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Another name for allopurinol: Uses, Side Effects, Dosages, Treatment, Interactions, Warnings

Содержание

Allopurinol: Uses, Interactions, Mechanism of Action

Indication

Allopurinol is indicated in Label:

1) the management of patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy).

2) the management of patients with leukemia, lymphoma and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels. Treatment with allopurinol should be discontinued when the potential for overproduction of uric acid is no longer present.

3) the management of patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients. Therapy in such patients should be carefully assessed initially and reassessed periodically to determine in each case that treatment is beneficial and that the benefits outweigh the risks.

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Associated Conditions
Contraindications & Blackbox Warnings

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Pharmacodynamics

Allopurinol decreases the production of uric acid by stopping the biochemical reactions that precede its formation Label. This process decreases urate and relieves the symptoms of gout, which may include painful tophi, joint pain, inflammation, redness, decreased range of motion, and swelling 2.

Mechanism of action

Allopurinol is a structural analog of the natural purine base, hypoxanthine. After ingestion, allopurinol is metabolized to its active metabolite, oxypurinol (alloxanthine) in the liver 11, which acts as an inhibitor of xanthine oxidase enzyme Label.

Allopurinol and its active metabolite inhibit xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Inhibition of this enzyme is responsible for the effects of allopurinol. This drug increases the reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis by a process that involves the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). This process results in an increased nucleotide concentration, which causes feedback inhibition of de novo purine synthesis. The end result is decreased urine and serum uric acid concentrations 15, which decreases the incidence of gout symptoms.

Accompanying the reduction of serum uric acid by allopurinol is an increase in the serum and urine concentrations of hypoxanthine and xanthine (due to inhibition of xanthine oxidase). In the absence of allopurinol, regular urinary excretion of oxypurines almost entirely occurs in the form of uric acid. After the ingestion of allopurinol, the contents of excreted urine are hypoxanthine, xanthine, and uric acid. Because each substance has its own individual solubility, the concentration of uric acid in plasma is decreased without exposing the renal tissues to a high load of uric acid, thereby decreasing the risk of crystalluria. By lowering the uric acid concentration in the plasma below its limits of solubility, allopurinol encourages the dissolution of gout tophi. Although the levels of hypoxanthine and xanthine are found to be increased after allopurinol ingestion, the risk of deposition in renal tissues is less than that of uric acid, as they become more soluble and are rapidly excreted by the kidney 15.

Absorption

This drug is about 90% absorbed from the gastrointestinal tract. Peak plasma levels normally occur at 1.5 hours and 4.5 hours post-dose for allopurinol and oxipurinol respectively. Following one oral dose of 300 mg of allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxipurinol were measured Label.

Volume of distribution

Allopurinol and oxypurinol are both substrates for the enzyme xanthine oxidase, which is present in the cytoplasm of endothelial cells of capillaries, including sinusoids, with the highest activity demonstrated in the liver and intestinal lining. Tissue concentrations of allopurinol have not yet been reported in humans, however, it is probable that allopurinol and the metabolite oxypurinol would be measured in the highest concentrations in the abovementioned tissues. In animals, allopurinol concentrations are found to reach the highest levels in the blood, liver, intestine and heart, and lowest in the brain and lung tissues 9.

Protein binding

Allopurinol and oxypurinol are only negligibly bound to plasma proteins 10,9.

Metabolism

Allopurinol is rapidly metabolized to the corresponding xanthine analog, oxipurinol (alloxanthine), which is also an inhibitor of xanthine oxidase enzyme Label.
Both allopurinol and oxypurinol inhibit the action of this enzyme. Allopurinol and oxypurinol are also converted by the purine salvage pathway to their respective ribonucleotides. The effect of these ribonucleotides related to the hypouricemic action of allopurinol in humans is not fully elucidated to this date. These metabolites may act to inhibit de novo purine biosynthesis by inhibiting the enzyme, amidophosphoribosyltransferase. The ribonucleotides have not been found to be incorporated in DNA 8.

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Route of elimination

Approximately 80% of orally ingested allopurinol is found excreted in the urine as various metabolites 9. About 20% of ingested allopurinol is excreted in the feces Label.

Half-life

The plasma half-life of allopurinol is 1-2 hours, due to its rapid renal clearance Label.

Clearance

Since allopurinol and its metabolites are mainly eliminated by the kidney, accumulation of this drug can occur in patients with renal dysfunction or failure, and the dose of allopurinol should, therefore, be reduced. With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of allopurinol is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not be higher than 100 mg. With severe renal impairment (creatinine clearance measured at less than 3 mL/min) a longer interval between doses may be required Label.

Adverse Effects

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Toxicity

Oral TDLO (rat): 10 mg/kg; Oral LD50 (mouse): 78 mg/kg; Oral TDLO (mouse): 100 mg/kg 14

Use in pregnancy

Reproductive studies have been completed using rats and rabbit models at doses up to twenty times the normal human dose ( about 5 mg/kg per day), and it was concluded that fertility was not impaired and there was no fetal harm. There is a published report of a study in pregnant mice administered 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams administered 100 mg/kg allopurinol, however, death did not occur in those given 50 mg/kg. There were higher numbers of external malformations in fetuses at both doses of allopurinol on gestation day 10 and higher numbers of skeletal malformations in fetuses at both doses on gestation day 13. Despite the above findings, there are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if it is absolutely required Label.

Use in nursing

Both allopurinol and the metabolite oxipurinol have been found in the milk of a mother who was receiving allopurinol. Since the effect of allopurinol on the nursing infant is unknown, it is advisable to exercise caution when allopurinol is taken by a nursing woman Label.

Mutagenicity and carcinogenicity

Cytogenic studies demonstrate that allopurinol does not induce chromosomal abnormalities in human blood cells in vitro at concentrations up to 100 g/mL and in vivo at doses up to 60 mg/day for an average duration of 40 months. Allopurinol does not form nitroso compounds (which may be carcinogenic) or affect lymphocyte transformation in vitro. Evidence suggests that allopurinol does not have deleterious effects on DNA at any stage of the cell cycle and was not found to be mutagenic. No evidence of carcinogenicity has been observed in mice treated with allopurinol for up to a 2 year period 15.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/Enzyme Allele name Genotype(s) Defining Change(s) Type(s) Description Details
HLA class I histocompatibility antigen protein P5 HLA-B*5801 (G;G) / (G;T) G allele ADR Directly Studied Patients who carry this allele are at a higher risk of experiencing severe cutaneous adverse reactions when treated with allopurinol. Details

Terry White Chemists Allopurinol Tablets

What is in this leaflet

Read this leaflet carefully before taking your medicine.

