8144 0
Allopurinol
Xanthine oxidase inhibitors
Table 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 xanthines in plasma does not disrupt the normal metabolism of nucleic acids; precipitation and precipitation of xanthines in plasma does not occur (high solubility). The renal clearance of xanthines is 10 times higher than the clearance of uric acid; increased urinary excretion of xanthines is not accompanied by an increased risk of nephrolithiasis.
Pharmacokinetics
Absorbed after a single oral dose of 300 mg is 80-90%. Passes into breast milk. In the liver, about 70% of the dose is metabolized into 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 of oxypurinol - 12-30 hours (on 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 unchanged through the intestines; kidneys - 10% allopurinol, 70% oxypurinol. Hemodialysis is effective.Indications
■ Gout (primary and secondary), which occurs in diseases accompanied by increased breakdown of nucleoproteins and increased uric acid in the blood, incl. for 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 enzyme disorders (Lesch-Nychen syndrome).■ Purine metabolism disorders in children.
■ Uric acid nephropathy with impaired renal function (renal failure).
■ Recurrent mixed oxalate-calcium kidney stones (if uricosuria is present).
Contraindications
■ Hypersensitivity■ Liver failure.
■ Chronic renal failure (azotemia stage).
■ Primary (idiopathic) hemochromatosis.
■ Asymptomatic hyperuricemia.
■ Acute attack of gout.
■ Pregnancy.
■ Breastfeeding.
Cautions
Therapy should not be started until the acute attack of gout has completely resolved.During treatment, daily diuresis of at least 2 liters should be ensured, and urine pH should be maintained at a neutral or slightly alkaline level.
It must be taken into account that with adequate therapy, it is possible for large urate stones to dissolve in the renal pelvis and enter the ureter (renal colic).
If an acute attack of gout develops, it is necessary to additionally prescribe anti-inflammatory drugs (during the first month of treatment, prophylactic use of NSAIDs or colchicine is recommended).
If renal and liver function is impaired (increased risk of side effects), it is necessary to reduce the dose of allopurinol.
Combine with vidarabine with caution.
Children are prescribed only for malignant neoplasms and congenital disorders of purine metabolism.
Prescribe with caution:
■ in case of renal failure;
■ chronic heart failure;
■ patients with diabetes mellitus;
■ patients with arterial hypertension.
Interactions
Side effects
■ Allergic reactions - skin rash, itching, 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 levels (in patients with initially reduced renal function), peripheral edema, hematuria, proteinuria, impotence, infertility, gynecomastia.
■ Hematopoietic system - agranulocytosis, anemia, aplastic anemia, thrombocytopenia, eosinophilia, leukocytosis, leukopenia.
■ Musculoskeletal system - myopathies, myalgia, arthralgia.
■ Sense organs—perversion of taste, loss taste sensations, visual impairment, cataracts, conjunctivitis, amblyopia.
■ Other reactions - furunculosis, alopecia, diabetes mellitus, dehydration, nosebleeds, necrotizing tonsillitis, lymphadenopathy, hyperthermia, hyperlipidemia.
Directions for use and doses
Orally 0.1 - 0.2 g 1-2 times a dayMaximum 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-EgisYu.B. Belousov
Dear Colleagues!
On the certificate of the seminar participant, which will be generated if you successfully complete test task, the calendar date of your online participation in the seminar will be indicated.
Seminar "GOUT: STATE 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 monosodium urate (MSU) crystals in various tissues, which is manifested by crystal-induced inflammation in the sites of urate fixation (joints, periarticular tissues, internal organs).
Epidemiology
The prevalence of gout in Europe is 1-2% in adults and 6% in people over 50 years of age. The incidence of gout in a number of regions of Ukraine is 400 per 100,000 adults. In the last two to three decades there has been a clear increase in its prevalence. Men suffer from gout much more often (according to various sources, the male:f ratio ranges 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 years is equivalent.
The peak incidence is observed 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 considered hyperuricemia. The formation of EOR crystals and their deposition in tissue occurs when the blood serum is supersaturated with urates (i.e., when the uric acid level 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% in men over 75 years of age. Premenopausal women rarely develop gout, but in those aged 75 years and older, the prevalence of gout reaches 2.5–3%.
Late development of gout in women may be associated with the uricosuric effects of estrogens.
The risk of developing gout increases by 4 times with obesity compared with individuals with a body mass index of 21–25 kg/m2.
Excessive daily consumption of meat increases the risk of developing gout by 20%.
In individuals who drink >50 g of alcohol daily, the incidence of gout is 2.5 times higher than in those who do not drink alcohol.
The use of medications (usually diuretics) is associated with increased serum urate levels. However, a number of studies have questioned this association, and the increase in uric acid values in people with arterial hypertension (HTN) and heart failure (HF) receiving diuretics is associated with the unfavorable effect of hypertension and HF on purine metabolism. The features of the mechanisms of renal excretion of urate when using various diuretics are ambiguous. The risk of hyperuricemia and gout is higher when using more potent loop diuretics than less potent thiazide diuretics.
Cyclosporine, acetylsalicylic acid and salicylates reduce urate excretion and contribute to the development of hyperuricemia. Metabolic syndrome, hypertension and heart failure also lead to the development of hyperuricemia.
Pathogenesis
For EOR crystals to form, there must be a high level of uric acid in the blood serum. Normally, a stable level of uric acid in the blood is the result of a balance between its production and excretion. Hyperuricemia develops with increased production of uric acid and/or impaired excretion (mainly renal). Urates are the end product of the metabolism of purine nucleotides, 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 are 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 impaired renal excretion of urate.
Hyperuricemia is the leading basic pathogenetic mechanism of gout and the main risk factor for its development.
