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 liquid media body, 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 taste sensations, blurred vision, cataract, 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

Dear colleagues!
On the certificate of the seminar participant, which will be generated in case of successful completion of the test task, the calendar date of your online participation in the seminar will be indicated.

Seminar "Gout: STATUS OF THE PROBLEM"

Conducts: Republican Medical University

The date of the: from 03.11.2014 to 03.11.2015

Definition

Gout is a chronic systemic metabolic disease characterized by impaired purine metabolism (hyperuricemia), leading to the deposition of sodium monourate crystals (MUN) in various tissues, which manifests itself as crystal-induced inflammation at the sites of urate fixation (joints, periarticular tissues, internal organs).

Epidemiology

The prevalence of gout in Europe is 1-2% in the adult population, and 6% in people over 50 years of age. The frequency of gout in a number of regions of Ukraine is 400 per 100,000 adults. In the last two or three decades, there has been a clear increase in its prevalence. Significantly more often men suffer from gout (according to various sources, the ratio m:f - from 7:1 to 19:1). A number of epidemiological studies have shown that the incidence of gout in men and women over the age of 60 is equivalent.

The peak incidence occurs at 40–50 years of age in men and at 60 years of age and older in women.

Etiology

Persistent hyperuricemia (elevated serum uric acid levels) is an obligate risk factor for the development of gout. The European League Against Rheumatism (EULAR) recommends that blood uric acid levels above 360 µmol/L be assessed as hyperuricemia. The formation of MUN crystals and their deposition in the tissue occur when the blood serum is supersaturated with urates (i.e., when the level of uric acid is more than 420 µmol/l).

Risk factors for the development of gout include age: in men under 35 years of age, the prevalence of gout is less than 0.5% and more than 7% - over the age of 75 years. Premenopausal women rarely develop gout, but at the age of 75 years and older, the prevalence of gout reaches 2.5–3%.

The late development of gout in women may be due to the uricosuric effects of estrogens.

The risk of developing gout increases with obesity by 4 times compared with individuals with a body mass index of 21–25 kg/m 2 .

Excessive daily consumption of meat increases the risk of developing gout by 20%.

Individuals who consume >50 g of alcohol daily have a 2.5 times higher incidence of gout than non-alcoholics.

The use of drugs (more often diuretics) is associated with an increase in serum urate levels. However, in a number of studies, such an association is questioned, and an increase in uric acid values in people with arterial hypertension (AH) and heart failure (HF) receiving diuretics is associated with the adverse effect of AH and HF on purine metabolism. Features of the mechanisms of renal excretion of urate in the application of various diuretics are ambiguous. The risk of developing hyperuricemia and gout is higher with more potent loop diuretics than with less potent thiazide diuretics.

Cyclosporine, acetylsalicylic acid and salicylates reduce the excretion of urates and contribute to the development of hyperuricemia. Metabolic syndrome, hypertension and heart failure also lead to the development of hyperuricemia.

Pathogenesis

For the formation of MUN crystals, the presence of a high level of uric acid in the blood serum is necessary. Normally, a stable level of uric acid in the blood is the result of a balance between its production and excretion. Hyperuricemia develops with an increase in the production of uric acid and / or a violation of its excretion (mainly renal). Urate is the end product of the metabolism of purine nucleotides, the components of cellular energy - ATP, DNA and RNA.

Increased production of urates, leading to the development of hyperuricemia and gout, may be due to enzymatic defects, as well as a consequence of increased cell destruction (malignancy, polycythemia vera, hemolytic anemia).

2/3 of urates is excreted by the kidneys, and the rest - by the intestines. Evidence has been presented that 85-95% of cases of gout are the result of a violation of the excretion of urate by the kidneys.

Hyperuricemia is the leading basic pathogenetic mechanism of gout and the main risk factor for its development.

The frequency of gout development is shown below, depending on the level of uric acid in the blood serum (Table 1).

The development of gouty inflammation is due to the complex effect of various cell types on the deposition of MUN crystals in the joints, which leads to an imbalance between the synthesis of pro-inflammatory and anti-inflammatory substances.

The main mechanism for the development of acute and chronic gouty arthritis is the deposition of urate crystals in the joints and periarticular tissues, the interaction of which with synoviocytes, monocytes, macrophages, neutrophils, osteoblasts leads to the synthesis of a wide range of pro-inflammatory cytokines: interleukin-1 (IL-1), interleukin-6 , tumor necrosis factor α, chemokines, arachidonic acid metabolites, superoxide oxygen radicals, proteinases, which, along with kinins, complement components and histamine, induce inflammation of the joints and periarticular tissues, as well as systemic reactions.

Table 1. The incidence of gout depending on the level of uric acid in the blood serum

Among the cells involved in the development of gouty inflammation, a special place is given to neutrophils, whose pronounced infiltration of the synovial tissue is considered as a leading factor in gouty arthritis. The interaction between leukocytes and vascular endothelial cells is a key stage in the development of gouty inflammation.

A feature of acute gouty arthritis is its self-limiting nature, which is to some extent associated with the synthesis of a number of anti-inflammatory mediators by urates (in particular, transforming growth factor).

Histopathology

The deposition of MUN crystals takes place in cartilage, tendons, synovial fluid and subcutaneous tissue. Avascularity of connective tissue (especially cartilage) is considered as a leading factor predisposing to crystal deposition. The earliest articular changes are the result of the deposition of EOR crystals. Tophi can be inter-, peri- and extra-articular. Gouty tophi are granulomas composed of mono- and multinuclear macrophages surrounding deposits of MUN crystals. In tophi, there are several zones, including the central one, consisting of MUN crystals, surrounded by a cellular coronal zone, in which a large number of macrophages and plasma cells are detected. This coronal zone separates the central region of MUN crystal deposits from the surrounding fibrovascular zone.

The granulomatous process in the bones and joints leads to the development of erosions, bone reduction and gouty arthritis. Deposition of MUN crystals is often associated with concomitant osteoarthritis.

Diagnosis of gout

Classification criteria for acute gouty arthritis:

1. Identification of characteristic EOR crystals in the joint fluid.

2. Presence of tophi containing EOR crystals.

3. The presence of 6 of the 12 signs listed below:

More than one attack of acute arthritis in history;

Maximum inflammation of the joint on the first day of illness;

Monoarthritis;

Hyperemia of the skin over the affected area;

Swelling, pain in the first metatarsophalangeal joint;

Unilateral lesion of the first metatarsophalangeal joint;

Unilateral damage to the joints of the foot;

Suspicion of tophi;

Hyperuricemia;

Asymmetric swelling of the joints;

Subcortical cysts without erosions;

Negative results on synovial fluid culture.

The diagnosis of gout is considered definitive when the presence of MUN crystals in the synovial fluid or tophi is confirmed by polarizing microscopy. The presence of 6 of the 12 clinical manifestations listed above makes it possible to suspect gout with great reason.

Clinical classification of gout

I. Clinical stages:

a) acute gouty arthritis;

b) interictal (interval) gout;

c) chronic gouty arthritis:

Aggravation;

Remission;

d) chronic tofus arthritis.

II. Periods:

a) premorbid (preclinical);

b) intermittent (acutely recurrent);

c) chronic.

III. Flow options:

a) easy;

b) moderate;

c) hard.

IV. Phase:

a) exacerbations (active);

b) remissions (inactive).

v. X-ray stages of joint damage:

I - large cysts (tophi) in the subchondral bone and in deeper layers, sometimes hardening of soft tissues;

II - large cysts near the joint and small erosions of the articular surfaces, constant compaction of the periarticular soft tissues, sometimes with calcifications;

III - large erosion on at least 1/3 of the articular surface, osteolysis of the epiphysis, significant compaction of soft tissues with lime deposition.

VI. Peripheral tophi and their localization:

a) there are;

b) are absent.

VII. Degree of functional insufficiency:

0 - functional ability is fully preserved;

I - professional ability is preserved;

II - lost professional ability;

III - the ability to self-service is lost.

VIII. Gouty nephropathy.

Clinical picture

The classic clinical picture of acute gouty arthritis is characterized by a sudden onset and rapid increase in intense pain, usually in one joint, swelling, reddening of the skin over it, and impaired function. The attack often develops at night or in the early morning hours, at the onset of the disease lasts 1-10 days (in the absence of adequate therapy) and ends with a complete recovery with no symptoms after the attack. Among the provoking factors of an acute attack, trauma, a large amount of meat food (especially in combination with alcohol), surgical interventions, and diuretics are distinguished. The first gouty attack is often manifested by a lesion of the first metatarsophalangeal joint of the foot.