Ask your doctor or pharmacist if you do not understand anything or are worried about taking your medicine.

This leaflet answers some common questions about allopurinol.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. Some more recent information on your medicine may be available. Speak to your pharmacist or doctor to obtain the most up-to-date information.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

Keep this leaflet with your medicine.

You may need to read it again.

What allopurinol is used for

The name of your medicine is Terry White chemists Allopurinol. It contains the active ingredient, allopurinol.

Allopurinol is used to treat:

  • gouty arthritis or gout
  • kidney stones
  • rare conditions where high levels of uric acid occur in the blood (for example, Lesch-Nyhan syndrome).

Allopurinol is used to treat the symptoms of these conditions, but it will not cure them. Also, it will not help treat the pain that occurs in an acute attack of gout.

How it works

Allopurinol belongs to a group of medicines called anti-uricaemic agents. These medicines work by reducing high levels of uric acid in the body, which are usually due to gout. Excess amounts of uric acid in the blood may lead to uric acid crystals being made and deposited in the joints, thereby causing pain, swelling and tenderness.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed allopurinol for another reason.

This medicine is available only with a doctor’s prescription.

There is no evidence that this medicine is addictive.

Use in children

There is very little information to recommend the use of this medicine in children. Allopurinol should only be taken by children if a doctor has prescribed it.

Before you take allopurinol

When you must not take it

Do not take this medicine if you have had an allergic reaction to allopurinol or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include: shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; muscle pain or tenderness or joint pain; or rash, itching or hives on the skin.

Do not take allopurinol if you or a member of your immediate family has been diagnosed with haemochromatosis (a disease involving too much iron in the body) and you are taking iron salts.

Do not take this medicine after the expiry date (EXP) printed on the pack.

If you take this medicine after the expiry date has passed, it may not work as well.

Do not take this medicine if the packaging is torn, shows signs of tampering or if the tablets do not seem quite right

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you:

  1. have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. have or have had any medical conditions, especially the following:
  • kidney problems, including kidney stones
  • liver problems
  • high blood pressure
  • heart problems
  • conditions where the levels of uric acid are abnormally high
  • cancer or tumours.
  1. are having an attack of gout.
    Treatment with allopurinol should not be started until the attack has stopped, otherwise more attacks may occur.
    (However, if an attack of gout occurs when a person is already taking allopurinol, it can be continued).
  2. are pregnant or intend to become pregnant.
    Your doctor will discuss with you the risks and benefits of taking allopurinol during pregnancy.
  3. are breast-feeding or plan to breast-feed.
    Allopurinol passes into breast milk and may affect your baby. Your doctor will discuss with you the risks and benefits of taking allopurinol when breast-feeding.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and allopurinol may interfere with each other. These include:

  • some medicines used to treat high blood pressure or heart problems
  • thiazide diuretics (a certain type of water tablet)
  • mercaptopurine, azathioprine or cyclosporin – medicines used to suppress the immune system
  • aspirin and other medicines known as salicylates
  • probenicid, a medicine used to treat gout
  • warfarin, used to help prevent blood clots
  • chlorpropamide, a medicine used to treat diabetes
  • phenytoin, a medicine used to treat epilepsy
  • certain antibiotics such as ampicillin and amoxycillin
  • theophylline, a medicine used to treat asthma
  • vidarabine, an anti-viral medicine.

These medicines may be affected by allopurinol or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

Your doctor and pharmacist can tell you if you are taking any of these medicines. They may also have more information on medicines to be careful with or avoid while taking allopurinol.

Other interactions not listed above may also occur.

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully.

They may be different to the information in this leaflet.

If you do not understand any written instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor or pharmacist will tell you how many tablets you need to take. This depends on your condition and whether or not you are taking any other medicines.

  • The usual adult dose range is: 100 – 200 mg per day for mild conditions
  • 300 – 600mg per day for moderately severe conditions
  • 700 – 900mg per day for severe conditions.

People over 65 years of age, and those with kidney and/or liver problems should be started on the lowest dose possible to control uric acid production.

Children under 15 years of age usually take 100 – 400 mg per day.

How to take it

Swallow the tablets with a glass of water.

When to take it

Take your medicine immediately after food, as this will lessen the chance of a stomach upset.

Take your medicine at the same time each day.

Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take it.

Allopurinol is usually taken once daily. However, if your dose is more than 300 mg, your doctor may advise you to take your medicine twice a day. Then, it should be taken morning and night, after breakfast and dinner.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Allopurinol helps to control the symptoms of your condition but does not cure it. It is important to keep taking your medicine, even if you feel well.

If you forget to take it

If you miss a dose, and it is more than 4 hours until your next dose is due, take the missed dose as soon as you remember.

If it is less than 4 hours to your next dose, do not take the dose you missed and take your next dose when you are meant to.

Then go back to taking your medicine as you would normally. Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency Department at your nearest hospital, if you think that you or anyone else may have taken too many allopurinol.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much allopurinol, you may feel some or all of the following:

  • nausea
  • vomiting
  • diarrhoea
  • dizziness.

While you are taking allopurinol

Things you must do

You must immediately stop taking allopurinol if a skin rash or signs of an allergic reaction occur – immediately tell your doctor.

The signs of an allergic reaction were listed earlier in this leaflet.

You should drink at least two litres (8 – 10 glasses) of fluid each day.

This will assist in reducing the uric acid levels in your body and prevent kidney stones from forming.

Tell your doctor if you have an acute attack of gout while you are taking allopurinol.

Your doctor may prescribe a medicine to relieve the acute attack.

You can continue taking allopurinol.

Tell any other doctors, dentists or pharmacists who are treating you that you are taking allopurinol.

Tell your doctor immediately if you become pregnant while you are taking this medicine.

If you are about to have any surgery, tell the surgeon, dentist or doctor that you are taking this medicine.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking this medicine.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

Go to your doctor regularly for a check-up.