The incidence of gout depending on the level of uric acid in the blood serum is shown below (Table 1).
The development of gouty inflammation is due to the complex influence of various cell types on the deposition of MUN crystals in the joints, which causes an imbalance between the synthesis of pro-inflammatory and anti-inflammatory substances.
The main mechanism of 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. 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, their pronounced infiltration of 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 (in particular, transforming growth factor) by urates.
Histopathology
Deposition of EOR crystals occurs in cartilage, tendons, synovial fluid, and subcutaneous tissue. Avascularity of connective tissue (especially cartilage) is considered 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 consisting of mono- and multinuclear macrophages surrounding deposits of MUN crystals. Tophi have several zones, including a central zone, 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 compartment of MUN crystal deposits from the surrounding fibrovascular zone.
The granulomatous process in 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. Presence of 6 of the 12 signs listed below:
History of more than one attack of acute arthritis;
Maximum joint inflammation on the first day of illness;
Monoarthritis;
Hyperemia of the skin over the affected area;
Swelling, pain in the first metatarsophalangeal joint;
Unilateral damage to the first metatarsophalangeal joint;
Unilateral damage to the joints of the foot;
Suspicion of tophi;
Hyperuricemia;
Asymmetric joint swelling;
Subcortical cysts without erosions;
Negative results on synovial fluid culture.
The diagnosis of gout is considered definitive when the presence of MUN crystals in synovial fluid or tophi is confirmed by polarizing microscopy. The presence of 6 of the 12 clinical manifestations listed above allows one to strongly suspect gout.
Clinical classification of gout
I. Clinical stages:
a) acute gouty arthritis;
b) interictal (interval) gout;
c) chronic gouty arthritis:
Exacerbation;
Remission;
d) chronic tophi arthritis.
II. Periods:
a) premorbid (preclinical);
b) intermittent (acutely recurrent);
c) chronic.
III. Flow options:
a) lung;
b) moderate;
c) heavy.
IV. Phase:
a) exacerbation (active);
b) remission (inactive).
V. X-ray stages of joint damage:
I - large cysts (tophi) in the subchondral bone and in deeper layers, sometimes compaction 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 erosions on at least 1/3 of the articular surface, osteolysis of the epiphysis, significant compaction of soft tissues with lime deposits.
VI. Peripheral tophi and their localization:
a) are available;
b) are absent.
VII. Degree of functional impairment:
0 - functional ability is completely preserved;
I - professional ability retained;
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 the sudden onset and rapid increase in intense pain, usually in one joint, swelling, redness of the skin over it and dysfunction. The attack most 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 complete recovery with the absence of any symptoms after the attack. Among the provoking factors of an acute attack are trauma, large amounts of meat food (especially in combination with alcohol), surgical interventions, and taking diuretics. The first attack of gout often involves the first metatarsophalangeal joint of the foot.
Most patients develop repeated attacks of gout, which subsequently become more frequent, asymptomatic periods shorten, and arthritis becomes prolonged. In the absence of adequate therapy (and often despite its implementation), 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 tenosynovitis and bursitis. They experience mild episodes of joint discomfort for a few days without swelling. In 10% of atypical attacks, multiple joints are affected (sometimes of a migratory nature). In this case, systemic manifestations of gout (weakness, fever) predominate.
Interictal periods
Between attacks in the initial stages of gout, there are asymptomatic periods (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 MUN crystals, many joints are affected, and the pain syndrome is chronic. The time from the first joint attack to the 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. Nodes of various shapes form mainly around the extensor surfaces of the forearms, on the elbows, ears, and in the area of the Achilles tendons. Tophi are asymmetrical in location and vary in size. In some cases, tophi can reach large sizes and ulcerate with the release of a crumbly white mass; cases of local inflammation (presence of erythema, pus) are possible. Tophi can be localized on the eyelids, tongue, larynx or in the heart (causing conduction disturbances and dysfunction of the valve apparatus).
Chronic tophi gout is characterized by progressive joint damage (restriction of movement, deformation) 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 a chronic course, attacks of gouty arthritis are more mild. 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 types of kidney damage, which can present either independently 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 10–20% of patients have oxalates or calcium phosphate in their 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 type of kidney damage is associated with a high risk of developing renal failure (RF).
Clinical and laboratory characteristics of patients with gout (expert recommendations EULAR )
1. Acute attacks rapidly develop severe joint(s) pain, swelling, marked erythema, and tenderness, peaking within 6 to 12 hours, with marked erythema fairly strongly suggestive of crystalline inflammation (although not specific for gout). ).
Thus, the classic clinical picture is a good marker of an acute attack of gout. However, for a final diagnosis, along with the above symptoms, it is necessary to identify MUN 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 aspirate of tophi, along with clinical manifestations, makes it possible to definitely establish the diagnosis of gout.
4. Thus, identification of MUN crystals is a decisive marker in the diagnosis of symptomatic gout. Examination of synovial fluid for the presence of MUN crystals should be carried out in all inflammatory arthritis, because In some cases, gout may have an atypical course.
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, then 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 exclude the presence of gout, since many individuals with hyperuricemia do not develop gout, and during acute gout attacks, serum uric acid levels may be normal.
8. In a number of patients with gout, determination of uric acid in urine is necessary, especially in cases of family history of onset of gout (onset of gout before 25 years of age) or in the presence of nephrolithiasis.
9. Although X-ray is important in differential diagnosis and can demonstrate typical signs of chronic gout (subcortical cysts without erosions), it is of little information 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 metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, hypertension, as well as HF and PN) in order to provide appropriate therapy.