Most patients develop repeated attacks of gout, in the future they become more frequent, asymptomatic periods are shortened, and arthritis becomes protracted. In the absence of adequate therapy (and often despite its implementation), the progression of the disease is observed with the involvement of other joints in the pathological process and the formation of tophi.

In some patients, acute attacks of gout are atypical and manifest as tendosynovitis, bursitis. They have mild episodes of joint discomfort for several days without joint swelling. In 10% of atypical attacks, several joints are affected (sometimes migrating). At the same time, systemic manifestations of gout (weakness, fever) predominate.

Interictal periods

Between attacks in the initial stages of the course of gout, asymptomatic periods are observed (in some cases, long). In some patients, attacks do not recur, in others they occur after several years. However, in most patients, repeated attacks develop within a year after the first gouty joint attack. Ultimately, as a result of repeated attacks and persistent deposition of EOR crystals, many joints are affected, and the pain syndrome is chronic. The time from the first articular attack to a persistent symptomatic picture of the disease ranges from several years to 10 or more.

Chronic tophi gout

The chronic course of gout is characterized by the formation of large deposits of crystals (tophi), localized subcutaneously, intradermally and in other organs. Knots of various shapes are formed mainly around the extensor surfaces of the forearms, on the elbows, auricles, and in the region of the Achilles tendons. Tophi are asymmetric in location and vary in size. In some cases, tophi can reach large sizes, ulcerate with the release of a crumbly white mass; there may be cases of local inflammation (presence of erythema, pus). Tophi can be localized on the eyelids, tongue, larynx, or in the heart (causing conduction disturbance and valvular dysfunction).

Chronic tophi gout is characterized by progressive joint damage (limitation of movement, deformity) with varying severity of synovitis (primarily in the first metatarsophalangeal, ankle, interphalangeal joints and in the joints of the hand). As in cases with tophi, joint damage is characterized by asymmetry. In the chronic course, attacks of gouty arthritis proceed more gently. In the later stages of the disease (especially in the absence of adequate therapy), damage to the hip, knee, shoulder joints, spine and sacroiliac joints is possible.

Gout is associated with several variants of kidney damage, which can be presented either alone or in various combinations. These include:

Nephrolithiasis, observed much more often with gout than without it. The basis of stones in most cases is uric acid. Only in 10–20% of patients, oxalates or calcium phosphate are found in the composition of the stones. Urate stones have a whitish tint and are usually X-ray negative;

Urate nephropathy, which is characterized by the deposition of MUN in the interstitium of the kidneys, which is associated with permanent hyperuricemia, hyperuricosuria, acidic urine and impaired ammonium production. This variant of kidney damage is associated with a high risk of developing renal failure (RF).

Clinical and laboratory characteristics of patients with gout (recommendations of experts EULAR )

1. In acute attacks, severe pain in the joint(s), swelling, severe erythema, and hypersensitivity rapidly develop, which peak within 6–12 hours, with severe erythema, which is quite convincing evidence of crystalline inflammation (although not specific for gout). ).

Thus, the classical clinical picture is a good marker of an acute attack of gout. However, for the final diagnosis, along with the above symptoms, it is necessary to identify EOR crystals, which is the standard for diagnosing the disease.

2. The given clinical picture is typical for gout with hyperuricemia, but to confirm the diagnosis, it is necessary to establish the presence of MUN crystals.

3. The presence of MUN crystals in the synovial fluid or in the tophi aspirate, along with clinical manifestations, makes it possible to definitely establish the diagnosis of gout.

4. Thus, the detection of MUN crystals is a decisive marker in the diagnosis of symptomatic gout. Examination of the synovial fluid for the presence of MUN crystals should be carried out in all inflammatory arthritis, because. in some cases, gout can occur atypically.

5. Identification of MUN crystals from “asymptomatic joints” makes it possible to diagnose gout in the interictal period.

6. Gout and sepsis can coexist. If septic arthritis is suspected, a bacteriological examination of the synovial fluid is necessary even in the presence of MUN crystals.

7. Although serum uric acid levels are the most important risk factor, they cannot confirm or rule out the presence of gout, as many individuals with hyperuricemia do not develop gout, and during acute attacks of gout, serum uric acid levels may be normal.

8. In a number of patients with gout, it is necessary to determine the uric acid in the urine, especially in cases of a family history of the onset of gout (the onset of gout before 25 years of age) or in the presence of nephrolithiasis.

9. Although X-ray examination is important in the differential diagnosis and may show typical signs of chronic gout (subcortical cysts without erosions), it is not very informative in the early stages of the disease or in acute attacks.

10. Risk factors for gout or the presence of comorbidity should be assessed, including manifestations of the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, hypertension, and HF and FR) in order to guide appropriate therapy.

Differential Diagnosis

Gout should be differentiated from sepsis, which can coexist with it, as well as from other crystal-associated synovitis (primarily with deposition of calcium pyrophosphate - especially in the elderly), reactive, psoriatic and rheumatoid arthritis. Diagnosis of gout requires examining the synovial fluid for infection (sepsis) or calcium pyrophosphate crystals (pyrophosphate arthropathy) or MUN crystals (gout).

Medical tactics

Therapeutic tactics for gout is determined by the characteristics of the clinical picture, the presence of systemic manifestations, lesions internal organs and their severity.

The goals of gout treatment include:

The fastest possible elimination of an acute attack of gout;

Prevention of relapses of acute gouty attacks;

Prevention or inhibition of the rate of development of the disease and its complications;

Prevention or elimination of factors associated with gout and worsening its course (obesity, metabolic syndrome, hypertension, HF, PN, hypertriglyceridemia, use a large number meat, alcohol, etc.).

Therapeutic tactics for gout include non-drug and drug approaches.

Non-drug approaches:

Patient education (lifestyle changes, dietary regimen, alcohol exclusion, weight loss in obesity, smoking cessation, regular monitoring of uric acid levels in the blood);

Informing about the symptoms of acute gouty arthritis, exacerbation of chronic gouty arthropathy and the consequences of uncontrolled hyperuricemia;

Training in the rapid relief of gouty joint attack (always have non-steroidal anti-inflammatory drugs (NSAIDs) in your pocket; avoiding analgesics);

Informing about prescribed medications (doses, side effects, interactions with other medications prescribed for concomitant diseases).

Diet regimen

In the last decade, several large clinical studies have been conducted and a number of reviews have been published on the effect of various foods on the risk of developing gout, its exacerbations and hyperuricemia.

These studies show that overweight, obesity, and the consumption of beer, spirits (alcohol, vodka, etc.), meat, seafood, fructose, and sugar-containing drinks are risk factors for gout and elevated serum uric acid levels. blood. Protective factors have also been identified, including weight loss, low-fat foods, and vitamin C and coffee. Other foods are neutral for gout risk factors (wine, tea, diet drinks, high-fat foods, and high-purine vegetables).

Medical therapy

The nature of drug therapy is determined by the peculiarity of the clinical course of gout, the presence of extra-articular lesions and concomitant diseases.

Acute gouty arthritis

The primary goal of drug therapy is to reduce inflammation, intra-articular hypertension, and pain. Hypouricemic drugs should be avoided prior to attack relief due to their ability to prolong an acute attack.

The first-line drugs for the relief of acute gouty arthritis are fast-acting NSAIDs used in tolerably high therapeutic dosages. When choosing a drug, one should take into account the patient's risk of side effects (gastrointestinal, cardiovascular, renal, etc.). More often prescribed ibuprofen 800 mg 3-4 times a day, diclofenac 200 mg/day, naproxen 500 mg 2 times a day. At a high risk of gastrointestinal complications, non-selective drugs should be used in combination with proton pump inhibitors, and as an alternative, COX-2 selective NSAIDs (celecoxib 200-400 mg / day) should be used. Used for decades, indomethacin is undesirable in the elderly due to the high risk from the gastrointestinal tract, kidneys and central nervous system.

Colchicine has been used successfully for many years to relieve acute gouty arthritis. Treatment with colchicine is more successful when administered on the first day and even hours after the development of an attack of gout. The clinical effect of colchicine appears faster than NSAIDs, but unlike the latter, it is associated with a higher incidence of side effects. In this regard, today caution is recommended when using colchicine: 0.5 mg of the drug every hour until the onset of the effect, or the development of adverse reactions (vomiting, diarrhea, diarrhea), or reaching the maximum dose (no more than 6 mg in 12 hours). Life-threatening colchicine toxicity can occur in patients with reduced renal function even at lower doses. In this regard, colchicine should be used after determining the levels of creatinine and glomerular filtration rate.

With intravenous use of colchicine, high toxicity is observed, which makes this route of drug administration unacceptable. Combination therapy of NSAIDs with colchicine has no advantages over their separate use. The ineffectiveness of NSAIDs, contraindications to their use or intolerance are the basis for the use of colchicine.