Your doctor may occasionally do tests to make sure this medicine is working and to prevent side effects.

Things you must not do

Do not take this medicine to treat an acute attack of gout.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not stop taking your medicine, or change the dosage, without checking with your doctor

Things to be careful of

Make sure you know how allopurinol affects you before you drive a car, operate machinery or do anything else that could be dangerous if you are drowsy.

As with other medicines, allopurinol may cause drowsiness, dizziness or lack of co-ordination in some people

Side effects of allopurinol

All medicines may have some unwanted side effects. Sometimes they are serious, but most of the time they are not.

If you are over 65 years of age, have kidney and/or liver problems, you may have an increased chance of getting side effects.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking allopurinol.

Ask your doctor or pharmacist to answer any questions you may have.

Following is a list of possible side effects. Do not be alarmed by this list. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • stomach upsets, including nausea, vomiting or diarrhoea
  • dizziness, drowsiness or unsteadiness when walking
  • change in bowel habits
  • headache
  • change in taste sensation
  • sleeplessness
  • hair loss or change in hair colour.

These are the more common side effects of allopurinol. Mostly these are mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • changes in vision
  • tingling or numbness of the hands or feet
  • fever, chills, sore throat or mouth ulcers
  • a change in the amount of urine passed, going to the toilet more often or a burning feeling while passing urine
  • blood in your urine
  • yellowing of the skin and eyes (jaundice)
  • generally feeling of being unwell or depressed
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily
  • angina or palpitations
  • swelling of the hands, ankles or legs.

These may be serious side effects. You may need medical attention. Most of these side effects are rare.

If any of the following happen, stop taking your medicine and tell your doctor immediately or go to Accident and Emergency of your nearest hospital:

  • asthma, wheezing or shortness of breath
  • swelling of the face, lips, tongue or throat which may cause difficulty in breathing
  • sudden or severe itching, skin
  • rash or hives, other skin problems
  • fainting, seizures or fits
  • pain or tightness in the chest.

These are very serious side effects.

You may need urgent medical attention or hospitalisation. These side effects are rare.

Other side effects not listed above may occur in some patients.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After taking this medicine

Storage

Keep your medicine in its original packaging until it is time to take them. If you take the tablets out of their original packaging they may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink.

Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and- a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.Where to go for further information

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition.

Product description

What Terry White chemists Allopurinol looks like

100 mg tablets:
White to off-white, round, biconvex tablets coded with “U4A” and scored on the upper face and bottom face plain..

They are packed in a bottle of 200 tablets.

300 mg tablets:
White, round, biconvex tablets coded with “C9B” and scored on the upper face and bottom face plain.

They are packed in a blister pack of 60 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 100 mg or 300 mg of allopurinol as the active ingredient.

It also contains the following inactive ingredients:

  • povidone
  • maize starch
  • lactose monohydrate
  • magnesium stearate

This medicine contains lactose but is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Terry White Chemists Allopurinol 100mg: AUST R 219904

Terry White Chemists Allopurinol 300mg: AUST R 219905

Sponsor

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

This leaflet was last updated in:
February 2017

Allopurinol – an overview | ScienceDirect Topics

Allopurinol This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Cimetidine This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Estrogen Contraceptives This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Disulfiram This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Fluoroquinolone antibiotics This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Ciprofloxacin This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Enoxacin This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Fluvoxamine This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Alpha Interferon This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Macroline antibiotics This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Clarithromycin This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Erythromycin This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Troleandomycin This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Methotrexate This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Mexiletine This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Propafenone This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Pentoxifylline This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Propranolol This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Tacrine This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Thiabendazole This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Ticlopidine This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Verapamil This agent decreases the clearance of theophylline, probably by inhibition of P-450 isoenzymes responsible for its metabolism.
Aminoglutethimide This agent increases the clearance of theophylline, probably by induction of P-450 isoenzymes responsible for its metabolism.
Carbamazepine This agent increases the clearance of theophylline, probably by induction of P-450 isoenzymes responsible for its metabolism.
Isoproterenol This agent increases the clearance of theophylline, probably by induction of P-450 isoenzymes responsible for its metabolism.
Moricizine This agent increases the clearance of theophylline, probably by induction of P-450 isoenzymes responsible for its metabolism.
Phenobarbital This agent increases the clearance of theophylline, probably by induction of P-450 isoenzymes responsible for its metabolism.
Phenytoin This agent increases the clearance of theophylline, probably by induction of P-450 isoenzymes responsible for its metabolism.
Rifampin This agent increases the clearance of theophylline, probably by induction of P-450 isoenzymes responsible for its metabolism.
Adenosine Concurrent use may antagonize the CV effects of adenosine.
Benzodiazepines Theophylline may reverse benzodiazapine-induced sedation.
Beta adrenoceptor agents Concurrent use may result in inhibition of the bronchodilatory response to oxtriphylline.
Ephedrine Concurrent use may increase the frequency of nausea, nervousness, or insomnia associated with oxtriphylline.
Halothane Concurrent use may result in ventricular arrhythmias.
Ketamine Concurrent use may lower seizure threshold.
Lithium Concurrent use may increase renal elimination of lithium.
Neuromuscular blocking agents Concurrent use may antagonize neuromuscular blocking effects.
Tobacco This agent increases the clearance of oxtriphylline probably due to induction of P-450 isoenzymes.
Marijuanna This agent increases the clearance of oxtriphylline probably due to induction of P-450 isoenzymes.

Allopurinol | Encyclopedia.com

Definition

This medication, also known as (Zyloprim), is used for the treatment and prevention of gout attacks and certain types of kidney stones. It is also used to treat elevated uric acid levels in the blood and urine, which can occur in patients receiving chemotherapy for the treatment of leukemia, lymphoma and other types of cancer. If left untreated, high uric acid levels in patients receiving cancer chemotherapy can cause kidney stones and kidney failure.

Description

Allopurinol decreases uric acid levels in the blood and urine by inhibiting a certain enzyme responsible for production of uric acid. It has been used for over three decades for prevention of gouty arthritis, kidney stones, and tumor lysis syndrome in cancer patients.

Recommended Dosage

Adults
GOUT.

