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Letter to the editor. Xanthinuria Dosage and administration

28.07.2022

Another important enzymatic source of O~2 and H2O2 is xanthine oxidoreductase, first discovered in cow's milk over 100 years ago. In mammals, under normal conditions, the enzyme is predominantly in the xanthine dehydrogenase form (EC 1.17.1.4, systematic name "xanthine: HA D+ oxidoreductase") and can be reversibly or irreversibly converted to xanthine oxidase (EC 1.17.3.2, systematic name "xanthine: oxygen oxidoreductase"), resulting, respectively, in the formation of disulfide bonds of cysteine residues Cys535 and Cys992 (possibly with the participation of sulfhydryl oxidases) or limited proteolysis involving calcium-dependent proteases; interestingly, in birds, the enzyme is present only in the dehydrogenase form. During organ ischemia, a rapid (within several minutes) transformation of xanthine dehydrogenase into xanthine oxidase is observed, and ACMs may be involved in this process. The same rapid transition of the enzyme to the oxidase form is observed during tissue homogenization, which significantly complicates the determination of the true ratio of different isoforms of the enzyme in vivo.

Rice. 14. Interconversions of xanthine oxidoreductase isoforms

The main physiological function of the enzyme is participation in the catabolism of purines; while the xanthine dehydrogenase form uses mainly NAD+ as an electron acceptor, while the oxidase form uses molecular oxygen (Fig. 15).

Using DNA cloning, an amino acid analysis (about 1330 amino acids) of enzymes isolated from human liver, rat, mouse, chicken, and also from Drosophila was carried out; they were found to be 90% homologous. The gene encoding xanthine oxidase is located on the 22nd human chromosome (section 2p22) and on the 17th chromosome of the mouse and contains 36 exons.

The basal expression of human xanthine oxidoreductase is low (especially compared to other mammals), but the transcription of the enzyme is significantly increased under the influence of cytokines (interferon, interleukin-1, interleukin-6, TNF-a), hormones (dexamethasone, cortisol, prolactin), lipopolysaccharide, hypoxia ; hyperoxia acts as a negative regulator. A change in the partial pressure of oxygen also affects the post-transcriptional level: the activity of xanthine oxidoreductase in bovine aortic endothelial cells under hypoxic conditions increased 2-fold without changing mRNA expression for 24 h (a similar effect of a decrease in pO2 was observed in fibroblasts), and under hyperoxia, the activity of the enzyme decreased faster than the rate of its de novo synthesis. It is assumed that a decrease in oxygen concentration contributes to the phosphorylation of the xanthine oxidoreductase molecule, as a result of which its enzymatic activity increases.

Structurally, xanthine oxidoreductase is a homodimer; each subunit has a molecular weight of about 150 kDa and contains 3 domains associated with specific cofactors (Fig. 16). The N-terminal domain (amino acids 1-165) consists of two subdomains, each of which includes 1 iron-sulfur center coordinated to 4 cysteine residues; the intermediate domain (amino acids 226-531) contains a deep FAD-binding pocket, positioning the flavin ring in close proximity to Fe2-S2-HeHTpy; The C-terminal domain (amino acids 590-1332) is linked to a molybdenum cofactor.

Limited proteolysis of xanthine

doreductase with trypsin leads to the formation of three fragments with a mass of 20, 40 and 85 kDa. Iron-sulfur centers are located in the low molecular weight fragment of 20 kDa, FAD - in the 40 kDa fragment, molybdenum atom - in the high molecular weight fragment of 85 kDa; all three fragments are in close relationship and decompose only under denaturation conditions. The molybdenum cofactor is an organic derivative of pterin (molybdopterin) containing 1 molybdenum atom pentacoordinated by two dithiolenic sulfur atoms, another sulfur atom and two oxygen atoms (Fig. 17).

Rice. 17. Structure of the molybdenum cofactor xanthine oxidase

Xanthine and hypoxanthine are oxidized on the molybdenum fragment, where Mo(U1) is reduced to Mo(IV); then the electrons are transferred through the iron-sulfur centers of the enzyme to FAD, and from the FAD-containing site to NAD+ or molecular oxygen (Fig. 16).

In early works, the question of the identity of xanthine oxidase and NADPH oxidase of phagocytes was discussed; at present, it is strictly established that these are different enzymes.