In acute attacks of gout resistant to NSAIDs or colchicine, the use of glucocorticoids (GC) is indicated, which allows to achieve a good clinical effect. Depending on the clinical features of an acute gouty attack, various ways of using HA are used. With single lesions of large or small joints, a good effect is achieved with intra-articular administration of HA (triamcinolone 40 mg or methylprednisolone 40-80 mg and 5-20 mg of triamcinolone or 20-40 mg of methylprednisolone, respectively). With a polyarticular attack of gout, GCs are used intramuscularly or intravenously. In this case, several intramuscular or intravenous injections of methylprednisolone are used (40 and 125 mg, respectively). For oral use, prednisolone or methylprednisolone is used in minimal or moderate dosages for several days.

An increase in the clinical effect has been reported with the combination of Gk with colchicine. In the pathogenesis of gout, an important place is given to IL-1β, and therefore the possibility of using IL-1 antagonists in the treatment of acute gouty attacks (canakinumab - anti-IL-1 monoclonal antibodies), etc. is being studied. The effectiveness and safety of this approach requires further study in the KRI .

Chronic tophi gout

The treatment strategy for chronic tophi gout involves a combination of non-drug approaches with drug therapy.

Non-drug approaches and dietary regimen for chronic tophi gout are similar to those for acute gouty arthritis, as presented above.

Indications for hypouricemic drug therapy:

Relapses of articular gouty attacks;

The presence of tophi;

Damage to the joints and cartilage;

Associated kidney damage

Urate nephrolithiasis;

Elevated serum uric acid levels.

Three groups of drugs are used to lower serum uric acid levels:

xanthine oxidase inhibitors (allopurinol, febuxostat);

Uricosuric agents (probenecid, sulfinpyrazone, benzbromarone);

Uricose drugs.

Xanthine oxidase inhibitors (allopurinol, febuxostat)

From uricodepressive agents, i.e. inhibiting the synthesis of uric acid, allopurinol has been used for decades, which is a structural analogue of hypoxanthine, which prevents the formation of uric acid by inhibiting xanthine oxidase, an enzyme that converts hypoxanthine to xanthine and uric acid. To a lesser extent, allopurinol inhibits the activity of hypoxanthine-guanine-phosphoribosyl transferase. The drug has an antioxidant and mild immunosuppressive effect (due to the accumulation of adenosine in immunocompetent cells).

The action of allopurinol begins on the second day after the start of its use. The half-life reaches 22 hours, which allows the daily dose of the drug to be taken once in the morning. The initial dose of the drug depends on the concentration of uric acid in the blood, age, kidney function and is usually 50-300 mg / day, but should not exceed 900 mg. It is not recommended to use allopurinol in combination with iron preparations and warfarin. Treatment is carried out for a long time (indefinitely). Patients with a blood uric acid concentration of less than 450 µmol/l are prescribed allopurinol at an initial dose of about 150 mg/day or 300 mg every other day. With an increase in the level of blood creatinine to 0.2 mmol / l and oxypurinol to 130 μmol / l, the dose of the drug should be halved, and in patients with a creatinine level of more than 0.4 mmol / l and oxypurinolemia over 230 μmol / l, allopurinol is contraindicated.

Side effects of allopurinol are more often caused by delayed-type hypersensitivity mechanisms and are characterized by fever, leukocytosis, accelerated ESR, skin rashes (from maculopapular rash to exfoliative dermatitis).

Some patients treated with allopurinol develop nausea, diarrhea, and increased levels of hepatic transaminases. In the acute period, allopurinol is not indicated. It is advisable to prescribe it after the cessation of clinical manifestations of acute arthritis; It is recommended to continue taking the selected dose in the interictal period to prevent gout exacerbations indefinitely. Several studies have recently been published showing that serum uric acid levels are an independent risk factor for the development and progression of PN in patients with diabetic and non-diabetic nephropathy, and the use of allopurinol, which reduces or normalizes hyperuricemia, was associated with a slowdown in the progression of PN.

In addition, the ability of allopurinol (average dose of 300 mg/day) has been demonstrated to cause regression of left ventricular hypertrophy by reducing afterload, as well as to improve endothelial function in patients with chronic kidney disease (stage 3) and the presence of left ventricular hypertrophy. Long-term follow-up (9 months) showed no decrease in kidney function in any of the patients.

Febuxostat is a new selective xanthine oxidase inhibitor. According to two randomized controlled trials (CRIs), it achieves a greater reduction in blood urate levels than allopurinol in elderly people with gout or hyperuricemia. Febuxostat is not excreted by the kidneys, and therefore it can be used in patients with severe renal failure. This is the fundamental difference between febuxostat and allopurinol. Among the side effects of febuxostat, arthralgia, myalgia, and diarrhea are distinguished. The presence of adverse effects of the drug on the cardiovascular system requires clarification.

Uricosuric drugs reduce reabsorption and increase the secretion of uric acid in the renal tubules. The mechanism of action of uricozurics limits their use in the nephrolithiasis type of gouty nephropathy and their complete rejection in PN. Usually, drugs are prescribed for daily uricuria less than 700 mg. Among them, the most commonly used benzbromarone and similar in composition benzodarone, which have a certain uricodepressive effect. Tolerability of drugs is usually good. Some patients experience side effects in the form of pain in the lumbar region, spine and abdomen, diarrhea, dizziness, urticaria.

Also widely used probenecid And etamide, although the effectiveness of these agents is inferior to benzbromarone and benziodarone. In the acidic environment of the renal tubules, these drugs are reabsorbed, and in the alkaline environment they are actively secreted. The initial dose of probenecid is 500–1000 mg/day; after 2 weeks it is increased to 1500-3000 mg / day. Etamide is applied at 2800 mg/day in courses of 10 days once a month. Of the side effects, headache, dizziness, nausea, dermatitis, fever, anemia should be noted. Probenecid and etamide enhance the effects of anticoagulants.

In the treatment of gout, it is possible to use a combination of allopurinol with uricosuric agents. This approach is acceptable in patients with resistance to monotherapy.

When prescribing allopurinol and / or uricosuric drugs, it is necessary to control the pH of the urine and alkalinize it with the use of citrates in order to reduce the risk of stone formation and the development of urate nephropathy.

As urico-destroying drugs enzymes are used urate oxidase, hepatocatalase. Urate oxidase oxidizes uric acid to form allantoin, alloxanoic acid and urea. She is prescribed 1000-3000 IU / day for two weeks. The drug is not contraindicated in urolithiasis. Of the side effects, urticaria sometimes develops. Hepatocatalase increases not only the breakdown of uric acid by oxidation, but also its synthesis in the body. This enzyme is administered at 10,000–20,000 IU 2–3 times a week for one month. Treatment courses are repeated quarterly. Tolerability of hepatocatalase is good. In the light of evidence-based medicine, the widespread use of these enzymes in clinical practice requires CRI.

Uricose agents

Uricose is an enzyme that metabolizes uric acid into a soluble form of allantoin. Modified recombinant uricose is an enzyme that lowers the level of uric acid, metabolizing it into metabolites that are easily excreted in the urine. The drug is used intravenously at a dose of 8 mg every 2 weeks (with prior antihistamine or Gc premedication) in order to prevent acute attacks of gout and allergic reactions. It is used in patients with chronic gout to reduce serum levels of uric acid, prevent the development of tophi or reduce their size.

The use of modified recombinant uricose is often accompanied by the development of allergic reactions. Other side effects include nausea, vomiting, chest pain, and bruising at the infusion site.

Other treatment approaches

In case of urolithiasis type of nephropathy, in combination with allopurinol, drugs containing potassium citrate, sodium citrate, citric acid, magnesium citrate, pyridoxine hydrochloride, etc. are prescribed. These drugs are designed to shift the pH of urine towards an alkaline reaction under the influence of citrate ions, as well as to inhibit formation and intensification of the dissolution of stones, consisting of calcium oxalate (under the action of magnesium ions and pyridoxine). Due to the large amount of sodium and the need to take excess fluids (up to 2 l/day), citrate mixtures are not indicated for patients with poorly corrected hypertension and heart failure.

Arterial hypertension significantly worsens the course of gout and, in particular, gouty nephropathy. One of the preferred antihypertensive drugs for gout is the angiotensin II receptor antagonist losartan, since it has a uricosuric effect. Losartan increases the excretion of urates by reducing their reabsorption in the proximal tubules of the kidneys. The uricosuric effect is also preserved when it is combined with diuretics, due to which the increase in the level of uric acid in the blood caused by diuretics is prevented. Calcium antagonists also have a hypouricemic effect.