200-300 mg per day for mild gout and 400-600 mg per day for severe gout. Patients greater than 65 years of age should be started at 100 mg per day. Their dose can be increased until desired uric acid levels in the blood are reached.

Children over 10 years of age and adults
PREVENTION OF URIC ACID KIDNEY STONES IN CANCER PATIENTS.

600-800 mg per day divided into several doses, usually starting 1-2 days before cancer chemotherapy and stopped two to three days after the chemotherapy is completed for that cycle.

Total daily dose greater than 300 mg should be given in divided doses.

Children less than 10 years of age
PREVENTION OF URIC ACID KIDNEY STONES IN CANCER PATIENTS.

10 mg per kg per day of allopurinol in two to three divided doses up to a maximum dose of 800 mg per day. Another alternative is to give 150 mg per day in three divided doses for children 6 years of age and 300 mg per day in two to three divided doses for children 6-10 years of age.

Administration

Allopurinol should be taken after meals to avoid stomach upset. Patients should drink plenty of fluids (at least eight glasses of water per day) while taking this medicine unless otherwise directed by a physician. Drinking a lot of water can prevent formation of kidney stones.

Precautions

The use of allopurinol in pregnant women should be avoided whenever possible because its effects on the human fetus are not known.

Allopurinol should be used with caution by the following populations:

  • Patients who have had an allergic reaction to allopurinol in the past.
  • Patients who are taking certain medicines for high blood pressure such as diuretics (water pills) or angiotensin converting enzyme (ACE) inhibitors (captopril, lisinopril, enalapril). These people may be at higher risk of hypersensitivity with allopurinol.
  • Breast-feeding mothers.
  • Children (except those who have high uric acid levels caused by cancer, chemotherapy, or genetic diseases).

Patients should call a doctor immediately if any of these symptoms develop:

  • rash, itching , swelling of lips or mouth, trouble breathing (also known as hypersensitivity reaction)
  • yellowing of the skin or eyes
  • pain when urinating or blood in the urine
  • unusual bleeding or bruising

Patients with kidney problems may need to use lower doses of allopurinol.

Patients taking allopurinol will need to see a physician before starting therapy and occasionally during therapy to do blood tests for monitoring of kidney and liver function and complete blood count.

Side effects

Allopurinol is usually well tolerated by most patients. The most common side effect is skin rash, hives and itching. Loss of hair, fever , and feelings of discomfort or uneasiness can happen alone or in combination with a rash. The risk of rash is higher in people with kidney disease or people taking amoxicillin or ampicillin. The use of allopurinol should be discontinued at first sign of a rash. Other side effects include nausea, vomiting, decreased kidney function and drowsiness (especially during the first few days of therapy). Because allopurinol can cause drowsiness, caution should be taken when performing tasks requiring alertness, such as cooking or driving.

Interactions

Patients should consult their doctor before drinking alcoholic beverages; alcohol can decrease the effectiveness of allopurinol. People consuming large amounts of vitamin C can be at an increased risk for kidney stones.

Allopurinol can prolong the effects of blood thinners such as warfarin (Coumadin) and put patients at
risk for bleeding. It can also increase chances of low blood sugar with chlorpropamide (Diabinese) and nerve toxicity with vidarabine. Allopurinol can decrease breakdown of azathioprine (Imuran), mercaptopurine (6-MP), cyclosporine (Neoral, Sandimmune) and theophylline (Theo-Dur, Theolair, Theo-24) by the liver, increasing blood levels and side effects. Doses of azathioprine and mercaptopurine need to be reduced when they are used together with allopurinol. Mercaptopurine can be substituted for thioguanine (6-TG) to avoid this interaction altogether.

The use of amoxicillin and ampicillin should be avoided if possible in patients taking allopurinol because of increased risk of rash. Water pills such as hydrochlorthiazide (Diuril) can increase the risk of toxicity and allergic reaction when used with allopurinol.

Olga Bessmertny, Pharm.D.

KEY TERMS

ACE inhibitors

—A group of drugs used to treat high blood pressure. These drugs work by decreasing production of a certain chemical in the kidneys that causes constriction of blood vessels.

Gout

—A disease, especially common in men, in which patients may have high uric acid levels in the blood and sudden attacks of severe joint pain and swelling caused by the deposits of uric acid crystals in those joints. These gout attacks most commonly affect the big toe.

Kidney stone

—A concretion in the kidney made of various materials, such as uric acid crystals, calcium, or lipids. These concretions, or stones, cause severe pain when they are transported from the kidney into the bladder and out of the body.

Tumor lysis syndrome

—A potentially life-threatening condition caused by cancer chemotherapy associated with very high blood levels uric acid, phosphate, and potassium, low calcium, and acute kidney failure.

Uric acid

—White, poorly soluble crystals found in the urine. Sometimes uric acid forms small solid stones or crystals that are deposited in different organs in the body, such as the kidney. High levels of uric acid can be seen in patients with gout or cancer.

The 4 Stages of Gout and Preventing Disease Progression

Gout is a type of inflammatory arthritis that happens when levels of uric acid — a normal byproduct of metabolic reactions in your body — become too high. When levels of uric acid get so high that your body can’t easily dissolve and excrete it (via urine), uric acid starts to crystallize. Uric acid crystals deposit themselves in the joints where they cause severe inflammation. The big toe is a well-known site of gout attacks, but gout can strike many different joints throughout the body.

Gout is one of the oldest recorded diseases, with accounts dating back to ancient Egypt. This incredibly painful arthritis affects millions of U.S. adults today just as it did in historic times, as described memorably by Dr. Thomas Sydenham in the 17th century:

“The victim goes to bed and sleeps in good health. About two o’clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep…The pain, which was at first moderate, becomes more intense…So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room.”

Fortunately, today gout is one of the most treatable forms of arthritis — some rheumatologists say it can be cured. But for too many patients with gout, the disease goes untreated or undertreated. In one recent study, for example, only 37 percent of people with gout were taking the uric acid-lowering medication allopurinol; among gout patients with frequent flares, only half were taking it.

Improperly treating gout can cause the disease to become more progressive. Over time, gout can begin to affect more joints throughout the body and cause problems like gout tophi and permanent bone damage.