In different animal species, the content of xanthine oxidoreductase varies significantly: for example, in the tissues of humans and rabbits it is much less than in the tissues of rats and dogs. The study of the enzyme content in different cells and tissues showed that in animals (rats) it is found in the highest concentrations in hepatocytes, epithelial and endothelial cells. Data on the content of xanthine oxidoreductase in human tissues and organs are contradictory, however, they mainly boil down to
the fact that the enzyme is present in the largest quantities in the cells of the liver and small intestine, while in the brain, heart, lungs, skeletal muscles, and kidneys, its level is extremely low, which contradicts the supposed role of xanthine oxidase in postischemic (reperfusion) damage to these organs and fabrics (see Chapter 3). This discrepancy can be explained by the existence in the microvessels of some tissues of individual subpopulations of endotheliocytes expressing a very high level of enzyme activity; during homogenization of large fragments of organs, the xanthine oxidoreductase of these quantitatively small subpopulations is “responsible” for the total content of the enzyme. In addition, it has recently been found that xanthine oxidoreductase is localized not only in the cytoplasm, but also on the outer surface of the plasmalemma of endotheliocytes, and that during ischemia/reperfusion, the enzyme can be released from the liver and intestines into the systemic circulation and bind to glycosaminoglycans located on the surface of endothelial cells.

Small amounts of xanthine oxidoreductase are found in extracellular fluids - for example, in human blood serum its activity ranges from 0 to 50 nmol uric acid / min / l, while almost all of it is in the oxidase form as a result of exposure to serum proteases. The level of extracellular enzyme increases significantly in some pathologies, especially in diseases associated with liver damage - chronic hepatitis, cirrhosis, obstructive jaundice; with viral hepatitis, especially in the acute stage, a 1000-fold increase in the concentration of the enzyme in the blood serum is shown.

In the oxidase form, the enzyme uses molecular oxygen as an electron acceptor, resulting in the formation of O~2 and H2O2; in this case, the higher p02, the more O 2 is formed and the less H2O2 is formed (under normal conditions, about 70% of O2 passes into H2O2). At the same time, we must not forget that in the xanthine dehydrogenase form, the enzyme can also reduce oxygen, although less efficiently than in the oxidase form: in the absence of NAD+ and in the presence of xanthine, its V^ and Kmax for O2 are, respectively, 25 and 600% of values characteristic of xanthine oxidase. Moreover, both isoenzymes (oxidase - to a lesser extent) exhibit NADH oxidase activity: electrons from NADH are transferred to FAD (Fig. 18), as a result of subsequent oxygen reduction, O 2 and H2O2 are formed, while the NADH oxidase activity of the dehydrogenase isoform can reach 40% of xanthine dehydrogenase proper. In the xanthine oxidase reaction, the formation of the OH* radical was also revealed, which, according to the authors, arises as a result of further reduction of H2O2.

Activation of xanthine oxidase in endotheliocytes leads to inhibition of NO-radicals, which enhances adhesion of circulating phagocytes and platelet aggregation; since NO* regulates vascular tone, hyperproduction of superoxide anion can lead to systemic hypertension - indeed, it has been shown that intravenous administration of xanthine oxidase inhibitors (allopurinol, alloxanthin, pyrizalopyrimidine derivative) led to a decrease in blood pressure in spontaneously hypertensive rats. At the same time, a paradoxical fact was recently discovered: it turned out that at a low partial pressure of oxygen, xanthine oxidoreductase can serve as a source of NO*, synthesizing it from nitrates and nitrites (both organic and inorganic) and using xanthine or NADH as an electron source (Fig. 18), therefore, some researchers consider the enzyme to be an important source of the NO* vasodilator in ischemic tissue. At the same time, it is necessary

take into account that as a result of the interaction of two products of the enzymatic activity of xanthine oxidoreductase, superoxide anion and nitric oxide, highly reactive peroxynitrite is formed, which again manifests the duality of the functions of the enzyme.