Differential diagnosis
Gout should be differentiated from sepsis, which can coexist with it, as well as with other crystal-associated synovitis (primarily with the deposition of calcium pyrophosphate - especially in the elderly), reactive, psoriatic and rheumatoid arthritis. Diagnosis of gout requires examination of the synovial fluid for the presence of infection (sepsis) or calcium pyrophosphate crystals (pyrophosphate arthropathy), or MUN crystals (gout).
Treatment tactics
Therapeutic tactics for gout are determined by the characteristics of the clinical picture, the presence of systemic manifestations, lesions internal organs and their heaviness.
Treatment goals for gout include:
The fastest possible elimination of an acute attack of gout;
Prevention of relapses of acute gout attacks;
Preventing or inhibiting 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, consumption large quantity meat food, alcohol, etc.).
Therapeutic tactics for gout include non-drug and drug approaches.
Non-drug approaches:
Patient education (lifestyle changes, dietary regimen, avoidance of alcohol, weight loss for 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; avoidance of analgesics);
Information about prescribed medications (dosages, side effects, interactions with other medications prescribed for concomitant diseases).
Dietary regime
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 excess weight, obesity, and consumption of beer, spirits (alcohol, vodka, etc.), meat, seafood, fructose, and sugar-containing drinks are risk factors for the development of gout and increased serum uric acid levels. blood. Protective factors have also been identified, including reducing excess body weight, consuming low-fat foods, as well as vitamin C and coffee. Other foods are neutral in terms of risk factors for gout (wine, tea, diet drinks, high-fat foods, and high-purine vegetables).
Drug therapy
The nature of drug therapy is determined by 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. Prescription of hypouricemic drugs should be avoided until the attack is stopped due to their ability to prolong the acute attack.
The first-line drugs for the relief of acute gouty arthritis are fast-acting NSAIDs, used in permissibly high therapeutic dosages. When choosing a drug, you should take into account the patient’s risk of side effects (gastrointestinal, cardiovascular, renal, etc.). More often prescribed are 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 not recommended for use in the elderly due to high gastrointestinal, renal and central nervous system risks.
Colchicine has been successfully used for many years to relieve acute gouty arthritis. Treatment with colchicine is more successful when prescribed in the first days and even hours after the development of a gout attack. The clinical effect of colchicine appears more quickly 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 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 may occur in patients with reduced renal function, even when lower doses are used. Therefore, colchicine should be used after determining creatinine levels and glomerular filtration rate.
When colchicine is used intravenously, high toxicity is observed, which makes this route of administration unacceptable. Combination therapy with NSAIDs and colchicine has no advantages over their separate use. The ineffectiveness of NSAIDs, contraindications to their use or intolerance serve as the basis for the use of colchicine.
In acute attacks of gout resistant to NSAIDs or colchicine, the use of glucocorticoids (Gc) is indicated to achieve a good clinical effect. Depending on the clinical characteristics of an acute gouty attack, various ways of using GC are used. For single lesions of large or small joints, a good effect is achieved with intra-articular administration of GC (triamcinolone 40 mg or methylprednisolone 40–80 mg and 5–20 mg triamcinolone or 20–40 mg methylprednisolone, respectively). For 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 administration, prednisolone or methylprednisolone is used in minimal or moderate dosages for several days.
An increase in clinical effect has been reported when combining GC with colchicine. IL-1β plays an important role in the pathogenesis of gout, 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 CRI .
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 gout attacks;
Presence of tophi;
Damage to joints and cartilage;
Concomitant kidney damage
Urate nephrolithiasis;
Increased serum uric acid levels.
Three groups of drugs are used to reduce serum uric acid levels:
Xanthine oxidase inhibitors (allopurinol, febuxostat);
Uricosuric agents (probenecid, sulfinpyrazone, benzbromarone);
Uricose drugs.
Xanthine oxidase inhibitors (allopurinol, febuxostat)
From uricodepressive drugs, i.e. inhibiting the synthesis of uric acid, allopurinol has been used for decades, which is a structural analogue of hypoxanthine that prevents the formation of uric acid due to the inhibition of xanthine oxidase, an enzyme that converts hypoxanthine into 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 effect 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 supplements and warfarin. Treatment is carried out for a long time (indefinitely). For patients with a blood uric acid concentration of less than 450 µmol/L, allopurinol is prescribed at an initial dose of about 150 mg/day or 300 mg every other day. If the blood creatinine level increases to 0.2 mmol/l and oxypurinol to 130 µmol/l, the dose of the drug should be halved, and in patients with creatinine levels more than 0.4 mmol/l and oxypurinolemia over 230 µmol/l, allopurinol is contraindicated.
Side effects of allopurinol are often caused by delayed-type hypersensitivity mechanisms and are characterized by fever, leukocytosis, accelerated ESR, and skin rashes (from maculopapular rash to exfoliative dermatitis).
Some patients treated with allopurinol develop nausea, diarrhea, and increased levels of liver transaminases. Allopurinol is not indicated in the acute period. It is advisable to prescribe it after the cessation of clinical manifestations of acute arthritis; It is recommended to continue taking the drug at a selected dose in the interictal period to prevent gout exacerbations indefinitely. Recently, several studies have 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 nondiabetic nephropathy, and the use of allopurinol, which reduces or normalizes hyperuricemia, is associated with a slower progression of PN.
In addition, the ability of allopurinol (average dose 300 mg/day) to cause regression of left ventricular hypertrophy by reducing afterload, as well as improving endothelial function in patients with chronic kidney disease (stage 3) and the presence of left ventricular hypertrophy, has been demonstrated. During long-term observation (9 months), there was no decrease in renal function in any of the patients.