Find out more here about how gout develops, how gout progresses through different stages, and how to treat gout to prevent symptoms, lower uric acid levels, and prevent long-term gout complications.

Stage 1: High Uric Acid Levels

Also called asymptomatic hyperuricemia, in this beginning stage of gout, uric acid is building up in the blood and starting to form crystals around joints, most often in the foot.

Uric acid is created when your body breaks down substances called purines, which are produced in your body and can also be found in certain foods and drinks. While eating high-purine foods can contribute to high uric acid levels, many experts believe that the role of diet in the development of gout is over-emphasized. Chronically high levels of uric acid happen when your kidneys aren’t able to efficiently get rid of uric acid, which can happen for a number of reasons, including:

  • Overweight
  • Kidney disease
  • Taking diuretics
  • Drinking alcohol in excess
  • Diabetes
  • Underactive thyroid
  • Genes/family history
  • Eating a high-purine diet

“In this first stage of gout, the person has no joint pain, no red or swollen joints, just an elevated uric acid blood test,” says Theodore R. Fields, MD, FACP, rheumatologist at the Hospital for Special Surgery in New York City. “This is the time that the uric acid, or urate, crystals are collecting in the joints and can cause inflammation later on.”

But high uric acid isn’t enough for a diagnosis of gout itself. “Most people with hyperuricemia never develop clinical gout,” says Alireza Meysami, MD, FACR, FACP, rheumatologist at the Henry Ford Health System in Michigan.

Stage 2: Acute Gout

At this point, that sudden, unexpected nighttime attack of gout symptoms might occur.

“This is when the person has pain, redness, and swelling of a joint, most commonly in the big toe, the foot, the ankle or the knee, but gout can start in other joints as well,” says Dr. Fields. “This is when the urate crystals are released into the joint fluid and cause an inflammatory reaction, bringing in many white blood cells and releasing inflammatory chemicals that cause the pain, redness, and swelling.”

If you think you’re experiencing a gout attack, see your primary care doctor or a rheumatologist to begin treatment for the disease. It’s important to see a doctor during a gout flare because your doctor may want to remove fluid from the affected joint and look at it under a microscope to check for the presence of uric acid crystals. Identifying uric acid crystals in joint fluid helps confirm a gout diagnosis.

Stage 3: Intercritical Gout

After a first gout flare, 75 percent of people will have a second within a year; but some people can go years before another attack, says Dr. Fields. The in-between stage is “where a person has already had a gout flare but is presently not having any joint pain or swelling,” he says. “Almost all gout patients will go through this phase, since it is the nature of gout to have flares and then quiet down for a period of time before the next flare.”

Even though it may seem like nothing is happening, this is the point in which patients should begin long-term treatment. Lowering uric acid levels with medication can prevent future gout flares and long-term complications that go with them.

Stage 4: Chronic Gout

This stage is also called “tophaceous gout” because the uric acid deposits can form nodules called “tophi,” often at the bunion point of the big toe or at the elbow. But tophi can form anywhere in the body. “This stage is where a person can have some joint pain from gout just about all the time,” Dr. Fields says. “It usually takes many years of uncontrolled gout for someone to get into this stage.”

During this stage, progressive joint damage develops, so patients with gout should be treated before this starts happening. “Treatment delays can make gout worse,” Dr. Meysami says.

How to Know If Your Gout Is Progressing

As you become more familiar with gout symptoms, you may be able to sense that a gout attack is coming on. “Worsening of pain, swelling, redness, and warmth of the affected joint during the attack is the sign of progression of that attack,” Dr. Meysami says.

In addition, the disease overall may progress with “recurrent or more frequent gout attacks with longer duration, the involvement of more joints, and the presence of tophi,” Dr. Meysami says.

If you have more than one gout flare a year, it’s really important to get on a regular gout medication, says Dr. Fields.

What Makes Gout Get Worse

Without treatment, gout will usually progress. In addition, certain factors may trigger gout flares. “Anything that makes urate levels go suddenly up or down can set off gout,” Dr. Fields says.

Diet

This may include eating foods high in purines, which get broken down into urate, such as red meat and shellfish. Foods high in fructose can also increase the body’s production of urate. Alcohol decreases the excretion of uric acid in urine, which can cause uric acid levels to increase. Specifically, “beer not only has the effect of alcohol on uric acid in the urine, but also has protein that breaks down to purine and then urate, so it increases urate in two ways,” Dr. Fields says.

Although you may want to limit foods high in purines to prevent flares, both doctors we interviewed said that diet alone isn’t enough to control gout. “Strict dietary purine restriction is rarely recommended, as it lowers mean serum [blood] urate levels by only about 1 mg/dl, which isn’t enough for most patients,” Dr. Meysemi says.

Gout was once called the “disease of kings,” but it was misunderstood to be simply caused by rich food and drink. “Gout is a genetic disease — in which your body either puts too much urate into the urine or makes too much urate — and not a dietary disease,” Dr. Fields says. “Watching your diet can definitely help with gout flares, but to counteract a genetic tendency to gout you almost always need medication.”

So if you notice that certain foods bring on gout symptoms, avoid them. “The consumption of alcoholic beverages or rich foods can trigger gout attacks in some patients, and the individual patient should avoid triggers known to cause attacks,” Dr. Meysemi says.

Obesity

However, one of the risk factors for gout is obesity. In fact, gout has become more prevalent recently possibly to due to rising levels of obesity. “Weight loss in someone who is obese will have a greater urate-lowering effect than a purine-free diet,” Dr. Meysemi says. To that end, a healthy diet and exercise can help you lose weight and reduce your chances of disease progression.

Stress and Injury

Emotional stress can also bring on a gout attack. So can physical trauma to the foot (such as might occur during running), which may release some crystals and cause an inflammatory reaction.

“We don’t discourage people with gout from running or other exercise,” Dr. Fields says. “But if someone has a gout flare in the foot, ankle, or knee, we suggest they stay off the foot as much as possible, since further trauma to a joint with a gout flare can prolong the flare.”

Starting a treatment regimen can also unintentionally set off a flare; but other medications can also be given to help mediate this risk.

How Gout Treatment Prevents Disease Progression

Fortunately, in part because of its long history, gout is one of the most well-understood and most medically treatable forms of arthritis. “The progression of gout is preventable by starting appropriate treatment as soon as possible,” Dr. Meysami says. “Uric acid-lowering agents, such as allopurinol [a medication that’s been used since the 1960s], can decrease uric acid levels and prevent gout attacks.”