It is believed that the generation of AKM by xanthine oxidase is necessary for iron metabolism, regulation of vascular tone, and cell proliferation. Particular importance is attached to the role of the enzyme in ensuring innate immunity. In favor of the barrier, antimicrobial role of xanthine oxidoreductase, in particular, its localization testifies - the enzyme is predominantly expressed in epithelial cells, especially in the basal and apical layers of the intestine, on the luminal surface of epithelial cells of the bile ducts, in hepatocytes; in the epithelial layers of the gastrointestinal tract of rats, partially destroyed bacteria surrounded by xanthine oxidase molecules are histochemically detected.

For newborns, mother's milk serves as an additional source of an enzyme that provides antimicrobial protection. Xanthine oxidoreductase is the main protein component of the membranes that surround the fat droplets of freshly produced milk; being derived from the corresponding apical membranes of the secretory glands, they carry the same antigens as epithelial cells. Since pathogenic intestinal bacteria are characterized by affinity for membrane antigens of epithelial cells of the gastrointestinal tract, they also effectively bind to similar membrane antigens of milk fat globules, thereby coming into close contact with xanthine oxidoreductase; contact is enhanced by the high affinity of the enzyme for acidic polysaccharides present in the cell walls of many bacteria. Interestingly, the activity of xanthine oxidase in breast milk in women increases dramatically during lactation, reaching a maximum (50-fold increase) in the first 15 days after birth and then decreasing to a basal level by the end of the first month. At the same time, the protein content of the enzyme changes slightly, which indicates its post-translational regulation, which, in particular, can be carried out by introducing a molybdenum cofactor. Thus, in the xanthine oxidoreductase of the milk of non-lactating women, less than 5% of the molybdopterin binding sites are occupied by the cofactor; for goats and sheep in periods not associated with lactation of the first postpartum weeks, the relationship of low active
of the milk enzyme with “desolation” of molybdenum sites - occupancy, respectively, 9 and 18% of the theoretically possible. The role of the enzyme in providing innate immunity is supported by experiments performed on mice knocked out in the xanthine oxidoreductase gene. Homozygous (-/-) animals died in the first 6 weeks after birth; heterozygotes (+/-) survived, had normal fertility and gave birth to full-fledged mice, which, however, died of starvation due to lactation disorders of the parents.

Apparently, xanthine oxidase is involved in the body's defense against viral infections. Thus, in mice infected with the influenza virus, a significant (hundreds of times) increase in xanthine oxidase activity in the lungs was observed. The production of 02 and H2O2 can be so powerful that it can cause pathology, as a result of which animals die from pneumonia 12 days after infection, while virus titers in the lungs are not detected already on the 10th day. The introduction of adenosine (a precursor of xanthine) decreased, while allopurinol and SOD increased the survival rate of animals. Similar results were obtained when mice were infected with cytomegalovirus. One of the inducers of O2 formation during viral infections is a-interferon, which stimulates the transcription of xanthine dehydrogenase, which subsequently turns into the oxidase form. At the same time, it must be remembered that xanthine oxidoreductase is the only metabolic source of uric acid, an important antioxidant in extracellular fluids (see Chapter 3), and an increase in its activity in pathological conditions can play a dual role. Thus, a more than 20-fold increase in the content of the enzyme in the brain of patients with bacterial meningitis allowed the authors of the work to suggest that the presence and inducibility of endothelial xanthine oxidoreductase protects the vascular endothelium from oxidative damage during inflammation.

It has been shown that 02 formed in the xanthine oxidase reaction inhibits the Ca2+-ATPase of the sarcoplasmic reticulum of vascular smooth muscle cells, thereby inhibiting Ca2+ transport, which is one of the causes of vascular damage in various pathological situations. In addition, 02 serves as a precursor for other forms of AKM, in particular, H2O2 and OH*, which have a more pronounced cytotoxic effect. Therefore, the interest of researchers in the development of specific inhibitors of xanthine oxidase is justified; allopurinol or its long-lived metabolite oxypurinol, as well as pterin aldehyde and folic acid, are widely used as such inhibitors.

I. Means for stopping attacks of gout: colchicine, piroxicam, indomethacin, phenylbutazone, diclofenac.

II. Remedies to prevent gout attacks:

A. Uricostatic agents: allopurinol.

B. Uricosuric agents: probenecid, sulfinpyrazone, benzbromarone.

C. Combined remedies: ugly, allomaron.

Colchicine (Colchicine) An alkaloid contained in the magnificent colchicum ( Colchicum speciosum Stev.) and autumn crocus ( Colchicum automnale).