Febuxostat is a new selective xanthine oxidase inhibitor. It has been shown to achieve greater reductions in blood urate levels than allopurinol in older people with gout or hyperuricemia, according to two controlled randomized trials (CRTs). Febuxostat is not excreted by the kidneys, and therefore can be used in patients with severe PN. This is the fundamental difference between febuxostat and allopurinol. Side effects of febuxostat include arthralgia, myalgia, and diarrhea. The presence of adverse effects of the drug on the cardiovascular system requires clarification.
Uricosuric drugs reduce reabsorption and increase secretion of uric acid in the renal tubules. The mechanism of action of uricosurics determines the limitation of their use in nephrolithiasis type of gouty nephropathy and their complete abandonment in cases of PN. Typically, drugs are prescribed for daily uricuria less than 700 mg. Among them, the most commonly used benzbromarone and similar in composition benziodarone, which have a certain uricodepressive effect. The drugs are usually well tolerated. Some patients experience side effects such as pain in the lumbar region, spine and abdomen, diarrhea, dizziness, and urticaria.
Also widespread probenecid And etamide, although the effectiveness of these drugs 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 used at a dose of 2800 mg/day in courses of 10 days, once a month. Side effects include headache, dizziness, nausea, dermatitis, fever, anemia. Probenecid and etamide enhance the effects of anticoagulants.
In the treatment of gout, it is possible to use a combination of allopurinol with uricosuric drugs. This approach is acceptable in patients with resistance to monotherapy.
When prescribing allopurinol and/or uricosuric drugs, it is necessary to control the urine pH and alkalinize it using 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, alloxanic acid and urea. It is prescribed at 1000–3000 units/day for two weeks. The drug is not contraindicated for urolithiasis. As a side effect, urticaria sometimes develops. Hepatocatalase increases not only the breakdown of uric acid through oxidation, but also its synthesis in the body. This enzyme is administered at a dose of 10,000–20,000 units 2–3 times a week for one month. Treatment courses are repeated quarterly. Hepatocatalase is well tolerated. 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 the soluble form of allantoin. Modified recombinant uricose is an enzyme that lowers uric acid levels by 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 preliminary antihistamine or GC premedication) to prevent acute gout attacks and allergic reactions. Used in patients with chronic gout to reduce serum uric acid levels, 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
For the 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 dissolution of stones consisting of calcium oxalate (under the influence of magnesium and pyridoxine ions). Due to the large amount of sodium and the need to take excess fluid volumes (up to 2 l/day), citrate mixtures are not indicated for patients with poorly controlled hypertension and heart failure.
Arterial hypertension significantly worsens the course of gout and, in particular, gouty nephropathy. I consider the angiotensin II receptor antagonist losartan to be one of the preferred antihypertensive drugs for gout, since it has a uricosuric effect. Losartan increases the excretion of urate by reducing its reabsorption in the proximal tubules of the kidneys. The uricosuric effect also persists when it is combined with diuretics, thereby preventing the increase in uric acid levels in the blood caused by diuretics. Calcium antagonists also have a hypouricemic effect.
EULAR rheumatology experts have developed recommendations for the management of patients with gout, based on the results of numerous CRIs assessing the effectiveness of various treatment approaches for gout.
1. Optimal treatment for gout should include non-drug and drug 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, renal function, taking drugs that increase serum urate levels, drug interactions, comorbidity).
2. Lifestyle changes (patient education): weight loss for obesity, dietary regimen, reducing 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 NSAID agents are first line for acute gout. In the absence of contraindications, NSAIDs are a fairly acceptable choice.
5. High doses of colchicine (initially 1 mg, 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 injection of long-acting GC are effective and safe in acute attacks of the disease, which is especially acceptable in severe monoarticular attacks, 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 GCs is not possible, the administration of systemic GCs is acceptable and effective.
7. Therapy to reduce blood uric acid levels is indicated for patients with repeated acute attacks, arthropathy, tophi or radiographic changes, multiple joint lesions, or urate nephrolithiasis.
8. The goal of urate-lowering therapy is to promote crystal dissolution and prevent crystal 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 to increase crystal dissolution. Serum uric acid levels should be maintained below 360 µcol/L, which is below the saturation point for monosodium urate.
9. Allopurinol is an acceptable drug for long-term therapy to reduce serum urate. Its use should be started at low dosages (100 mg/day) and increased by 100 mg every 2–4 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 may be used as an alternative to allopurinol in patients with normal renal function but are relatively contraindicated in patients with urolithiasis. Benzbromarone can be used in patients with mild to moderate renal impairment, but is associated with a risk of hepatotoxicity.
11. Prevention of relapses of gout exacerbation after the first attack can be achieved by using colchicine (0.5–1.0 g/day) and/or NSAIDs (with gastroduodenal protection, if necessary).
12. If the development of gout is associated with diuretic therapy, if possible, it should be discontinued. For hypertension and hyperlipidemia, the use of 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 cases, nephrolithiasis develops, complicated by secondary pyelonephritis and the development of PN, which is the leading cause of death; the development of PN can also be caused by gouty nephropathy.
Examples of formulation of diagnoses
Acute gouty arthritis, I attack with damage to the first toe, X-ray stage 0, SFS III.
Chronic gouty arthritis, polyarthritis, exacerbation with damage to the joints of the foot, knee joints with the presence of peripheral tophi in the area of the auricles, X-ray stage II, FN II, urolithiasis.
PROBLEM ARTICLESUDC 577.152.173
XANTHINE OXIDASE AS A COMPONENT OF THE SYSTEM FOR GENERATING REACTIVE OXYGEN SPECIES
V.V. Sumbaev, Ph.D., A.Ya. Rozanov, Doctor of Medical Sciences, Prof.