During flares, gout patients can take NSAIDs (non-steroidal anti-inflammatory drugs) or corticosteroids to calm the attack. Local steroid injections may also be given. A medication called colchicine (Colcrys) is also often used to stop acute attacks, but it’s given now at a much lower dose in order to avoid side effects, including stomach upset.

After a flare ends, long-term treatment can begin. “Almost all people with gout will need medication to control their urate,” Dr. Fields says. “To get a good outcome, people with gout need to get their blood urate level below 6.0 mg/dl and keep it there. By doing that, the body will gradually pull the urate crystals out of their joints, and the flares can stop.” Tophi will also gradually disappear.

Medications called xanthine oxidase inhibitors limit the amount of uric acid your body produces. These include allopurinol (Zyloprim and Aloprim) and febuxostat (Uloric). Colchicine, which decreases the inflammatory response to gout, may also be given along with allopurinol at the start of long-term treatment after a flare subsides.

Another class of drugs called uricosurics help your kidneys remove uric acid from the body. These include probenecid (Probalan) and lesinurad (Zurampic). An infused drug called pegloticase (Krystexxa) can help the body eliminate uric acid in people whose gout hasn’t been well controlled with other medication. New medications, including a biologic currently FDA-approved for rheumatoid arthritis, are on the horizon for gout treatment as well.

Your doctor will review your medical history for any contraindications for gout medications. You may be directed to stop taking diuretics (water pills), as these can contribute to uric acid buildup.

In addition to weight loss, diet, and physical exercise, talk to your doctor about any other home remedies for gout — but you’ll almost always need meds as well. For example, “cherry juice may slightly lower urate level but in general is not advised [alone], since if someone is having trouble with gout they should be on a medication such as allopurinol, which is much more potent,” Dr. Fields says.

Can Gout Be Cured?

“‘Cure’ is a very strong word, but we can certainly treat the gout and put it in remission by giving the treatment as mentioned,” Dr. Meysami says.

Whether to use the word “cure” may be a matter of semantics: A patient’s gout tendency may never go away but can be well-controlled. “Treatments for gout are extremely good, and the vast majority of gout patients can expect to be ‘cured,’” Dr. Fields says. “‘Cured’ is in quotes since it means that gout flares can completely disappear, but the person would need to stay on their medicine.”

Gout progression, though, certainly isn’t inevitable, which is close to the best news any gout patient can hear.

Keep Reading

Allopurinol – Pharmasave – Pharmasave

Before you begin taking a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should take this medication.

Drowsiness/reduced alertness: This medication may cause drowsiness, affecting your ability to drive or operate machinery. Avoid driving, operating machinery, or performing other potentially hazardous tasks until you have determined how you are affected by this medication.

Use appropriate caution if you plan to do activities requiring alertness.

Gout: Do not start allopurinol treatment until an acute attack of gout has completely subsided, as further attacks may be caused by this medication. Acute gout attacks may occur at the start of treatment with allopurinol for people who have not taken the medication before. If an acute gout attack develops after starting this medication, call your doctor.

Hypersensitivity syndrome: A severe allergic reaction called hypersensitivity syndrome has occurred for some people with the use of allopurinol. This reaction involves a number of organs in the body and may be fatal if not treated quickly. Stop taking the medication and get immediate medical attention if you have symptoms of a severe allergic reaction, including fever, swollen glands, yellowing of the skin or eyes, or flu-like symptoms with skin rash or blistering.

Kidney function: Kidney disease or reduced kidney function may cause this medication to build up in the body, causing side effects. If you have reduced kidney function or kidney disease, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Liver function: Allopurinol may reduce liver function and can cause liver failure. If you have liver problems, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed. Your doctor may want to test your liver function regularly with blood tests while you are taking this medication.

If you experience symptoms of liver problems such as fatigue, feeling unwell, loss of appetite, nausea, yellowing of the skin or whites of the eyes, dark urine, pale stools, abdominal pain or swelling, and itchy skin, contact your doctor immediately.

Skin rash: If you develop a skin rash, stop taking this medication and contact your doctor. The skin rash may be the first sign of a serious allergic reaction to the medication.

Pregnancy: Allopurinol is not recommended for women who are or may become pregnant unless the potential benefits outweigh the possible risks. If you are or may be pregnant, talk to your doctor about the risks and benefits of this medication.

Breast-feeding: This medication passes into breast milk. If you are a breast-feeding mother and are taking allopurinol, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

Children: Children should not take allopurinol, except in cases where increased uric acid levels in the blood are associated with cancer or with Lesch-Nyhan syndrome. The safety and effectiveness of allopurinol for this age group have not been established in treatment of other conditions.

Allopurinol in Gout: Is There a Mortality Benefit?

The effects of allopurinol treatment on mortality among patients with gout remain uncertain, with a new meta-analysis finding conflicting results.

In a systematic review of the literature that identified four studies assessing all-cause or cardiovascular mortality in patients with gout receiving allopurinol, two of the studies found protective effects, one found no significant association, and another found no benefits for patients with dose escalation, reported Edward Roddy, PhD, and colleagues from Keele University in Staffordshire, England.

As shown in their study online in Arthritis Care & Research, pooled data for all-cause mortality in the four studies demonstrated no significant association with allopurinol use in gout, with an adjusted hazard ratio of 0.80 (95% CI 0.60-1.05).

Effective treatment is available for gout, and international guidelines recommend that all patients with confirmed gout be offered urate-lowering therapy. Allopurinol is the first-line choice, starting in dosages of 100 mg/day or less and titrating upward until serum urate is below 6 mg/dL. At that urate target, urate crystals can resolve and new depositions can be prevented.

Aside from its efficacy in lowering urate levels and successfully treating gout, allopurinol has other beneficial effects, including reducing the risks of renal events such as doubling of serum creatinine and the initiation of dialysis in patients with chronic kidney disease. The drug also has demonstrated improvements in endothelial function in patients with heart failure.