MD: Colchicine binds to specific receptors on the surface of macrophage and neutrophil tubulin dimers and disrupts their polymerization into microtubules.

Microtubules are special cell organelles. They are a cylinder of polymerized tubulin ab-dimers. At the same time, 2 processes continuously proceed on each microtubule: polymerization and attachment of more and more tubulin molecules proceed from one end, and from the other end, the tube also continuously depolymerizes. If polymerization prevails, the tubule grows and performs the following specific functions in the cell:

Microtubules form the spindle of division and ensure the transport of genetic material during cell division.

· Microtubules provide transport of vesicles in the cytoplasm of the cell to its membrane for subsequent isolation.

Since colchicine blocks the polymerization of tubulin, the process of depolymerization begins to predominate in the microtubules of macrophages and leukocytes and they are destroyed. This leads to several consequences:

The division of macrophages and neutrophils in the focus of inflammation is disrupted, which means that the size of the lesion decreases.

Destruction of microtubules causes cessation of exocytosis of vesicles and release of their contents from the cell. LTB 4 is not released from macrophages and neutrophils, which means that pain and swelling are reduced. Glycoprotein is not released, which means that the formation of lactic acid decreases and the pH shifts to a more alkaline side. This increases the urate solubility and slows down the formation of new crystals. Finally, lysosomal enzymes that damage the joint are not released.

PK: Colchicine after oral administration is well absorbed and its plasma concentration reaches a peak within 2 hours. However, it should be remembered that the level of colchicine in plasma does not allow to control its effectiveness - the effect of colchicine is determined solely by its concentration in leukocytes. The metabolism of colchicine occurs in the liver.

PE: Colchicine relieves pain and inflammation in an attack of gouty arthritis. The action of colchicine is unique in its accuracy and selectivity - it eliminates pain and inflammation, which are caused exclusively by gout and is not able to stop joint pain of other origin. Sometimes this selectivity of colchicine action is used for diagnostic purposes for therapy. ex juvantibus.

The effect of colchicine develops in 75% of individuals within 12-24 hours and is more pronounced, the earlier after the onset of the attack, colchicine was administered.

Colchicine also has some other effects:

It lowers body temperature.

Colchicine interferes with the synthesis of amyloid and collagen in connective tissue.

Indications for use and dosing regimens:

1. Relief of an acute attack of gout. Colchicine is prescribed orally. The first dose is 0.5 mg, then 0.25-0.5 mg every 2 hours, but not more than 6 mg / day. It should be remembered that the lethal dose of colchicine is 8 mg/day. As a rule, in 95% of patients, a dose of 0.5-1.0 mg / day is sufficient.

2. Long-term treatment of gout (prevention of a gout attack). Use the lowest possible doses, ie. doses that still prevent the onset of seizures. These doses can range from 0.5 mg 2 times a week, up to 0.5-1.0 mg / day. Patients with gout should remember that for any planned surgical intervention to prevent a gout attack, they should take colchicine 0.5 mg 3 times a day 3 days before surgery and within 3 days after it.

3. Colchicine is also used to treat periodic illness (familial Mediterranean fever). Periodic disease is a hereditary disease associated with a recessive gene on chromosome 16. It occurs mainly in representatives of the "ancient nations" - Armenians, Arabs, Jews and is manifested by bouts of pain in the chest and abdomen, fever and arthralgia. Such patients are often erroneously operated on several times for appendicitis, cholecystitis, pancreatitis, and the like. However, attacks of the disease resolve spontaneously. As the periodic disease progresses, a special protein, amyloid, begins to be deposited in the kidneys, which leads to the development of severe CRF.

The cause of the disease has not been fully established. It is believed that the patient has abnormally high activity of the enzyme dopamine-β-hydroxylase, which leads to excessive production of norepinephrine and octopamine in them, which contribute to the synthesis of amyloid.

Taking colchicine at a dose of 0.5 mg / day can dramatically reduce the activity of dopamine-b-hydroxylase and stop the synthesis of amyloid.

4. At a dose of 0.5 mg/day, colchicine is used to treat biliary cirrhosis. It allows you to slow down the development of connective tissue in the liver and the progression of cirrhosis.