Odessa State University them. I.I. Mechnikov
Xanthine oxidase was discovered independently by the Ukrainian scientist Gorbachevsky and the German Schardinger. This enzyme (EC: 1.2.3.2) catalyzes the conversion of hypoxanthine to xanthine and then to uric acid, as well as the oxidation of a number of pteridines, aldehydes and imidazoles. In oxygen deficiency, xanthine oxidase functions as 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 research into 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 to form 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 utilized sufficiently, can cause myalgia and kidney infarctions.
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 divided into monomers, it is discovered that each of them individually has catalytic activity. The molecular mass of the enzyme, determined using disk electrophoresis in PAGE, is 283 kDa. Each monomer consists of three non-identical subunits linked by disulfide bonds. The molecular mass of the subunits, determined by the same method, is 135, 120 and 40 kDa, 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 the 2 Fe - 2 S cluster type. The enzyme contains molybdenum, which in an unexcited state is pentavalent and is found in the form of the so-called molybdenum cofactor - it is connected by two s-bonds with FAD, two - with hexasubstituted pterin , protonated at position 7 and one with cysteine sulfur. It has been shown that the composition of xanthine oxidase also includes one supersulfide group (- S - SH) per monomer, which possibly serves to bind molybdenum. In the course of research, it was found that pterin and the supersulfide group do not directly participate in the catalytic act. In a homogeneous state, the enzyme is quickly inactivated due to conformational changes arising due to the presence large number free SH-groups. It has been shown that the enzyme is capable of gradually losing molybdenum. It turned out that the activity of xanthine oxidase and xanthine dehydrogenase directly depends on the molybdenum content in the body.
The mechanism of action of xanthine oxidase is quite complex. Initially, the oxidation of iron occurs in the iron-sulfur center of the enzyme with the formation of a superoxide radical. FAD dehydrogenates the substrate, turning into a super active semiquinone, capable of dehydrogenating 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 dehydrogenation of water on two xanthine oxidase monomers condense into a H 2 O 2 molecule. By donating an electron, molybdenum splits hydrogen peroxide into OH · and OH -, while changing its valency. 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. The mechanism of action of xanthine oxidase is shown schematically in Fig. 1 .
The mechanism of action of xanthine dehydrogenase is relatively simple compared to that of xanthine oxidase. The enzyme initially 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 a 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 dehydrogenated with the participation of FAD, which is immediately oxidized, transferring electrons and protons to NAD +, which is the final acceptor of electrons and protons 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 must proceed faster, due to the need to neutralize it. That is why hydration of the substrate does not occur and the substrate immediately undergoes dehydrogenation.
Regulation of xanthine oxidase activity
As we have already mentioned, the path along which hypoxanthine is converted into xanthine and then into uric acid depends primarily on the conditions under which the enzyme responsible for this process . With oxygen deficiency, decreased pH, and an excess of nicotinamide coenzymes, xanthine oxidase functions as an NAD-dependent xanthine dehydrogenase. Inducers of xanthine oxidase activity are interferon and molybdates. Interferon induces the expression of genes encoding subunits of xanthine oxidase, and molybdenum (in molybdates) activates the release of the xanthine oxidase apoenzyme from the vesicles of the Golgi apparatus, 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 into the body. The daily human need for molybdenum is 1-2 mg. It has been shown that xanthine oxidase activity increases 5-20 times in cancer cells. In addition, reducing agents such as ascorbic acid, glutathione and dithiothreitol, in 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 produced 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 hyperreduction of FAD, which makes normal dehydrogenation of the substrate difficult. All described reducing agents at concentrations of 0.1 mM and higher non-competitively inhibit xanthine dehydrogenase, which is due to the reduction of FAD, which causes inhibition of 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, resulting in its irreversible inactivation. In addition, the hypoxanthine isomer allopurinol, as well as many pteridine (including folic acid) and imidazole (histidine) derivatives, isosterically inhibit xanthine oxidase. Caffeine (1,3,7-trimethylxanthine) is also a competitive inhibitor of xanthine oxidase. However, when entering 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 also neutralize the superoxide it produces, are diaryltriazole derivatives. The structure of xanthine oxidase contains an allosteric center, represented, as 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 polychlorodibenzodioxins, which bind to the allosteric center of the enzyme. It is interesting to note that allosteric xanthine oxidase inhibitors reduce the enzyme's production of superoxide. In Fig. Figure 3 shows the location of 4,9-dichlorodibenzodioxin in the allosteric center of xanthine oxidase.
Substrate specificity of xanthine oxidase and xanthine dehydrogenase
Xanthine oxidase and xanthine dehydrogenase are not strictly specific to 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-dioxypteridine, etc.) to oxypterins, as well as adenine to 2,8-dioxyadenine. It has been established that both functional forms of the enzyme oxidize histidine to 2-hydroxyhistidine. The oxidation mechanism is the same as in the case of hypoxanthine and xanthine. It is also known that the oxygen-dependent form of the enzyme (i.e. xanthine oxidase itself) oxidizes cysteine to cysteine sulfinate. Dehydrogenated cysteine captures the hydroxyl bound to molybdenum, turning into cysteine sulfenate, which is oxidized in the presence of H 2 O 2 into cysteine sulfinate. Xanthine oxidase is capable of exhibiting NAD-diaphorase activity, as well as oxidizing 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 formed in the liver. After the liver, in terms of the amount of xanthine oxidase (xanthine dehydrogenase), comes the mucous membrane of the small intestine, where the specific activity of the enzyme is an order of magnitude lower than in the liver, and then the kidneys and brain, but in these organs the specific activity of xanthine oxidase is quite low. The enzyme is also present in large quantities 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 when the activity of xanthine oxidase increases, the activity of glutathione peroxidase increases. Since the xanthine oxidase reaction results in the formation of a large amount of hydrogen peroxide, such a process is quite possible. At the same time, xanthine oxidase is a powerful generator of superoxide radical (for each monomer of the enzyme there is only 1 molecule of FAD 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, glutathione peroxidase activity may also increase. We have found that induction of sodium xanthine oxidase by molybdate causes activation of glutathione peroxidase and glutathione reductase, and also reduces the reduction potential of glutathione in the liver of rats. In this case, the level of diene conjugates increases significantly, and the content of malondialdehyde remains virtually unchanged. Suppression of xanthine oxidase activity in rats by introducing 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. Indicators of lipid peroxidation (the amount of diene conjugates and malondialdehyde) are significantly reduced.
