. T.2. - M.: New Wave, 2000. - 648 p.]. The induction of phenobarbital was determined in relation to the cumulative amount of the antipyrin contained in saliva before and after receiving the phenobarbital in the daily dose of 0.09. The exams were carried out in the group of 5 healthy volunteers (Zakirov, Valitova, Shitov, Yermolaeva, Galutdinov - examples 9-13). The calculation of induction (%) is made according to Formula 1:

With total.1 - the cumulative amount of antipyrin (μg) derived from saliva within 12 hours before receiving a phenobarbital;

C general. 2 is a cumulative amount of antipyrin (μg) derived from saliva within 12 hours after receiving a phenobarbital.

The results are shown in Table 2.

Patient Zakirova is a healthy volunteer.

Example 10.

Patient Valitova is a healthy volunteer.

Example 11.

Patient Shitova is a healthy volunteer.

Example 12.

Patient Ermolaeva - a healthy volunteer.

Example 13.

Patient Galutdinov is a healthy volunteer.

The results obtained show that the use of xymedon makes it possible to increase the activity of microsomal human liver oxidases, and the induced effect caused by xymedon, comparable to the induction of phenobarbital.

The use of xymedon as an inducer of microsomal liver oxidases is effective in the prevention and treatment of acute and chronic intoxication by drugs, the biotransformation of which depends on the activity of the oxidation system enzymes.

Regulation of the activity of oxidative enzymes using the xymedon inductor is safe in terms of an overdose of the inducer itself due to its low toxicity.

Table 1
Induction of microsomal human liver oxidases under the action of xymedon
No. Exender	Test number	A (optical density)		With total.1 (cumulative amount of excreted antipyrin general), μg	A (optical density)	C (number of antipyrin excreted), μg	With total 2 (cumulative amount of excreted antipyrin general), μg	Induction,%
1	1	0,185	9,893	29,678	0,100	5,347	16,842	43,25
	2	0,190	10,160		0,060	3,208
	3	0,120	6,417		0,105	5,614
	4	0,060	3,208		0,050	2,673
2	1	0,015	0,802	7,486	0,040	2,139	6,401	14,49
	2	0,045	2,406		0,060	3,208
	3	0,040	2,139		0,010	0,534
	4	0,040	2,139		0,010	0,534
3	1	0,140	7,486	21,121	0,035	1,871	9,356	55,70
	2	0,070	3,743		0,075	4,010
	3	0,105	5,614		0,025	1,336
	4	0,080	4,278		0,040	2,139
4	1	0,250	13,360	35,273	0,145	7,754	31,817	9,79
	2	0,210	11,220		0,130	6,951
	3	0,130	6,950		0,160	8,556
	4	0,070	3,743		0,160	8,556
5	1	0,025	1,336	12,565	0,030	1,604	8,554	68,07
	2	0,100	5,347		0,035	1,871
	3	0,080	4,278		0,075	4,010
	4	0,030	1,604		0,020	1,069
6	1	0,075	4,010	12,298	0,040	2,139	4,544	63,05
	2	0,12	6,417		0,010	0,534
	3	0,020	1,069		0,030	1,604
	4	0,015	0,802		0,005	0,267
7	1	0,080	4,278	15,240	0,060	3,208	10,158	33,19
	2	0,120	6,417		0,025	1,336
	3	0,040	2,139		0,060	3,208
	4	0,045	2,406		0,045	2,406
8	1	0,045	2,406	11,495	0,015	0,802	2,405	79,07
	2	0,045	2,406		0,02	1,069
	3	0,100	5,347		0,005	0,267
	4	0,025	1,336		0,005	0,267

table 2 Induction of microsomal human liver oxidases under the action of phenobarbital
Examples	With Promet1 (cumulative amount of antipyrin excreted before inductor intake), μg	With general 2 (cumulative amount of excreted antipyrin after the intake reception), μg	Induction,%
9	13,635	3,474	74,52
10	10,159	7,217	28,95
11	13,635	4,544	66,67
12	17,646	7,217	59,10
13	20,854	13,635	34,62

CLAIM

The use of xymedon to increase the activity of microsomal human liver oxidases.

What it is?

hydrolase - accelerate the splitting of complex compounds on the molecules;
synthetases participate in the reactions of the synthesis of complex biological compounds from simple substances;
transferases - participate in the transport of molecules through membranes;
oxy subcatases - are the main condition for the normal flow of oxidative reducing reactions at the cellular level;
isomerase - necessary for the processes change configuration of simple molecules;
liazes are formed additional chemical bonds between molecules.

IMPORTANT! The activity of enzymes affects the presence of other compounds (co-factors). These include proteins, vitamins and vitamin-like substances.

Groups of hepatic enzymes

Depending on which functions are performed by enzymes and where they are in the body, they are divided into 3 large groups:

secretory - after secretion of liver cells enter the blood and are here in the maximum concentration (blood coagulation factors, cholinesterase);
indicator - normally contained inside the cells and are released into blood only when they are damaged, therefore they can serve as indicators of the degree of liver damage during its diseases (ALT, AST and others);
excretory - removed from the liver with bile, and the increase in their blood level indicates a violation of these processes.

For the definition of hepatic enzymes need venous blood collected in the morning on an empty stomach

Enzymes that are determined to diagnose liver disease

Cholestasis indicators

excretory enzymes are increased;
components of bile, including bilirubin, bile acids, cholesterol and phospholipids, are also increased.