NE: Colchicine stops the division of all rapidly proliferating cells: hematopoietic, gastrointestinal epithelium, hair follicles. This can lead to the development of anemia, severe diarrhea and ulcerative necrotic lesions of the gastrointestinal tract. Diarrhea caused by damage to the epithelium is aggravated by the effect of colchicine on the motor centers of the gastrointestinal tract and stimulation of its peristalsis.

Colchicine penetrates the BBB and affects the central nervous system:

Inhibits the respiratory center;

Increases the activity of the vasoconstrictor department of the vasomotor center and the level of blood pressure;

Enhances the effect of substances that depress the central nervous system.

Poisoning with colchicine develops when it is taken in a dose of more than 8 mg / day. It is manifested by hemorrhagic enteritis (abdominal pain, bloody vomiting and diarrhea), burning of the skin, severe dehydration and the development of acute renal and hepatic failure. A very characteristic feature is the appearance of ascending paralysis of the muscles. In severe cases, death occurs from respiratory depression or acute heart failure. Treatment of poisoning is symptomatic, there are no antidotes, hemodialysis is ineffective.

VW: dragee 0.5 mg.

To stop attacks of gout, some NSAIDs are also used: indomethacin, diclofenac, piroxicam, phenylbutazone, or they resort to parenteral administration of glucocorticosteroids. These methods of treating an attack are safer than colchicine, although their effectiveness is somewhat lower.

Allopurinol (Allopurinol, Purinol) It is an isomer of hypoxanthine. MD: Allopurinol is a competitive inhibitor of xanthine oxidase. It binds to the active site of the enzyme and prevents it from oxidizing hypoxanthine and xanthine to uric acid. Allopurinol itself is oxidized extremely slowly, in the process of its oxidation, alloxanthin (oxypurinol) is formed. Alloxanthin also, like allopurinol, inhibits xanthine oxidase, while it acts as a non-competitive inhibitor - it connects to the allosteric center of the enzyme and reduces its affinity for hypoxanthine and xanthine.

That. allopurinol acts not just as an inhibitor of the enzyme, but as a substrate of "lethal synthesis": xanthine oxidase itself synthesizes a substance from allopurinol that inhibits its activity.

Scheme 2. Uricostatic effect of allopurinol.Xanthine oxidase oxidizes hypoxanthine and xanthine to uric acid. Allopurinol is oxidized by this enzyme to alloxanthin. Both allopurinol and alloxanthin are potent inhibitors of xanthine oxidase (shown by blue arrows) and block the enzyme.

After the use of allopurinol, the synthesis of uric acid stops and the metabolism of purines ends at the stage of hypoxanthine and xanthine. At physiological pH values, the solubility of xanthine is 3 times, and the solubility of hypoxanthine is 30 times higher than that of uric acid. That. the patient stops the formation of urate crystals in the joints and the progression of the disease stops.

PK: Allopurinol is well absorbed after oral administration (absorption »80-90%). The half-life of allopurinol is 1-2 hours, while it is transformed into alloxanthin, the half-life of which is 18-30 hours. In terms of its uricostatic effect, alloxanthin is somewhat inferior to allopurinol.

Allopurinol is evenly distributed throughout the tissues of the body, with the exception of the central nervous system (in the brain, its level is ⅓ of the level of other tissues). It is interesting to note that the plasma levels of allopurinol and alloxanthin do not correlate at all with its therapeutic effect.

1. Uricostatic effect. Allopurinol stops the synthesis of uric acid within 24 hours after a single dose. After the course treatment is stopped, the effect persists for 3-4 days. Allopurinol is especially indicated for those patients whose urinary excretion of urates exceeds 600 mg / day (this indicates their excessive formation).

2. Antioxidant effect. Allopurinol blocks xanthine oxidase in ischemic tissues and does not allow reactive oxygen species (superoxide and hydroxide radicals) to be generated in them. That. allopurinol protects ischemic tissues from damage.

Indications for use. Allopurinol is used for the planned treatment of gout (prevention of attacks), as well as for the prevention of the development of gout during cytostatic and radiation therapy of tumor diseases (since the patient undergoes an intensive breakdown of nucleic acids and purines with the formation of a large amount of uric acid).