As we have already noted, for each monomer of xanthine oxidase there is one molecule of FAD, which 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 - 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. Convincing evidence has been obtained that DNA damage 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 induction of xanthine oxidase activity occurs in almost all cases simultaneously with the induction of nitric oxide synthase activity due to activation of gene expression 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-hydroxyarginine. 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 mainly common inducers, such as, for example, interferon, which equally induces the activity of xanthine oxidase and NO synthase. Superoxide has been shown to readily react with NO to form toxic peroxynitrite (ONOO -). Peroxynitrite is even more active than superoxide in damaging DNA, and in addition, the membranes of cells in the walls of blood vessels, thus facilitating the penetration of cancer cells through them.
Superoxide, NO and peroxynitrite are heme ligands and therefore readily inhibit the activity of all cytochrome P450 isoforms. In addition, these compounds suppress the expression of genes encoding any isoforms of cytochrome P450.
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) interacts 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. The binding of these four proteins at promoter regions activates 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 eliminates the calcium barrier and Ca 2+ ions in large quantities penetrate into the cell, where they activate Ca 2+ -dependent endonuclease, which cleaves DNA, as well as calcium-dependent proteinases - calpains I and II. Calpains I and II activate protein kinase C, cleaving from it a peptide fragment that suppresses 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 of caspases is interleukins 1b-IL. In addition, it has been established that caspase-3, through limited proteolysis, activates a specific DNase, which fragments DNA into high-molecular-weight fragments. During the process of apoptosis, at the same stage, activation of serine proteases - granzyme A and granzyme B, which cleave histone and non-histone chromatin proteins, as well as nuclear matrix proteins and other nuclear proteases of unknown nature, cleave histone proteins and DNA - topoisomerases, is observed. It is assumed that the activation of these proteinases is mediated by p53. Thus, the DNA is fragmented, the vital proteins of the cell are destroyed and the cell dies. The apoptosis process is completed in 3-12 hours.
In addition, it has been established that superoxide generated by xanthine oxidase causes depolarization of mitochondria, releasing cytochrome c from them, which binds to the protein Apaf-1 (Apoptotic protease activating factor) and caspase 9. This complex activates caspase 3, which in turn activates caspases 6, 7, whose role in apoptosis was described above.
It has been shown that culturing cells under conditions of oxidative stress caused by xanthine oxidase (created by adding a highly purified preparation of xanthine oxidase and xanthine to the culture), the apoptogenic protein p53 accumulates and the cells die by the mechanism of apoptosis. Activation of NO formation under these conditions inhibits gene expression and, accordingly, the synthesis of the p53 protein, 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.
Currently, 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, aldehydrase, Schardinger enzyme, xanthine (and aldehyde) -> O 2 transhydrogenase] - an enzyme that catalyzes 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-. K. is an important enzyme in the metabolism of purines, catalyzing the reaction that completes the formation of uric acid in the body of animals and humans (see Purine bases). In 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 under normal conditions and in pathol conditions.
With a genetically determined congenital defect of K. and a violation of the reabsorption of xanthine 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; at the same time, the content of uric acid (see) in the blood serum (normal 2.0-5.0 mg%) and urine (normal 0.4-1.0 g daily) is sharply reduced. There is evidence that genetic deficiency K. is inherited in a recessive manner.
K. is widespread in nature. Highly purified K. preparations are obtained from milk and from the liver of mammals and birds. K. is also found in microorganisms. Mol. weight (mass) K. - approx. 300 000. The K molecule consists of two subunits, they say. the weight (mass) of each of them is approx. 150,000. As prosthetic components, the K molecule contains two FAD molecules and two molybdenum atoms, 8 non-heme iron atoms and 8 acid-labile sulfur atoms. K. is distinguished by wide substrate specificity; it has the property of oxidizing not only xanthine (see), but also various derivatives of purines, pyrimidines, pteridines, and various aldehydes, while reducing not only oxygen, but also many other electron acceptors (tetrazolium salts, derivatives indophenol, methylene blue). It is believed that in mammalian tissues the dehydrogenase (reductase) form of the enzyme predominates, which has the property of reducing NAD during the oxidation of xanthine. When isolated and purified, the enzyme is usually transformed into its oxidase form. There are two types of transformation of enzymes: reversible (initiated by the oxidation of SH groups of the enzyme, their mercaptidation, and the formation of mixed disulfides) and irreversible (initiated by partial proteolysis of the enzyme or alkylation of its SH groups). Commercial preparations of K. have already been transformed; they do not have dehydrogenase activity.
Methods for measuring K.'s activity are usually based on recording the formation of uric acid by increasing the optical density of the solution at 295 nm during the oxidation of xanthine in the presence of O 2.