EULAR rheumatologists have developed recommendations for the management of gout patients based on the results of numerous CRIs evaluating the effectiveness of various treatment approaches for gout.

1. Optimal treatment of gout should include non-pharmacological and pharmacological approaches and be based on:

With specific risk factors (level of uric acid in the blood, previous attacks of the disease, radiological changes);

Clinical phase (acute / recurrent gout, subacute gout, chronic tophi gout);

General risk factors (age, gender, obesity, alcoholism, kidney function, use of drugs that increase serum urate levels, drug interactions, comorbidity).

2. Change in lifestyle (education of the patient): weight loss in obesity, dietary regimen, reduction in alcohol consumption (especially beer), which is one of the leading factors in the effectiveness of therapy.

3. Adequate therapy of comorbid diseases (pathological conditions), elimination or optimal control of risk factors (hyperlipidemia, hypertension, HF, PN, hyperglycemia, obesity and smoking) should be considered as an important component in the management of patients with gout.

4. Oral colchicine and/or first line NSAID agents for acute gout. In the absence of contraindications, NSAIDs are a reasonable choice.

5. High doses of colchicine (initially 1 mg and then 0.5 mg every 2 hours) are associated with side effects(nausea, vomiting, diarrhea). At the same time, low doses (for example, 0.5 mg 3 times a day) may have a sufficient effect in some patients.

6. Intra-articular aspiration and long-acting HA injection are effective and safe in acute attack of the disease, which is especially acceptable in severe monoarticular attack, as well as in patients where colchicine and NSAIDs are contraindicated. IN severe cases where colchicine and NSAIDs are contraindicated and/or intra-articular administration of HA is not possible, systemic HA administration is acceptable and effective.

7. Blood uric acid-lowering therapy is indicated for patients with recurrent acute attacks, arthropathy, tophi or radiological changes, multiple joint disease, or urate nephrolithiasis.

8. The goal of urate-lowering therapy is to promote the dissolution of crystals and prevent their formation. This is achieved by monitoring serum uric acid levels below the saturation point for monosodium urate (≤ 360 µmol/L). The goal of urate-lowering therapy is to prevent the formation of urate crystals and increase the dissolution of the crystals. Serum uric acid should be maintained below 360 µcol/L, which is below the monosodium urate saturation point.

9. Allopurinol is an acceptable drug for long-term therapy that reduces serum urate levels. It should be started at low doses (100 mg/day) and increased by 100 mg every 2 to 4 weeks (usually up to 300 mg/day) if necessary. The dose of the drug should be adjusted to the state of renal function. If treatment with allopurinol is accompanied by the development of toxic effects, then therapy can be carried out with uricosuric drugs (probenecid or sulfinpyrazone).

10. Uricosuric agents such as probenecid and sulfinpyrazone can be used as an alternative to allopurinol in patients with normal renal function, but are relatively contraindicated in patients with urolithiasis. Benzbromarone may be used in patients with mild to moderate renal impairment but is associated with a risk of hepatotoxicity.

11. Prevention of recurrence of gout exacerbation after the first attack can be achieved by the use of colchicine (0.5-1.0 g / day) and / or NSAIDs (with gastroduodenal protection, if necessary).

12. When the development of gout is associated with diuretic therapy, if possible, it should be discontinued. For hypertension and hyperlipidemia, losartan and fenofibrate, respectively, should be considered (both drugs have a moderate uricosuric effect).

Forecast

The prognosis for gout is relatively favorable, especially with adequate therapy. In 20–50% of rays, nephrolithiasis develops, which is complicated by secondary pyelonephritis and the development of PN, which is the leading cause of death; the development of PN can also be due to gouty nephropathy.

Examples of the formulation of diagnoses

Acute gouty arthritis, I attack with damage to the first toe, x-ray stage 0, SFN III.

Chronic gouty arthritis, polyarthritis, exacerbation with damage to the joints of the foot, knee joints with the presence of peripheral tophi in the auricles, x-ray stage II, SFN II, urolithiasis.

PROBLEM ARTICLES

UDC 577.152.173

Xanthine oxidase as a component of the system for generating reactive oxygen species

V.V. Sumbaev, Ph.D., A.Ya. Rozanov, MD, prof.

Odessa State University them. I.I. Mechnikov

Xanthine oxidase was discovered independently by the Ukrainian scientist Gorbachevsky and the German Shardinger. This enzyme (EC: 1.2.3.2) catalyzes the conversion of hypoxanthine to xanthine and further to uric acid, as well as the oxidation of a number of pteridines, aldehydes and imidazoles. In oxygen deficiency, xanthine oxidase functions as an NAD + -dependent xanthine dehydrogenase (EC: 1.2.1.37), and the mechanisms of action of these two functional forms are fundamentally different. In the late 1980s, the study of xanthine oxidase became increasingly relevant due to the discovery of the powerful superoxide-forming, carcinogenic, and apoptogenic activities of the enzyme. The "second wave" of studies of the role of xanthine oxidase in biochemical processes began, when it became clear that xanthine oxidase is the main system for generating reactive oxygen species in living organisms.

The main function of xanthine oxidase is the formation of uric acid from the primary oxidation products of adenine and guanine. Xanthine oxidase (xanthine dehydrogenase) is, in fact, central to the breakdown of purines. These two functional forms are the main factor limiting the formation of uric acid in the animal body. As already mentioned, uric acid in some animals, including humans, is the end product of the breakdown of purines, and therefore the intensity of utilization of purine deamination products in them directly depends on the activity of xanthine oxidase and xanthine dehydrogenase. In other organisms capable of breaking down uric acid, the intensity of the breakdown of uric acid and subsequent components depends entirely on the activity of xanthine oxidase and xanthine dehydrogenase, since the activity of uricase directly depends on the amount of uric acid formed. Xanthine oxidase and xanthine dehydrogenase ensure the utilization of all "excess" xanthine, which, if not properly utilized, can cause myalgia and kidney infarction.

In animals, plants and aerobic microorganisms, uric acid is formed during the xanthine oxidase reaction, and only a small part of it is formed through the xanthine dehydrogenase pathway.

Structure and mechanisms of action of xanthine oxidase and xanthine dehydrogenase

The structural organization of xanthine oxidase (xanthine dehydrogenase) is quite complex. The enzyme has a dimeric structure, and when it is separated into monomers, it is found that each of them individually has catalytic activity. The molecular weight of the enzyme, determined by PAGE disk electrophoresis, is 283 kDa. Each monomer consists of three non-identical subunits linked by disulfide bonds. The molecular weight of the subunits, determined by the same method, is 135, 120, and 40 kD, respectively. The enzyme contains FAD covalently bound to its protein part. There is one FAD molecule for each monomer. The protein part of the enzyme is rich in cysteine and contains 60–62 free SH groups. The structure of xanthine oxidase also contains iron-sulfur centers with a 2 Fe - 2 S cluster type. The enzyme contains molybdenum, which is pentavalent in the unexcited state and is in the form of the so-called molybdenum cofactor - it is connected by two s-bonds to FAD, two to six-substituted pterin , protonated at position 7 and one with cysteine sulfur. It has been shown that the composition of xanthine oxidase per each monomer also includes one persulfide group (- S - SH), which, possibly, serves to bind molybdenum. In the course of research, it was found that pterin and the persulfide group are not directly involved in the catalytic act. In a homogeneous state, the enzyme is quickly inactivated due to conformational changes that occur due to the presence of a large number free SH-groups. It has been shown that the enzyme is able to gradually lose molybdenum. It turned out that the activity of xanthine oxidase and xanthine dehydrogenase directly depends on the content of molybdenum in the body.

The mechanism of action of xanthine oxidase is quite complex. Initially, iron is oxidized as part of the iron-sulfur center of the enzyme with the formation of a superoxide radical. FAD dehydrates the substrate, turning into a super active semiquinone, capable of dehydrating even water with the formation of FADH 2 , which immediately reduces superoxide to H 2 O 2 . The electron remaining in FAD can restore the oxidized iron-sulfur center. Two hydroxyls formed as a result of water dehydrogenation on two xanthine oxidase monomers condense into an H 2 O 2 molecule. By donating an electron, molybdenum splits hydrogen peroxide into OH · and OH -, while changing its valence. Excited molybdenum binds to the hydroxyl anion, takes away the lost electron from it, and hydroxylates the substrate, transferring the hydroxyl radical to the latter. Schematically, the mechanism of action of xanthine oxidase is shown in fig. one .