Indicators of cytolysis

Definition of alkaline phosphatase

Gamma-glutamylTranspend of blood

The final diagnosis can be delivered only on the basis of a comprehensive examination, which includes ultrasound

Liver transaminases (ALT, AST)

hepatitis, intoxication with damage to the liver, cirrhosis;
myocardial infarction;
chronic diseases of the cardiovascular system, which manifest themselves necrosis of the functional fabric;
injuries, damage or bruises of muscles;
heavy degree of pancreatitis - inflammation of the pancreas.

AST (aspartate dehydrogenase) is not only in the liver. It can also be found in the mitochondria of the heart, kidneys and skeletal muscles. The increase in this enzyme in the blood indicates the destruction of cellular elements and the development of one of the pathologies:

myocardial infarction (one of the most common causes);
liver diseases in acute or chronic form;
heart failure;
injury, inflammation of the pancreas.

IMPORTANT! In the study of blood and the determination of transferase, the relationship between them (ritis coefficient) is important. If it is AST / Als exceed 2, we can talk about serious pathologies with extensive destruction of the liver parenchyma.

Lactate dehydrogenase

LDH refers to cytolytic enzymes. It is not specific, that is, it is found not only in the liver. However, its definition is important in the diagnosis of jaundice syndrome. In patients with zhilber disease (genetic disease, which is accompanied by a violation of bilirubin binding) it is within normal limits. With other types of yellow, its concentration increases.

How determine the activity of substances?

Biochemical blood test for liver enzymes is one of the main diagnostic events. This requires venous blood, collected on an empty stomach in the morning. During the day before the study, it is necessary to exclude all the factors that can affect the work of the liver, including the reception of alcoholic beverages, fatty and sharp dishes. In the blood, the standard set of enzymes determine:

Alt, AST;
common bilirubin and its fractions (free and related).

Some groups of medicines can affect the activity of liver enzymes. They can also change normally during pregnancy. Before analysis, it is necessary to notify the doctor about the reception of any drugs and the chronic diseases of any anamnesis organs.

Norms for patients of different ages

For the treatment of liver diseases, complete diagnostics must be carried out, which includes a biochemical blood test. The activity of enzymes is investigated in the complex, since various indicators may indicate different violations. The table presents normal values \u200b\u200band their oscillations.

Compound	Normal indicators
Common protein	65-85 g / l
Cholesterol	3.5-5.5 mmol / l
Common Bilirubin	8.5-20.5 μmol / l
Direct Bilirubin	2.2-5.1 μmol / l
Indirect Bilirubin	No more than 17.1 μmol / l
Alt.	For men - no more than 45 U / L; For women - no more than 34 units / l
AST	For men - no more than 37 units; For women - no more than 30 units / l
Ritis coefficient	0,9-1,7
Alkaline phosphatase	No more than 260 units / l
GGT	For men - from 10 to 70 units; For women - from 6 to 42 units / l

The Alc enzyme has the most important diagnostic value in suspected hepatitis, fatty dystrophy or liver cirrhosis. Its values \u200b\u200bare normal over time. This compound is measured in units per 1 liter. Normal indicators at different ages will be:

in newborns - up to 49;
in children under 6 months - 56 or more;
until a year - no more than 54;
from 1 to 3 years - up to 33;
from 3 to 6 years - 29;
children of older age and adolescents - up to 39.

Drugs accumulate in the liver parenchyma and can cause an increase in its enzyme activity.

IMPORTANT! Biochemical blood test is an important, but not the only study according to which the liver condition is determined. Also carry out ultrasound and additional surveys as needed.

Features of determining during pregnancy

With the normal course of pregnancy, almost all enzyme indicators remain within the normal range. In the Late time, a minor increase in the level of alkaline phosphatase in the blood is possible - the phenomenon is associated with the formation of this compound of the placenta. Increased liver enzymes can be observed during prestal (toxicosis) or indicate the exacerbation of chronic diseases.

Changes in cirrhosis enzymes

Cirrhosis is the most dangerous state at which the healthy liver parenchyma is replaced by scars from the connective tissue. This pathology is not treated, since the restoration of the body is possible only at the expense of normal hepatocytes. In the blood there is an increase in all specific and nonspecific enzymes, an increase in the concentration of the associated and unbound bilirubin. The level of protein, on the contrary, decreases.

Special Group - Microsomal Enzymes

Microsomal liver enzymes is a special group of proteins that are produced by an endoplasmic network. They take part in the reactions of the neutralization of xenobiotics (substances that are alien for the body and can cause symptoms of intoxication). These processes are held in two stages. As a result of the first of them, water-soluble xenobiotics (with low molecular weight) are derived with urine. Insoluble substances are a number of chemical transformations with the participation of microsomal liver enzymes, and then eliminated as part of a bile in the thin division of the intestine.

The main element, which is produced by the endoplasmic network of liver cells, is cytochrome P450. For the treatment of certain diseases, drug-inhibitors or inducers of microsomal enzymes are used. They influence the activity of these proteins:

inhibitors - accelerate the effect of enzymes, due to which the active substances of drugs are increasing faster from the body (rifampicin, carbamazepine);
inductors - reduce the activity of enzymes (flukonazole, erythromycin and others).

IMPORTANT! The processes of induction or inhibition of microsomal enzymes are taken into account when selecting a diagram of treating any disease. The simultaneous reception of drugs of these two groups is contraindicated.

Liver enzymes are an important diagnostic indicator for determining liver disease. However, for a comprehensive study, additional analyzes should also be carried out, including ultrasound. The final diagnosis is made on the basis of clinical and biochemical blood tests, urine and feces, ultrasound organs of the abdominal cavity, as necessary - radiography, CT, MRI or other data.