Bibliography: Gorkin V. 3. Transformation of enzymes, Molecular Biol., vol. 10, century. 4, p. 717, 1976, bibliogr.; McKusick V. A. Hereditary characteristics of man, 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 presented for a routine consultation due to elevated blood pressure (BP). At the time of examination, blood pressure was 142/90 mm Hg. art., pulse - 72 beats/min. Laboratory studies showed normal renal tests and a uric acid (UA) level of 9.2 mg/dL. Will this indicator influence your testing and treatment decisions?
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 within the framework of the scientific and practical conference “Medical and social problems of arterial hypertension in Ukraine” (May 24-26, Kiev).
Chief Researcher of the State Institution "National Scientific Center" Institute of Cardiology named after. N.D. Strazhesko "NAMS of Ukraine" (Kiev), Doctor of Medical Sciences, Professor Elena Gennadievna Nesukai described 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), which occurs due to increased UA production, decreased UA excretion, or a combination of these processes. When this limit is exceeded, deposition of monosodium urate crystals begins in the soft tissues around the joints, 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 patients under 45 years of age to 40% among people over 75 years of age (Wallace S. et al., 2004). However, even asymptomatic hyperuricemia increases the risk of developing CVD and metabolic disorders. The number of publications devoted to the relationship of urinary vascular disease with cardiovascular outcomes has increased almost 4 times 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, increased UA levels were detected in 25-60% of patients with untreated essential hypertension and in approximately 90% of patients with recently developed hypertension (Feig D.J. et al., 2008). According to the US National Health and Nutrition Examination Survey (NHANES, 1999-2006), it was found that when the sUA concentration threshold is exceeded 5.5 mg/dL, the likelihood of detecting elevated blood pressure in American adolescents increases by 2 times (Loeffler L.F. et al., 2012) . Moreover, another study showed that increased levels of sUA in childhood are a predictor of increased blood pressure in adulthood (Alper A.B. et al., 2005).
Experimental increases in sUA levels in rodents lead to clinical, hemodynamic and histological changes characteristic of hypertension, and treatment with xanthine oxidase inhibitors helps normalize 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 UA, with a more stable pattern observed in men (Dawson J. et al., 2013). A correlation has also been shown 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 pattern of increase in the absolute frequency of all adverse events depending on the serum concentration of sUA (Fig. 1).
The association of serum sUA level with cardiovascular mortality in the general US population was confirmed in the NHANES-III study (1988-1994), and the prognosis worsened when the sUA level 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 uric acid and the incidence of comorbid conditions such as 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, an initially elevated sUA level was 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 were presented (Rha S.-W., Choi B.G., Choi S.Y.), which showed the association of hyperuricemia with an increased risk of developing diabetes mellitus (DM) by 72% in 5-year perspective.
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 high level MK is classified as a non-traditional risk factor. The expert consensus of the American College of Chest Physicians and the American Heart Association on hypertension in the elderly (2011) indicated that serum sUA is an independent predictor of cardiovascular events in elderly patients with hypertension.
The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines note that the therapeutic goal in patients with gout and hyperuricemia is to achieve serum UA levels<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 remained the only xanthine oxidase inhibitor used in clinical practice. Today, it is being replaced in many countries by febuxostat, a more powerful non-purine selective xanthine oxidase inhibitor with a better safety and tolerability profile. Febuxostat inhibits both forms of xanthine oxidase - reduced and oxidized, 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 elimination 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 failure. 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 that demonstrated febuxostat to be superior to allopurinol in achieving target sUA levels (Figure 3).
As a result of clinical studies, the following advantages of febuxostat were identified:
Higher efficacy compared to allopurinol in patients with impaired renal function (CONFIRMS study, Becker M. et al., 2010);
Sustainable maintenance of sUA levels<6,0 мг/дл (360 мкмоль/л) при длительной терапии в течение 5 лет (исследование FOCUS, Schumacher H. et al., 2009);
Excellent tolerability, frequency of side effects comparable to placebo (APEX study, Schumacher H. et al., 2008).
Does urate-lowering therapy in patients with gout or hyperuricemia affect the outcome of comorbid CVD? This question remains to be answered in new studies, but some data have already been obtained that link a decrease in UA levels 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 the 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 was previously shown that febuxostat and allopurinol lower urinary sUA levels and suppress the expression of the inflammatory marker monocyte chemoattractant protein (MCP-1), which is involved in the pathogenesis and progression of heart failure 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 treatment of CHF. After 12 months, the febuxostat group achieved a significantly greater reduction in sUA and MCP-1 levels compared to baseline than in the allopurinol group. Over 12 months, LVEF increased in both groups, but a more significant increase was observed in patients taking febuxostat. The percentage increase in LVEF was 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 reducing sUA levels and inflammation and may improve cardiac function in patients with CHF and hyperuricemia, at least in part by suppressing inflammation.
A convenient algorithm for choosing tactics for managing patients with hyperuricemia was proposed by Japanese researchers in 2012 (Fig. 4). The decision to prescribe drug therapy to patients with hyperuricemia, but without clinical signs of gout, is made based on the presence of complications and comorbid diseases, such as kidney damage, hypertension, coronary artery disease, and diabetes.
Based on the materials reviewed, practical conclusions can be drawn.
1. Hyperuricemia is an independent risk factor for CVD and kidney diseases with a serum sUA level >6 mg/dl.
2. Determination of serum UA levels should be considered as a test for routine screening of patients with hypertension.
3. The therapeutic goal in patients with hyperuricemia should be to reduce and maintain sUA levels<6 мг/дл.
4. Febuxostat (Adenuric) is more effective than allopurinol in reducing serum UA levels, making it the drug of first choice for the treatment of hyperuricemia and comorbid conditions.