The mechanism of action of xanthine dehydrogenase is relatively simple compared to that of xanthine oxidase. Initially, the enzyme attacks the p-bond in the substrate structure. This happens as follows: molybdenum donates an electron, breaks the p-bond between n and c in positions 2 and 3 or 7 and 8 in the structure of the purine core of the substrate with the addition of an electron to nitrogen. The activated substrate easily attaches water, water dissociates into H + and OH -, after which the proton attaches to nitrogen, and molybdenum binds to the hydroxyl anion, takes away the lost electron from it and hydroxylates the substrate, transferring the hydroxyl radical to the latter. Thus, the substrate is hydrated. The resulting substrate hydrate is easily dehydrated with the participation of FAD, which is immediately oxidized, transferring electrons and protons to NAD +, which is the final electron and proton acceptor in this reaction. In the case of xanthine dehydrogenase, the iron-sulfur centers do not function and superoxide is not formed. In this regard, the reaction proceeds along a slower dehydrogenase pathway through the stage of substrate hydration. In the case of xanthine oxidase, superoxide is formed, and therefore the reaction should go faster, due to the need to neutralize it. That is why the hydration of the substrate does not occur and the substrate immediately undergoes dehydrogenation.

Regulation of xanthine oxidase activity

As we have already mentioned, the way in which hypoxanthine is converted into xanthine and then into uric acid depends primarily on the conditions in which the enzyme responsible for this process . With oxygen deficiency, a decrease in pH, as well as an excess of nicotinamide coenzymes, xanthine oxidase functions as an NAD-dependent xanthine dehydrogenase. Xanthine oxidase activity inducers are interferon and molybdates. Interferon induces the expression of genes encoding xanthine oxidase subunits, and molybdenum (as part of molybdates) activates the release of xanthine oxidase apoenzyme from the Golgi vesicles, which leads to an increase in the number of active xanthine oxidase molecules. It should be noted that the activity of xanthine oxidase largely depends on the intake of exogenous molybdenum. The daily human need for molybdenum is 1-2 mg. It has been shown that xanthine oxidase activity in cancer cells increases by 5-20 times. In addition, reducing agents, such as ascorbic acid, glutathione, and dithiothreitol, at concentrations of 0.15-0.4 mM activate xanthine oxidase, maintaining FAD and iron-sulfur centers in the enzyme structure in a reduced state, which increases the amount of superoxide formed by the enzyme and, accordingly, the amount oxidized substrate molecules. At concentrations of 0.6 mM and above, all reducing agents noncompetitively inhibit xanthine oxidase. The inhibitory effect may be due to competition between reducing agents and the enzyme for the addition of molecular oxygen, as well as FAD hyperreduction, which hinders the normal dehydrogenation of the substrate. All the described reducing agents at concentrations of 0.1 mM and above non-competitively inhibit xanthine dehydrogenase, which is due to the reduction of FAD, which causes inhibition of the dehydrogenation of substrate hydrates, which, in turn, as unstable compounds decompose into substrate and water. Tungstates are inhibitors of xanthine oxidase activity. Tungsten replaces molybdenum in the active site of the enzyme, which leads to its irreversible inactivation. In addition, the isomer of hypoxanthine, allopurinol, as well as many derivatives of pteridine (including folic acid) and imidazole (histidine), isosterically inhibit xanthine oxidase. Caffeine (1,3,7-trimethylxanthine) is also a competitive inhibitor of xanthine oxidase. However, getting into the animal body, caffeine is demethylated to 1-methylxanthine and cannot be an inhibitor of xanthine oxidase. Moreover, this metabolite is converted with the participation of xanthine oxidase into 1-methyluric acid. Powerful isosteric inhibitors of xanthine oxidase, which, in addition, neutralize the superoxide it forms, are diaryltriazole derivatives. The structure of xanthine oxidase has an allosteric center, represented, as it was calculated, by one histidine residue, one serine residue, two tyrosine residues and one phenylalanine residue. Allosteric inhibitors of xanthine oxidase are corticosteroids, polychlorinated biphenyls and polychlordibenzodioxins, which bind to the allosteric center of the enzyme. It is interesting to note that allosteric inhibitors of xanthine oxidase reduce the production of superoxide by the enzyme. On fig. 3 shows the location of 4,9-dichlorodibenzodioxin at the allosteric center of xanthine oxidase.

Substrate specificity of xanthine oxidase and xanthine dehydrogenase

Xanthine oxidase and xanthine dehydrogenase are not strictly specific for hypoxanthine and xanthine and can catalyze the oxidation of about thirty aliphatic and aromatic aldehydes. In addition, both functional forms of the enzyme can oxidize various pterins (2,6-dioxipteridine, etc.) to oxypterins, as well as adenine to 2,8-dioxyadenine. Both functional forms of the enzyme were found to oxidize histidine to 2-oxyhistidine. The mechanism of oxidation is the same as in the case of hypoxanthine and xanthine. The oxygen-dependent form of the enzyme (that is, xanthine oxidase itself) is also known to oxidize cysteine to cysteine sulfinate. Dehydrogenated cysteine captures the hydroxyl associated with molybdenum, turning into cysteine sulfenate, which is oxidized in the presence of H 2 O 2 to cysteine sulfinate. Xanthine oxidase is able to exhibit NAD-diaphorase activity, as well as oxidize nitric oxide (NO) to NO 2 - .

Localization of xanthine oxidase and xanthine dehydrogenase in animal tissues

Xanthine oxidase and xanthine dehydrogenase are present in almost all tissues of the animal body. These two functional forms have the highest specific activity in the liver, in the cytosol of hepatocytes, Kupffer cells and endothelial cells. Almost all uric acid in the body is produced in the liver. After the liver, in terms of the amount of xanthine oxidase (xanthine dehydrogenase), the mucous membrane of the small intestine follows, where the specific activity of the enzyme is an order of magnitude lower than in the liver, and then the kidneys and brain, however, in these organs, the specific activity of xanthine oxidase is quite low. In large quantities, the enzyme is also present in milk, which very often serves as an object for its isolation.

The role of xanthine oxidase as a generator of reactive oxygen species in biochemical processes

In 1991, it was found that an increase in xanthine oxidase activity causes a significant increase in the activity of superoxide dismutase and catalase. IN last years it was found that with an increase in the activity of xanthine oxidase, the activity of glutathione peroxidase increases. Since a large amount of hydrogen peroxide is formed as a result of the xanthine oxidase reaction, such a process is quite possible. At the same time, xanthine oxidase is a powerful superoxide radical generator (for each enzyme monomer there is only 1 FAD molecule and two iron-sulfur centers, and therefore superoxide can be formed in excess), capable of inducing free radical oxidation processes with the formation of organic hydroperoxides. Se-dependent glutathione peroxidase destroys hydroperoxides. In this regard, the activity of glutathione peroxidase can also increase. We found that the induction of sodium xanthine oxidase by molybdate causes the activation of glutathione peroxidase and glutathione reductase, and also reduces the reduction potential of glutathione in the liver of rats. The level of diene conjugates in this case increases significantly, and the content of malondialdehyde practically does not change. Suppression of xanthine oxidase activity in rats by the introduction of a specific inhibitor - sodium tungstate causes the opposite effect - a decrease in the activities of glutathione peroxidase and glutathione reductase, an increase in the reduction potential of glutathione in the liver of animals. The indicators of lipid peroxidation (the amount of diene conjugates and malondialdehyde) are significantly reduced.

As we have already noted, for each xanthine oxidase monomer, there is one FAD molecule that neutralizes superoxide and two iron-sulfur centers that generate it, and therefore this radical can be formed in excess. In addition, superoxide is a precursor to other reactive oxygen species, the hydroxyl radical and hydrogen peroxide. It has been established that an increase in the amount of reactive oxygen species not only induces the processes of free radical lipid peroxidation, but also causes DNA damage, which is accompanied by the occurrence of point mutations. There is strong evidence that damage to DNA by reactive oxygen species generated by xanthine oxidase leads to the transformation of a normal cell into a cancer cell. It has also been established that the induction of xanthine oxidase activity proceeds in almost all cases simultaneously with the induction of nitric oxide synthase activity due to the activation of the expression of the genes of its inducible isoform. Nitric oxide synthase (NO-synthase, NOS - nitric oxide synthase, EC 1.14.13.19) catalyzes the formation of NO and citrulline from arginine and O 2 through N-oxyarginine. The enzyme uses NADH+H+ as an electron donor. NOS in animals is represented by three isoforms - inducible (iNOS) and two constitutive - endothelial (eNOS) and neuronal (nNOS). All three isoforms consist of homodimers, including reductase, oxygenase, and calmodulin-binding domains, have a similar mechanism of action, but differ molecular weight. The manifestation of the catalytic activity of NOS requires cofactors - calmodulin, Ca 2+ , (6R) - 5, 6, 7, 8-tetrahydro-L-biopterin, FAD and FMN. The function of the catalytic center is performed by thiol-bound heme. It has been established that xanthine oxidase and inducible nitric oxide synthase have basically common inductors, such as, for example, interferon, which equally induces the activity of xanthine oxidase and NO-synthase. It has been shown that superoxide readily reacts with NO to form poisonous peroxynitrite (ONOO -). Peroxynitrite damages DNA even more actively than superoxide, and in addition, cell membranes of vessel walls, thus facilitating the penetration of cancer cells through them.