Sometimes allopurinol is prescribed to patients with urolithiasis with urate stones. The use of allopurinol can slow down the growth of urate stones, because. decreased synthesis of uric acid.

Dosing regimen. Allopurinol is started at 100 mg/day and, if well tolerated, the dose is increased by 100 mg every week. The optimal doses are:

With mild gout - 100-300 mg / day;

In moderate course - 300-600 mg / day;

In severe gout - 700-900 mg / day.

To prevent hyperuricemia in the treatment of neoplastic diseases, allopurinol is prescribed at a dose of 600-800 mg 2-3 days before the start of treatment and continues to be taken throughout the course of therapy.

NE: In general, allopurinol is well tolerated and rarely causes adverse effects (>3% of patients).

1. Allergic reactions (exanthema, fever) - most often develop in the first 2 months of treatment.

2. Dyspeptic symptoms - nausea, vomiting, abdominal pain, diarrhea, increased levels of liver enzymes.

3. Transient thrombocytopenia, leukopenia or leukocytosis, aplastic anemia.

4. Provocation of an acute attack of gout at the beginning of treatment. The intake of allopurinol leads to a drop in the level of urates in the blood, while the mobilization of uric acid from gouty nodules in the joints and other depots begins. This causes an attack of gout. In connection with this feature, it is recommended to start treatment with allopurinol only after the elimination of an acute attack of gout and, in the first 2-3 months of treatment, use NSAIDs to prevent an acute attack of gout.

5. Since allopurinol blocks xanthine oxidase, it will slow down the metabolism of anticancer drugs from the group of purine analogues (mercaptopurine, thioguanine, etc.) and increase their therapeutic and toxic effects. Therefore, if the patient is taking allopurinol, then the dose of such drugs should be reduced by 25-30%.

6. Allopurinol enhances the undesirable effects of indirect anticoagulants, phenytoin, theophylline, tk. slows down their metabolism. Enhances the deposition of iron in the liver.

VW: tablets of 100 and 300 mg.

Probenecid It is a weak organic acid. MD: As mentioned above, the excretion of uric acid in the kidneys after its filtration is associated with 2 processes - reabsorption and subsequent secretion.

Probenecid, after being administered to the body, enters the bloodstream and is delivered to the kidneys. There, by secretion, it enters the urine, where it passes into an ionized form. Probenecid molecules bind to weak acid anion carrier proteins, which provide the process of reabsorption and secretion of organic acids into the urine. Once bound to probenecid, these carriers lose their activity.

8144 0

Allopurinol (Allopurinol)
Xanthine oxidase inhibitors
Tab. 100 mg; 300 mg

Mechanism of action

Inhibits xanthine oxidase, prevents the transition of hypoxanthine to xanthine and the formation of uric acid from it. Reduces the concentration of uric acid and its salts in body fluids, promotes the dissolution of existing urate deposits, prevents their formation in tissues and kidneys. By reducing the transformation of hypoxanthine and xanthine, it enhances their use for the synthesis of nucleotides and nucleic acids.

The accumulation of xanthine in plasma does not disturb the normal exchange of nucleic acids, precipitation and precipitation of xanthine in plasma does not occur (high solubility). The renal clearance of xanthines is 10 times greater than the clearance of uric acid, and an increase in the excretion of xanthines in the urine is not accompanied by an increased risk of nephrolithiasis.

Pharmacokinetics

Absorbed after a single oral dose of 300 mg - 80-90%. Penetrates into breast milk. In the liver, about 70% of the dose is metabolized to the active metabolite, oxypurinol. After a single dose of 300 mg Cmax of allopurinol (2-3 μg / ml) - 0.5-2 hours, oxypurinol (5-6 μg / ml) - 4.5-5 hours. T1 / 2 - 1-3 hours (fast oxidation to oxypurinol and high glomerular filtration), T1 / 2 oxypurinol - 12-30 hours (average 15 hours). In the renal tubules, oxypurinol is largely reabsorbed (the mechanism of reabsorption is similar to that of uric acid). About 20% of the dose is excreted through the intestine unchanged; kidneys - 10% allopurinol, 70% oxypurinol. Hemodialysis is effective.