Still, despite the evidence for benefit, fewer than one-third of patients receive allopurinol, and of those, only 40% undergo treatment escalation to the serum urate target. The reasons for suboptimal use of allopurinol are complex, but “one contributing factor relates to the apprehension of patients and clinicians to initiate lifelong treatment without a clear understanding of the long-term effects,” Roddy and co-authors observed.

In a study of almost 10,000 veterans with hyperuricemia (serum urate above 7 mg/dL) with or without gout diagnoses, treatment with allopurinol was associated with a 25% reduced risk of death.

However, whether mortality is decreased among patients who have confirmed gout is still uncertain, so Roddy’s group conducted a systematic review and meta-analysis of the available data in cohort studies, identifying four that were published through 2018.

  • The first study, by Chen et al., included 286 patients with gout whose medical insurance data were obtained from the MJ Health Screening Center in Taiwan from 1997 to 2002. Patients’ mean age was 52.7, and, as in the other three studies, the majority of patients were male. The adjusted hazard ratio for all-cause mortality in this study was 0.39 (95% CI 0.22-0.70)
  • A second study, by Dubreuil et al., conducted in the U.K. with data from the Health Improvement Network from 2000 to 2010 also found protective effects for allopurinol on all-cause mortality. This study included 483 patients with gout whose mean age was 67, and found an adjusted hazard ratio of 0.81 (95% CI 0.70-0.92)
  • But in the third study, also from the U.K. and analyzing outcomes from the Clinical Practice Research Datalink from 1995 to 2013, Kuo et al. found no association of all-cause mortality with allopurinol use. The sample included 3,519 patients with gout whose mean age was 64. In a 1-year landmark analysis, the adjusted hazard ratio for all-cause mortality was 0.99 (95% CI 0.87-1.12) and at 3 years, the hazard ratio was 1.01 (95% CI 0.92-1.09)
  • The fourth study, by Coburn et al., included 6,428 patients with gout who escalated their allopurinol doses with a goal of serum urate below 6 mg/dL, comparing them with an equivalent number of patients who did not have dose escalation. Dose escalators had a significant increase in all-cause mortality, with a hazard ratio of 1.08 (95% CI 1.01-1.17), and in a sensitivity analysis that limited the analysis to patients who achieved the target serum urate level, a nonsignificant reduction of 7% was seen for cardiovascular mortality (HR 0.93, 95% CI 0.76-1.14)

As to why Roddy and colleagues were unable to detect any significant protective effects of allopurinol on mortality, they said their analysis focused on observational data in real-world clinical use rather than clinical trials. In routine use, the team noted, doses of allopurinol are often far below what is needed for optimal urate control, and previous studies that have demonstrated mortality benefits have involved the use of higher doses, up to and exceeding 600 mg/day, rather than the typical 100 to 300 mg/day.

“The small number of studies suitable for inclusion and the evidence from the wider literature that allopurinol may have cardiovascular and renal benefits, suggests that further studies into the effect of allopurinol use on mortality in people with gout are required, particularly regarding the role of allopurinol dose and the importance of reaching target serum urate levels,” the researchers concluded.

Last Updated April 16, 2020

Disclosures

The authors received support from the U.K. National Institute for Health Research.

They reported no conflicts of interest.

90,000 results of a randomized study CARES (Cardiovascular Safety of Febuxostat and Allopurino

MI – myocardial infarction

KKr – creatinine clearance

MK – uric acid

NSAIDs – non-steroidal anti-inflammatory

preparations

CVD – cardiovascular disease

Prerequisites for the study

Gout is a chronic disease characterized by hyperuricemia, arthropathy, tophus formation and urolithiasis, which is associated with an increased risk of cardiovascular disease (CVD) and chronic kidney disease [1].In patients with gout, the risk of CVD complications, including the risk of death, is significantly higher than in those without gout [2, 3]. The publication by experts of the US Food and Drug Administration of a recommendation document, which emphasized the requirements for assessing the safety of hypoglycemic drugs in terms of their effect on the risk of CVD complications [4], became the basis for verification in similar studies of such safety and other therapeutic agents. including drugs for the treatment of patients with gout.

Febuxostat is a non-purine xanthine oxidase inhibitor that is used to reduce the severity of hyperuricemia in patients with gout. Febuxostat inhibits both oxidized and reduced forms of xanthine oxidase and reduces the formation of uric acid (MC) [5]. The use of febuxostat provides highly selective and potent suppression of xanthine oxidase and a more pronounced hypouricemic activity compared with the use of allopurinol in commonly used doses [6]. During development, febuxostat was compared with placebo and allopurinol in clinical trials involving more than 5,000 patients with gout [5-7].The results of such studies suggested a slight increase in the incidence of CVD complications with febuxostat.

Purpose of the study

In accordance with the requirements of the US Food and Drug Administration, test the hypothesis that taking febuxostat is as safe as taking allopurinol in terms of its effect on the risk of severe CVD complications in patients with gout and an established CVD diagnosis.

Study structure

A multicenter, randomized, double-blind study carried out in 320 research centers in North America to test the hypothesis that febuxostat is not less safe than allopurinol; median follow-up is 32 months (maximum follow-up is 85 months).

The study included patients who were diagnosed with gout according to the criteria of the American Rheumatology Association [8] and had a history of CVD prior to randomization.In addition, for inclusion in the study, it was required that the concentration of MC was not less than 420 μmol / L or not less than 360 μmol / L in case of insufficiently effectively treated gout after a washout phase for 1-3 weeks, in which the patient did not take previously used drugs for treating gout. A history of CVD was a criterion for inclusion in the study if the patient had previously suffered myocardial infarction (MI), was hospitalized for unstable angina pectoris, suffered a stroke, was hospitalized for transient cerebrovascular accident, had peripheral vascular disease, as well as diabetes mellitus with signs of micro- or macrovascular disease.Details of the initial characteristics of patients are presented in the table. Table. Baseline characteristics of patients included in the study Note. Data are presented as percentages of patients, mean ± SD, or median (interquartile range), unless otherwise indicated. CVD – cardiovascular disease; CKD is a chronic kidney disease.

Intervention

Patients were assigned to the febuxostat group or the allopurinol group.Both drugs were prescribed once a day. Randomization was performed with stratification depending on the calculated creatinine clearance (CCr) at enrollment in the study (60 ml / min or more, or in the range from 30 ml / min or more to less than 60 ml / min).