Superoxide, NO, and peroxynitrite are heme ligands and therefore easily inhibit the activity of all cytochrome P450 isoforms. In addition, these compounds suppress the expression of genes encoding any cytochrome P450 isoform.

Superoxide generated by xanthine oxidase, as well as NO, but not peroxynitrite, at high concentrations, are inducers of apoptosis (genetically programmed death) of cells. It is precisely because of the formation of peroxynitrite during the interaction of superoxide and NO that the simultaneous induction of xanthine oxidase and nitric oxide synthase in cancer cells prevents their death by the mechanism of apoptosis. Superoxide or NO (but not peroxynitrite) interact with thioredoxin, releasing the associated threonine/tyrosine protein kinase ASK-1 (Apoptotic signal regulating kinase 1), which is responsible for activating the expression of the gene encoding the p53 protein, the main apoptogenic protein. This protein prevents the possibility of mitotic cell division by suppressing the activity of the mitogenic factor MPF. MPF consists of cyclin A, which binds to the tyrosine protein kinase p33cdk2. The cyclin A-p33cdk2 complex, in turn, binds to the transcription factor E2F and phosphorylates the p107Rb protein. Binding of these four proteins at the promoter regions activates the genes required for DNA replication. The protein, firstly, inhibits the phosphorylation of the p107Rb protein, a member of the mitogenic factor MPF, and, secondly, causes the synthesis of the p21 protein, an inhibitor of cyclin-dependent tyrosine kinases.

The protein, p53, removes the calcium barrier and Ca 2+ ions penetrate into the cell in large quantities, where they activate the Ca 2+ -dependent endonuclease that cleaves DNA, as well as calcium-dependent proteinases - calpains I and II. Calpains I and II activate protein kinase C, cleaving a peptide fragment from it that inhibits the activity of this enzyme, and also cleave cytoskeletal proteins. At this stage, p53 also activates the biosynthesis of cysteine proteinases - caspases. Caspases (caspase - cysteine proteinases that cleave proteins at aspartic acid residues) cleave poly-(ADP-ribose) polymerase (PARP), which synthesizes poly-ADP-ribose from NAD +. Poly-ADP-ribosylation of class 1H histone chromatin proteins during DNA fragmentation stimulates repair and prevents further DNA fragmentation. The main substrate for caspases are interleukins 1b-IL. In addition, it was found that caspase-3, through limited proteolysis, activates a specific DNase, which fragments DNA into high-molecular fragments. During apoptosis, at the same stage, activation of serine proteinases - granzyme A and granzyme B, cleaving histone and non-histone chromatin proteins, as well as nuclear matrix proteins and other nuclear proteinases of unknown nature, cleaving histone proteins and DNA - topoisomerases, is observed. The activation of these proteinases is thought to be mediated by p53. Thus, the DNA is fragmented, and the vital proteins of the cell are destroyed and the cell dies. The process of apoptosis is completed in 3-12 hours.

In addition, it was found that superoxide generated by xanthine oxidase causes depolarization of mitochondria, releasing cytochrome c from them, which binds to the Apaf-1 protein (Apoptotic protease activating factor) and caspase 9. This complex activates caspase 3, which in turn activates caspases 6, 7, the role of which in apoptosis was described above.

It has been shown that culturing cells under conditions of oxidative stress caused by xanthine oxidase (created by the introduction of a highly purified preparation of xanthine oxidase and xanthine into the culture), accumulation of the apoptogenic p53 protein occurs and cells die by the apoptosis mechanism. Activation of NO formation under these conditions inhibits gene expression and, accordingly, p53 protein synthesis, as a result of which cells do not die. It has been proven that this effect is caused by the formation of peroxynitrite during the interaction of superoxide and NO. That is, peroxynitrite has a cytoprotective effect in this case.

At present, the mechanisms of induction of carcinogenesis, as well as apoptosis with the participation of reactive oxygen species generated by xanthine oxidase, remain poorly understood. However, there is no doubt that xanthine oxidase, one of the most important enzymes in living organisms, is the main system for generating reactive oxygen species.

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Xanthine oxidase [xanthine: oxygen oxidoreductase; CF 1.2.3.2; syn.: hypoxanthine oxidase, aldehyderase, Shardinger enzyme, xanthine (and aldehyde) -> O 2 transhydrogenase] - an enzyme catalyzing the oxidation of xanthine, hypoxanthine and aldehydes with the absorption of oxygen and the formation, respectively, of uric acid, xanthine or carboxylic acids and superoxide radicals O 2 2-. To. is the important enzyme of an exchange of purines catalyzing the reaction completing formation uric to - you in an organism of animals and the person (see. Purine bases ). In the reactions catalyzed by K., superoxide radicals are formed, which are used in the processes of peroxidation of unsaturated fatty acids and in the detoxification of foreign compounds in normal conditions and in patol, conditions.

With a genetically determined congenital defect K. and a violation of xanthine reabsorption in the renal tubules, a disease called xanthinuria develops. It is characterized by the excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones; while the content of uric acid (see) in the blood serum (normal 2.0-5.0 mg%) and urine (normal 0.4-1.0 g per day) is sharply reduced. There is evidence that K.'s genetic deficiency is inherited in a recessive manner.

K. is widespread in nature. Highly purified preparations K. are obtained from milk, from the liver of mammals and birds. To. meets also at microorganisms. Mol. weight (mass) K. - approx. 300,000. The K. molecule consists of two subunits, they say. the weight (mass) of each of which is approx. 150,000. As prosthetic components, the K. molecule contains two FAD molecules and two molybdenum atoms, 8 atoms of non-heme iron and 8 atoms of acid-labile sulfur. K. has a wide substrate specificity, it has the ability to oxidize not only xanthine (see), but also various derivatives of purines, pyrimidines, pteridines, various aldehydes, while reducing not only oxygen, but also many other electron acceptors (tetrazolium salts, derivatives indophenol, methylene blue). It is believed that the dehydrogenase (reductase) form of the enzyme, which has the ability to restore NAD in the process of xanthine oxidation, predominates in mammalian tissues. During isolation and purification, the enzyme is usually transformed into the oxidase form. There are two types of transformation K.: reversible (initiated by the oxidation of the SH groups of the enzyme, their mercaptiation, the formation of mixed disulfides) and irreversible (initiated by partial proteolysis of the enzyme or alkylation of its SH groups). Commercial preparations To. are already transformed; they do not have dehydrogenase activity.

Methods of measurement of activity To. are usually based on registration of formation uric to - you on increase in optical density of solution at 295 nanometers at xanthine oxidation in the presence of O 2 .

Bibliography: Gorkin V. 3. Transformation of enzymes, Molecular biol., t. 4, p. 717, 1976, bibliogr.; Makkyusik V. A. Hereditary traits of a person, trans. from English, p. 432, M., 1976; The enzymes, ed. by P. D. Boyer, v. 10, N. Y., 1971; W a u d W. R. a. R a j a g o p a-1 a n K. V. The mechanism of conversion of rat liver xanthine dehydrogenase from an NAD+-dependent form (type D) to an 02-dependent form (type O), Arch. Biochem., v. 172, p. 365, 1976.

A 54-year-old man came for a routine consultation due to high blood pressure (BP). At the time of examination, blood pressure was 142/90 mm Hg. Art., pulse - 72 beats / min. Laboratory tests showed normal kidney tests and a uric acid (UA) level of 9.2 mg/dL. Will this indicator influence your decision on examination and treatment?

The role of xanthine metabolism disorders and elevated UA levels in the pathogenesis of cardiovascular diseases (CVD), as well as promising direction their prevention by prescribing urate-lowering therapy was discussed by Ukrainian specialists in the framework of the scientific and practical conference "Medical and social problems of arterial hypertension in Ukraine" (May 24-26, Kiev).