Indications

■ Gout (primary and secondary) that occurs in diseases accompanied by increased breakdown of nucleoproteins and an increase in the content of uric acid in the blood, incl. with various hematoblastomas (acute leukemia, chronic myeloid leukemia, lymphosarcoma, etc.), with cytostatic and radiation therapy of tumors (including in children), psoriasis, extensive traumatic injuries due to enzymatic disorders (Lesch-Nychen syndrome).
■ Violations of purine metabolism in children.
■ Uric acid nephropathy with impaired renal function (renal failure).
■ Recurrent mixed oxalate-calcium kidney stones (in the presence of uricosuria).

Contraindications

■ Hypersensitivity
■ Liver failure.
■ Chronic renal failure (azotemia stage).
■ Primary (idiopathic) hemochromatosis.
■ Asymptomatic hyperuricemia.
■ Acute attack of gout.
■ Pregnancy.
■ Breastfeeding.

Cautions

You should not start therapy until complete relief of an acute attack of gout.

During treatment, a daily diuresis of at least 2 liters should be ensured, and urine pH should be maintained at a neutral or slightly alkaline level.

It should be borne in mind that with adequate therapy, it is possible to dissolve large urate stones in the renal pelvis and enter them into the ureter (renal colic).

With the development of an acute attack of gout, it is necessary to additionally prescribe anti-inflammatory drugs (during the first month of treatment, prophylactic administration of NSAIDs or colchicine is recommended).

In case of impaired renal and hepatic function (increased risk of side effects), it is necessary to reduce the dose of allopurinol.

Combine with caution with vidarabine.

Children are prescribed only for malignant neoplasms and congenital disorders of purine metabolism.

Prescribe with caution:
■ with renal failure;
■ chronic heart failure;
■ patients with diabetes;
■ patients with arterial hypertension.

Interactions

Side effects

■ Allergic reactions - skin rash, pruritus, urticaria, exudative erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), purpura, bullous dermatitis, eczematous dermatitis, exfoliative dermatitis, rarely - bronchospasm.
■ Gastrointestinal tract - dyspepsia, diarrhea, nausea, vomiting, abdominal pain, stomatitis, hyperbilirubinemia, cholestatic jaundice, increased activity of "liver" transaminases and alkaline phosphatase, rarely - hepatonecrosis, hepatomegaly, granulomatous hepatitis.
■ CNS - headache, peripheral neuropathy, neuritis, paresthesia, paresis, depression, drowsiness.
■ Cardiovascular system - pericarditis, increased blood pressure, bradycardia vasculitis.
■ Urinary system - acute renal failure, interstitial nephritis, increased urea (in patients with initially reduced kidney function), peripheral edema, hematuria, proteinuria, impotence, infertility, gynecomastia.
■ Hematopoietic system - agranulocytosis, anemia, aplastic anemia, thrombocytopenia, eosinophilia, leukocytosis, leukopenia.
■ Musculoskeletal system - myopathy, myalgia, arthralgia.
■ Sense organs - taste perversion, loss of taste sensations, visual impairment, cataracts, conjunctivitis, amblyopia.
■ Other reactions - furunculosis, alopecia, diabetes mellitus, dehydration, nosebleeds, necrotic tonsillitis, lymphadenopathy, hyperthermia, hyperlipidemia.

Dosage and administration

Inside, 0.1 - 0.2 g 1-2 r / day
Maximum single dose: 0.6 g
Maximum daily dose: 0.8 g
Average daily dose in children: 5-20 mg/kg

Overdose

Symptoms: nausea, vomiting, diarrhea, dizziness, oliguria.
Treatment: forced diuresis, hemo-and peritoneal dialysis.

Synonyms

Allopurinol, Allopurinol tablets 0.1 g, Allupol, Milurit, Purinol, Allopurinol-Egis

Yu.B. Belousov

The drugs in this group are antagonists of natural metabolites. In the presence of neoplastic diseases, the following substances are mainly used (see structures).

Folic acid antagonists: Methotrexate (ametopterin).

Purine antagonists: Mercaptopurine (leupurine, purinethol).

Pyrimidine antagonists: Fluorouracil (fluorouracil); Ftorafur (tegafur); Cytarabine (cytosar).

Figure 11. Chemical structures of a number of metabolites and their antimetabolites.