Head of the Department of Therapy and Nephrology of the Kharkov Medical Academy of Postgraduate Education, Doctor of Medical Sciences, Professor Alexander Viktorovich Bilchenko commented in more detail on the mechanisms of the influence of hyperuricemia on cardiovascular outcomes and presented the concept of xanthine oxidase inhibition as a promising direction for 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. The metabolism of xanthines with the formation of uric acid occurs in two ways: xanthine dehydrogenase (reduction reactions, antioxidant effect) or xanthine oxidase (oxidative). In the reactions of the second pathway, the same final product, MK, is formed from xanthine and hypoxanthine, but a by-product is the formation of a large number of free oxygen radicals (Fig. 5). The enzyme xanthine oxidase is activated during ischemia and inflammation, so hyperuricemia occurs more often in patients with hypertension and CVD than in the general population. An increase in the level of sUA in the 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, the 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 the questions of how the negative effects of xanthine metabolism disorders are realized and how they can be influenced.
Among the possible mechanisms for the development of CVD in individuals with hyperuricemia, interactions with other risk factors, urate deposition in blood vessels, genetic mechanisms, kidney damage, and oxidative stress are being studied. Population and cohort studies have confirmed the linear dependence of blood pressure and abdominal obesity on the level of sUA (Borghi C. et al., 2013). As a result of activation of xanthine oxidase and oxidative stress, endothelial dysfunction develops and a cascade of events occurs that contribute to the maintenance of elevated blood pressure and atherogenesis. On the other hand, an increase in blood pressure is promoted by activation of the renin-angiotensin system (RAS) under the influence of excess sUA and increased sodium reabsorption in the kidneys.
The classic SHEP study was the first to show how hyperuricemia affects outcomes in patients with hypertension: 4327 patients over 60 years of age with isolated systolic hypertension were treated with chlorthalidone or placebo for 5 years. It turned out that in those participants whose sUA levels increased after diuretic administration, cardiovascular events occurred almost 2 times more often than in individuals with normal sUA levels. 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 incidence of cardiovascular events and overall mortality increased not only with hyperuricemia, but also with low UA concentrations (<268 мкмоль/л).
Another category of patients in whom the value of MK has been well studied is patients with MS. Hyperuricemia was one of the first criteria for diagnosing MS. Several mechanisms have been described for increasing UA levels in abdominal obesity through the mediation of proinflammatory 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 has been proven, which increases with activation of the oxidase pathway of UA synthesis.
The role of hyperuricemia in kidney damage has also been proven. Decreased renal function is one of the cardiovascular risk factors. This is especially true for patients with MS and diabetes. In one of the recent studies on this issue, in patients with type 2 diabetes and the fifth quintile of sUA levels, compared with the first quintile, the risk of developing renal failure increased by 2.6 times (de Cosmo S. et al., 2015).
It should be noted that oxidative stress, which accompanies excessive synthesis of uric acid by the oxidase pathway, is a universal factor in increasing blood pressure, kidney damage, and the development of metabolic syndrome. Therefore, not so much UA itself, but 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, which studied xanthine metabolism in patients with CHF with reduced EF and concomitant chronic renal failure (Bilchenko A.V. European Journal of Heart Failure, 2016; 18 (Suppl. 1) : P1492). Not only the level of UA in the blood plasma was determined, but also the activity of xanthine oxidase. A significant increase in UA levels 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 failure.
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 uric acid by the kidneys. These include some antihypertensive agents (losartan, calcium channel blockers), lipid-lowering agents (fenofibrate, atorvastatin), and drugs for the treatment of gout (probenecid, benzbromarone). Experts agree that hyperuricemia itself is not an indication for starting therapy with uricosuric drugs. Additional indications are required: hypertension (losartan), atherosclerosis, coronary artery disease (statins), gout (probenecid, benzbromarone).
A more promising direction is the inhibition of xanthine oxidase. Currently, two inhibitors are available in Ukraine: classical 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 commenting on the research, 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 terms of the effectiveness of xanthine oxidase inhibition, since it affects both of its forms - oxidized and reduced, present in different proportions in the 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 S., Perez-Ruiz F., 2016).
It has been shown that optimal control of uric acid during febuxostat therapy is accompanied by an antiatherosclerotic effect (Nomura J. et al., 2014), as well as a positive effect on a number of indicators of lipid metabolism and hemodynamics. 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 who were undergoing cardiac surgery were randomized to febuxostat or allopurinol. After 1 month, sUA levels were significantly lower in the febuxostat group. Plasma creatinine, urine albumin, cystatin-C and oxidized low-density lipoprotein were also significantly lower in the febuxostat group compared to the allopurinol group. Systolic blood pressure, pulse wave velocity, and LV mass index remained virtually unchanged in the allopurinol group, but decreased significantly in patients taking febuxostat. Thus, febuxostat demonstrated superiority in reducing sUA levels and a significant effect on markers of cardiovascular risk in cardiac surgery patients. The authors concluded that febuxostat suppresses oxidative stress, has a renoprotective, antiatherogenic effect, reduces blood pressure, and indicators of vascular and cardiac remodeling.
In a 6-month prospective randomized study in which patients with hypertension and hyperuricemia were selected, it was shown that a decrease in sUA levels while taking febuxostat was accompanied by inhibition of the RAS and improvement in renal 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), and MK 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.
Thus, febuxostat (Adenuric) is now considered not only as an effective treatment for gout, but also as a cardio- and renoprotective drug with great potential for improving cardiovascular outcomes. Febuxostat provides reliable control of hyperuricemia, including in patients with hypertension, a vascular protective effect, elimination of metabolic disorders, cardio-renoprotection and, perhaps, in the near future, will take its place in the strategy for reducing the risk of cardiovascular events and death.
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