Chief Researcher, State Institution “NSC “Institute of Cardiology named after N.N. N.D. Strazhesko "NAMS of Ukraine" (Kyiv), doctor of medical sciences, professor Elena Gennadievna Nesukai characterized hyperuricemia as a risk factor for diseases of the cardiovascular system. Hyperuricemia is defined as an increase in plasma UA levels >408 µmol/L (6.8 mg/dL) due to an increase in UA formation, a decrease in UA excretion, or a combination of these processes. When this limit is overcome, the deposition of sodium monourate crystals in the soft tissues around the joints begins, which sooner or later leads to the development of clinically manifest gout. The prevalence of gout and clinically significant hyperuricemia increases with age: from 2-3% in the group of patients younger than 45 years to 40% among those older than 75 years (Wallace S. et al., 2004). However, even asymptomatic hyperuricemia increases the risk of CVD and metabolic disorders. The number of publications on the association of MC with cardiovascular outcomes has increased almost 4-fold over the past 20 years. Arterial hypertension (AH), kidney disease, metabolic syndrome (MS), atherosclerosis, coronary heart disease (CHD), stroke, and vascular dementia are associated with elevated UA levels.

According to numerous epidemiological studies, an increase in the level of sUA was detected in 25-60% of patients with untreated essential hypertension and in approximately 90% of patients with newly developed hypertension (Feig D.J. et al., 2008). According to the US National Health and Nutrition Survey (NHANES, 1999-2006), it was found that when the UA concentration threshold of 5.5 mg / dl is exceeded, the probability of detecting high blood pressure in American adolescents increases by 2 times (Loeffler LF et al., 2012) . Moreover, another study showed that elevated UA in childhood is a predictor of elevated BP in adulthood (Alper A.B. et al., 2005).

An experimental increase in the level of UA in rodents leads to clinical, hemodynamic and histological changes characteristic of hypertension, and treatment with xanthine oxidase inhibitors contributes to the normalization of blood pressure (Sanchez-Lozada L.G. et al., 2008). Among men and women with hypertension, the overall mortality rate increases in proportion to the level of serum sUA, and a more stable pattern is observed in men (Dawson J. et al., 2013). Also shown is a correlation between hyperuricemia and subclinical renal dysfunction in the form of microalbuminuria and changes in the renal arteries according to Doppler ultrasound (Viazzi F. et al., 2007).

Multivariate analysis of the relationship between hyperuricemia and the frequency of cardiovascular events in the population, according to the Brisighella Heart Study, confirmed a significant increase in the absolute frequency of all adverse events depending on the serum concentration of UA (Fig. 1).

The association of serum UA levels with cardiovascular mortality in the general US population was also confirmed in the NHANES-III study (1988-1994), and the prognosis worsened when the level of UA exceeded 6 mg / dl, regardless of the presence or absence of clinical manifestations of gout. In the next phase of the NHANES study (1999-2008), a proportional relationship between the level of sUA and the incidence of comorbid conditions - chronic kidney disease, hypertension and obesity was demonstrated (Fig. 2).

According to E. Krishnan et al. (2011), hyperuricemia is an independent risk factor for the development of subclinical atherosclerosis in young people. Korean authors studied the effect of hyperuricemia on two-year clinical outcomes in patients after percutaneous coronary interventions with implantation of covered stents (Rha S. -W. et al.). Of the 1812 patients included in the study, 376 had confirmed hyperuricemia (>6 mg/dl for women and >7 mg/dl for men). According to the results of multivariate analysis, initially elevated sUA levels were an independent predictor of cardiac death and Q-myocardial infarction. Thus, hyperuricemia may play an important role in predicting long-term clinical outcomes in patients after PCI.

At the congress of the European Society of Cardiology in 2016, the results of another Korean study (Rha S. -W. , Choi BG, Choi SY) were presented, which showed the association of hyperuricemia with an increase in the risk of developing diabetes mellitus (DM) by 72% in 5 year term.

The definition of hyperuricemia as an independent risk factor for CVD, and not just as a laboratory marker, has already been included in some expert recommendations. Thus, in the recommendations of the American Association of Endocrinologists and the American College of Endocrinology (2017) for the management of patients with dyslipidemia and the prevention of CVD, a high level of sUA is attributed to non-traditional risk factors. The expert consensus of the American College of Thoracic Physicians and the American Heart Association on Hypertension in the Elderly (2011) indicates that β-serum UA is an independent predictor of cardiovascular events in elderly patients with AH.

The European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) guidelines state that the therapeutic goal in patients with gout - and -hyperuricemia - is to achieve serum UA<6,0 мг/дл. Для реализации этой цели в качестве терапии первой линии рекомендованы ингибиторы ксантиноксидазы - ключевого фермента синтеза МК в цикле пуринового обмена.

For many years, allopurinol was the only xanthine oxidase inhibitor used in clinical practice. Today it is being replaced in many countries by febuxostat, a more potent non-purine selective xanthine oxidase inhibitor with a better safety and tolerability profile. Febuxostat inhibits both reduced and oxidized forms of xanthine oxidase, while allopurinol inhibits only the reduced form, which explains the more pronounced urate-lowering effect of febuxostat. Due to the presence of two routes of excretion from the body (metabolization in the liver and filtration by the kidneys), there is no need to adjust the dose of febuxostat in elderly patients, as well as in people with mild to moderate renal insufficiency. In Ukraine, febuxostat is available under the name Adenuric.

Febuxostat is included in the EULAR, ACR, and many national consensus guidelines for the treatment of gout and hyperuricemia based on the results of randomized controlled trials, which demonstrated that febuxostat was superior to allopurinol in achieving sUA targets (Fig. 3).

As a result of clinical studies, the following advantages of febuxostat were identified:

Better efficacy than allopurinol in patients with impaired renal function (CONFIRMS study, Becker M. et al., 2010);

Sustained maintenance of the level of MK<6,0 мг/дл (360 мкмоль/л) при длительной терапии в течение 5 лет (исследование FOCUS, Schumacher H. et al., 2009);

Excellent tolerability, side effect rate comparable to placebo (APEX study, Schumacher H. et al., 2008).

Does urate-lowering therapy in patients with gout or hyperuricemia affect comorbid CVD outcomes? This question has yet to be answered in new studies, but some data have already been obtained that allow us to associate a decrease in the level of sUA with a positive effect on the pathogenetic mechanisms of cardiac remodeling.

In 2015, the results of a Japanese study evaluating the effects of febuxostat and allopurinol on systemic inflammatory response and cardiac function in patients with chronic heart failure (CHF) and hyperuricemia were published (Nakagomi A. et al., 2015). Inflammation associated with endothelial dysfunction may play a critical role in the pathogenesis and progression of CHF. It has been previously shown that febuxostat and allopurinol lower UA levels and suppress the expression of the monocyte chemoattractant protein (MCP-1) inflammatory marker, which is involved in the pathogenesis and progression of HF as a mediator of myocardial dysfunction and remodeling (Baldwin W. et al., 2011; Nomura J. et al., 2013). These data served as a prerequisite for comparing the effects of these hypouricemic drugs in patients with CHF.

Thus, 61 patients with hyperuricemia and an average left ventricular ejection fraction (LVEF) of 37.1±6.7% were randomized to receive febuxostat or allopurinol in addition to the basic therapy for CHF. After 12 months, the febuxostat group achieved a significantly greater decrease in UA and MCP‑1 levels compared to baseline than the allopurinol group. Within 12 months, LV EF increased in both groups, but a more significant increase was observed in patients taking febuxostat. The percentage increase in LV EF significantly correlated with a decrease in MCP‑1 (r=-0.634; p<0,001) в группе фебуксостата.

Thus, febuxostat is more effective than allopurinol in lowering UA and reducing inflammation, and may improve cardiac function in patients with CHF and hyperuricemia, at least in part by suppressing inflammation.

A convenient algorithm for choosing the tactics of managing patients with hyperuricemia was proposed in 2012 by Japanese researchers (Fig. 4). The decision to prescribe drug therapy to patients with hyperuricemia, but without a gout clinic, is made on the basis of the presence of complications and comorbid diseases, such as kidney damage, hypertension, coronary artery disease, and diabetes.

On the basis of the considered materials, practical conclusions can be drawn.

1. Hyperuricemia is an independent risk factor for CVD and kidney disease at serum UA >6 mg/dL.

2. Determination of the serum UA level should be considered as an analysis for routine screening of patients with hypertension.

3. The therapeutic goal in patients with hyperuricemia should be to reduce and maintain the level of sUA<6 мг/дл.

4. Febuxostat (Adenuric) is more effective than allopurinol in lowering serum UA levels, making it the drug of first choice for the treatment of hyperuricemia and comorbidities.

Head of the Department of Therapy and Nephrology of the Kharkiv Medical Academy of Postgraduate Education, Doctor of Medical Sciences, Professor Alexander Viktorovich Bilchenko commented in more detail on the mechanisms of the effect of hyperuricemia on cardiovascular outcomes and presented the concept of xanthine oxidase inhibition as a promising direction in the prevention of CVD.