Chemically, antimetabolites are only similar to natural metabolites, but not identical to them. In this regard, they cause a violation of the synthesis of nucleic acids.

This negatively affects the process of division of tumor cells and leads to their death.

Antimetabolites act at different stages of the synthesis of nucleic acids, inhibiting the enzymes of their synthesis. So, the mechanism of the antiblastoma effect of methotrexate, obviously, is that it inhibits dihydrofolate reductase, as well as thymidyl synthetase. This disrupts the formation of purines and thymidine, resulting in inhibition of DNA synthesis. Mercaptopurine appears to prevent the incorporation of purines into polynucleotides. It is believed that fluorouracil disrupts the synthesis of nucleotides or thymidine and their incorporation into DNA. There is evidence that fluorouracil is converted in tumor cells to 5-fluoro-2-deoxy-uridine-5-monophosphate, which is an inhibitor of the enzyme thymidyl synthetase.

55. Disorders of nucleotide metabolism: orotaciduria, xanthinuria. (not enough xanthinuria)

Orotaciduria

This is the only violation of the synthesis of pyrimidines de novo. It is caused by a decrease in the activity of UMP synthase, which catalyzes the formation and decarboxylation of OMF. Since in embryogenesis from the formation of pyrimidines de novo depends on the provision of DNA synthesis by substrates, then the life of the fetus is impossible in the complete absence of the activity of this enzyme. Indeed, all patients with orotaciduria have marked, albeit very low, activity of UMF synthase. It has been established that the content of orotic acid in the urine of patients (1 g/day or more) significantly exceeds the amount of orotate that is normally synthesized daily (about 600 mg/day). The decrease in the synthesis of pyrimidine nucleotides, observed in this pathology, disrupts the regulation of the CAD enzyme by the mechanism of retroinhibition, which causes hyperproduction of orotate.

Clinically, the most characteristic consequence of orotaciduria is megaloblastic anemia, caused by the inability of the body to provide a normal rate of division of erythrocyte cells. It is diagnosed in children on the basis that it does not respond to treatment with folic acid preparations.

The insufficiency of the synthesis of pyrimidine nucleotides affects the intellectual development, motor ability and is accompanied by disorders of the heart and gastrointestinal tract. The formation of the immune system is disrupted, and there is an increased sensitivity to various infections.

Hyperexcretion of orotic acid is accompanied by disorders of the urinary system and the formation of stones. If left untreated, patients usually die in the first years of life. At the same time, orotic acid does not have a toxic effect. Numerous disturbances in the work of various body systems are caused by "pyrimidine hunger".

To treat this disease, uridine is used (from 0.5 to 1 g / day), which turns into UMF along the "backup" path.

Uridine + ATP → UMF + ADP.

Loading with uridine eliminates "pyrimidine hunger", and since all other nucleotides of the pyrimidine series can be synthesized from UMF, the release of orotic acid decreases due to the restoration of the mechanism of retroinhibition of the CAD enzyme. For patients with orotaciduria, treatment with uridine continues throughout life, and this nucleoside becomes an indispensable nutritional factor for them.

In addition to genetically determined causes, orotaciduria can be observed:

with hyperammonemia caused by a defect in any of the enzymes of the ornithine cycle,

with the exception of carbamoyl phosphate synthetase I. In this case, carbamoyl phosphate synthesized in mitochondria enters the cytosol of cells and begins to be used for the formation of pyrimidine nucleotides. The concentration of all metabolites, including orotic acid, increases. The most significant excretion of orotate is observed with insufficiency of ornithinecarbamoyltransferase (the second enzyme of the ornithine cycle);

in the treatment of gout with allopurinol, which is converted to oxypurinol mononucleotide and becomes a strong inhibitor of UMF synthase. This leads to the accumulation of orotic acid in tissues and blood.

Xanthinuria is a hereditary enzymopathy associated with a defect xanthine oxidase, which leads to a violation of the catabolism of purines to uric acid. In blood plasma and urine, a 10-fold decrease in the level of uric acid can be observed, but the excretion of xanthine and hypoxanthine increases by 10 or more times. The main clinical manifestation is the formation of xanthine calculi, up to several millimeters in size, brown in color, and relatively soft in consistency. Gradually, kidney pathology may develop.