The paradox of MK is that normally this molecule is a product of antioxidant reactions, but under conditions of ischemia and systemic inflammation it becomes a marker of oxidative stress and endothelial dysfunction, which are associated with the pathogenesis of CVD. Metabolism of xanthines with the formation of UA is carried out in two ways - xanthine dehydrogenase (reduction reactions, antioxidant effect) or xanthine oxidase (oxidative). In the reactions of the second pathway, the same final product, UA, is formed from xanthine and hypoxanthine, however, a large amount of free oxygen radicals is formed as a side result (Fig. 5). The enzyme xanthine oxidase is activated during ischemia and inflammation, so hyperuricemia is more common in patients with hypertension and CVD than in the general population. An increase in the level of UA in blood plasma due to a slowdown in its excretion from the body is not as important as a risk factor for CVD as an increase in its synthesis as a result of activation of xanthine oxidase.

To date, evidence that elevated sUA levels are associated with CVD and adverse outcomes is no longer discussed. This has been shown in numerous studies in Asian and European populations (Fang J., Alderman M.N., 2000; Niskanen L.K. et al., 2004; Ioachimescu A.G. et al., 2008; Chien K.L., 2005). Currently, researchers are interested in how the negative effects of xanthine metabolism disorders are realized and how they can be influenced.

Of the possible mechanisms for the development of CVD in individuals with hyperuricemia, interactions with other risk factors, urate deposition in the vessels, genetic mechanisms, kidney damage, and oxidative stress are being studied. In population and cohort studies, a linear dependence of BP and abdominal obesity on the level of UA has been confirmed (Borghi C. et al., 2013). As a result of xanthine oxidase activation and oxidative stress, endothelial dysfunction develops and a cascade of events occurs that contribute to the maintenance of elevated blood pressure and atherogenesis processes. On the other hand, an increase in blood pressure is promoted by activation of the renin-angiotensin system (RAS) under the influence of an excess of sUA and increased sodium reabsorption in the kidneys.

The classic SHEP study showed for the first time how hyperuricemia affects outcomes in patients with hypertension: 4327 patients over 60 years of age with isolated systolic hypertension received chlorthalidone or placebo therapy for 5 years. It turned out that in those participants in whom the level of UA increased after the appointment of a diuretic, cardiovascular events occurred almost 2 times more often than in those with normal values of UA. This should be kept in mind when choosing therapy for hypertension in patients with initially elevated sUA levels.

The uniqueness of the Italian PIUMA study is that it showed a J-shaped dependence of outcomes on the level of sUA. In patients with mild and moderate hypertension, the frequency of cardiovascular events and overall mortality increased not only with hyperuricemia, but also with low values of UA concentration (<268 мкмоль/л).

Another category of patients in whom the significance of MC has been well studied is patients with MS. Hyperuricemia was included in the first criteria for diagnosing MS. Several mechanisms have been described for increasing the level of sUA in abdominal obesity through the mediation of pro-inflammatory cytokines (tumor necrosis factor, interleukin-6) and other humoral factors (leptin, adiponectin). On the other hand, the role of oxidative stress in the pathogenesis of MS, which is enhanced by activation of the oxidase pathway of UA synthesis, has been proven.

Also proven is the role of hyperuricemia in kidney damage. Decreased renal function is one of the cardiovascular risk factors. This is especially true for patients with MS and DM. In one of the recent studies on this issue, patients with type 2 diabetes and the fifth quintile of sUA levels, compared with the first quintile, had a 2.6-fold increase in the risk of developing renal failure (de Cosmo S. et al., 2015).

It should be noted that oxidative stress, which accompanies excessive synthesis of UA by the oxidase pathway, is a universal factor in the increase in blood pressure, kidney damage, and the development of MS. Therefore, not so much UA itself as xanthine oxidase activity can serve as a marker of cardiovascular risk, which will be taken into account when planning further studies.

At the European Congress on Heart Failure in 2016, we reported the results of our own study, in which we studied xanthine metabolism in CHF patients with reduced EF and concomitant chronic renal failure (Bilchenko AV European Journal of Heart Failure, 2016; 18 (Suppl. 1) : P1492). Not only the level of UA in blood plasma was determined, but also the activity of xanthine oxidase. A significant increase in the level of UA and xanthine oxidase activity was shown in patients with functional class III (FC) HF (Fig. 6). A strong relationship has been established between β-xanthine oxidase activity and a decrease in glomerular filtration rate (GFR) in patients with renal insufficiency.

In recent years, the metabolic and cardiovascular effects of drug correction of asymptomatic hyperuricemia have been actively studied. There are two different approaches to controlling xanthine metabolism. Drugs belonging to different pharmacological groups have a uricosuric effect, facilitating the excretion of UA by the kidneys. These include certain antihypertensive agents (losartan, calcium antagonists), lipid-lowering agents (fenofibrate, atorvastatin), and gout medications (probenecid, benzbromarone). Experts agree that hyperuricemia alone is not an indication for initiation of uricosuric therapy. Additional indications are needed: hypertension (losartan), atherosclerosis, ischemic heart disease (statins), gout (probenecid, benzbromarone).

A more promising direction is the inhibition of xanthine oxidase. Two inhibitors are currently available in Ukraine, the classic allopurinol and febuxostat (Adenuric). Two cohort studies published in 2016 showed a positive effect of allopurinol on the incidence of cardiovascular events in patients with hyperuricemia (Larsen K.S. et al., 2016) and hypertension (MacIsaac R.L. et al., 2016). In an editorial with comments on the studies, European experts C. Borghi and G. Desideri (Hypertension, 2016; 67: 496-498) raise two questions: is xanthine oxidase inhibition a new therapeutic strategy in reducing cardiovascular mortality and what is the role of the degree of xanthine oxidase inhibition in reducing cardiovascular mortality?

The second question is directly related to the differences between the two most available xanthine oxidase inhibitors. Adenuric (febuxostat) is superior to allopurinol in the effectiveness of xanthine oxidase inhibition, since it affects both of its forms - oxidized and reduced, in different proportions presented in body tissues. Accordingly, the proportion of patients who achieve the target level of sUA is higher when using febuxostat, which was confirmed by comparative studies and a recent meta-analysis (Borghi C., Perez-Ruiz F., 2016).

It has been shown that optimal UA control on febuxostat therapy is accompanied by an anti-atherosclerotic effect (Nomura J. et al., 2014), as well as a positive effect on a number of lipid metabolism and hemodynamic parameters. In particular, these effects were studied in detail in cardiac surgery patients in the NU-FLASH study (Sezai A. et al., 2013). Patients with baseline hyperuricemia undergoing cardiac surgery were randomized to either febuxostat or allopurinol. After 1 month, the level of sUA was significantly lower in the febuxostat group. Plasma creatinine, urinary albumin, cystatin-C, and oxidized low-density lipoprotein were also significantly lower in the febuxostat group compared to the allopurinol group. Systolic BP, pulse wave velocity, and LV mass index remained virtually unchanged in the allopurinol group, but significantly decreased in patients who took febuxostat. Thus, febuxostat demonstrated superiority in reducing UA levels and a significant effect on markers of cardiovascular risk in patients undergoing cardiac surgery. The authors concluded that febuxostat suppresses oxidative stress, has a renoprotective, antiatherogenic effect, reduces blood pressure, blood vessel and heart remodeling indicators.

In a 6-month prospective randomized study, in which patients with hypertension and hyperuricemia were selected to participate, it was shown that a decrease in the level of sUA while taking febuxostat was accompanied by inhibition of the RAS and an improvement in kidney function (Tani S. et al., 2015). In the febuxostat group, a decrease in plasma renin activity was achieved by 33% (p=0.0012), aldosterone concentration - by 14% (p=0.001), UA by 29% (p<0,0001). СКФ достоверно увеличилась на 5,5% (p=0,001). В контрольной группе таких изменений не наблюдалось. Снижение уровня МК под влиянием фебуксостата достоверно коррелировало со снижением активности компонентов РАС, креатинина плазмы, а также с повышением СКФ. Эти данные поддерживают гипотезу о том, что фебуксостат подавляет РАС и улучшает функцию почек у гипертензивных пациентов с гиперурикемией, и это может иметь значение в профилактике ССЗ.

So, febuxostat (Adenuric) is now considered not only as an effective treatment for gout, but also as a cardio- and renoprotective drug with great potential to improve cardiovascular outcomes. Febuxostat provides reliable control of hyperuricemia, including in patients with hypertension, a vascular protective effect, elimination of metabolic disorders, cardio-, renoprotection and, possibly, in the near future will take its place in a strategy to reduce the risk of cardiovascular events and death.

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