The dose of allopurinol was adjusted according to renal function. Patients in whom the calculated CCr was at least 60 ml / min began to take allopurinol 300 mg once a day, and then the dose was increased by 100 mg every month, either until the MC concentration was less than 360 μmol / L or the dose of allopurinol 600 mg was reached. Once a day.Patients in whom the calculated CCr was in the range from 30 ml / min to less than 60 ml / min began to take allopurinol 200 mg once a day and then the dose was increased by 100 mg per month until the MC concentration in the blood was less than 360 μmol / l or reaching a dose of allopurinol 400 mg once a day.

Febuxostat dose did not change with renal function. Patients assigned to the phlebuxostat group started taking the drug 40 mg once a day and continued to use this dose if the MC concentration remained less than 360 μmol / L after 2 weeks of therapy.If the blood MC level was more than 360 μmol / L during the visit to the study center 2 weeks after randomization, the dose of febuxostat was increased to 80 mg once a day and this dose was maintained until the end of the study.

Information on MK concentration was provided to investigators only during the 10-week dosing period in order to facilitate dose escalation of study drugs based on a response assessed by blood MK level.During this period, study drugs were administered according to a double-blind, double, placebo-controlled study protocol using an interactive voice system. This approach was used to prevent blinding impairment in patients who did not receive study drug dose adjustments. After the completion of dose selection, information about the level of MC in the blood was hidden from both the researchers and representatives of the company funding the study, and the interactive voice system was used only to regulate the dispensing of the drug during the course of the study.

At the first visit to the study center, all hypouricemic drugs were discontinued and, in the absence of a history of unacceptable side effects with colchicine, colchicine 0.6 mg / day was prescribed to prevent exacerbation of gout. All patients received prophylactic colchicine during the first 6 months after randomization. If the intake of colchicine led to the development of unacceptable side effects and the calculated CCr was not less than 50 ml / min, the patients were prescribed naproxen (250 mg twice a day) in combination with lansoprazole (15 mg once a day).If the patient could not take either colchicine or naproxen, other non-steroidal anti-inflammatory drugs (NSAIDs) or prednisolone could be used for prophylaxis, or the investigator could choose a treatment strategy for an exacerbation of gout.

Patients had to visit the research center for the first examination and then after 2, 4, 6, 8, 10 and 12 months, and then 24 months after randomization and then every 6 months until the end of the study. Patients with reduced renal function or patients aged 65 years and older at randomization also visited the study center 9 and 15 months after randomization to assess blood biochemical parameters.If the patient agreed to be monitored but did not attend the research center, the patient was contacted by telephone, but this was not considered preferred or recommended.

Assessment Criteria / Clinical Outcomes

Main composite indicator: the incidence of such a first adverse outcome as death from CVD complications, non-fatal MI, non-fatal stroke, or myocardial revascularization for unstable angina.

Additional indicators: combined mortality rate from CVD complications, incidence of non-fatal MI, non-fatal stroke, as well as selected components of the main indicator.

Key Outcomes

In the period from April 2010 to May 2017, 6198 patients were included in the study. Eight patients did not take any study drug pills, so 6190 patients were included in the modified analysis assuming that all patients accepted the prescribed treatment.There were no significant differences between groups in terms of baseline characteristics.

In the febuxostat group, the final study drug dose was 40 and 80 mg in 61 and 39% of patients, respectively. In the allopurinol group, in accordance with a specific protocol for the study of CCr, the dose of allopurinol 200, 400, 300, 500 and 600 mg was taken by 21.8, 44.6, 25.2, 4.3 and 4.1% of patients, respectively.

Overall, 56.6% of patients steadfastly discontinued the study drug: 57.3% and 55.9% in the febuxostat and allopurinol groups, respectively.The proportion of patients who did not attend the research center for the next scheduled examination, in general, reached 45%: in the febuxostat group and the allopurinol group, 45 and 44.9%, respectively. The median duration of taking febuxostat and allopurinol was 728 and 719 days, respectively. Median follow-up times in the febuxostat and allopurinol groups were 968 and 942 days, respectively.

The proportion of patients whose blood MC concentration was less than 360 μmol / L 2 weeks after the start of therapy was higher in the febuxostat group than in the allopurinol group; after that, in the course of the study, in a larger number of patients in the febuxostat group compared with the allopurinol group, the blood MC concentration was less than 360 μmol / L according to the data of most analyzes, despite the fact that the differences between the groups were small.In addition, in the febuxostat group as compared to the allopurinol group as a whole, the proportion of patients with blood MC levels of less than 300 μmol / L was higher during the study. The incidence of exacerbation of gout was similar in the febuxostat group and the allopurinol group, amounting to 0.68 and 0.63 cases per person per year, respectively.

In the course of the study, there were no statistically significant differences between the groups in the concentration of electrolytes, glucose and lipids in the blood, as well as in the level of blood pressure and the frequency of use of drugs for the treatment of CVD.

Additional adverse clinical outcomes developed after the development of 624 adverse clinical outcomes, which became the basis for the end of the study, and before the closure of the database. The results of the full analysis indicated a similar incidence of adverse outcomes included in the main indicator: such outcomes in the febuxostat group and the allopurinol group developed in 10.8 and 10.4% of patients, respectively, during follow-up, the median duration of which reached 32 months (hazard ratio 1 , 03 at the upper limit of one-sided 98.5% CI 1.23; p = 0.002 for the analysis performed to test the hypothesis of no less high efficacy of febuxostat compared with allopurinol).In the analysis of additional indicators of the incidence of non-fatal adverse outcomes, the risk ratios were similar to those in the study as a whole.

However, the risk of death from any cause and the risk of death from CVD complications were higher in the febuxostat group than in the allopurinol group. In the febuxostat and allopurinol groups, 7.8% and 6.4% of patients died from any cause, respectively (hazard ratio 1.22, 95% CI 1.01 to 1.47; p = 0.04), and from CVD complications – 4.3 and 3.2% of patients, respectively (hazard ratio 1.34 at 95% CI 1.03 to 1.73; p = 0.03).Among the causes of death from CVD complications, the most frequent was sudden death from complications of heart disease: this cause of death in the febuxostat group and the allopurinol group was observed in 2.7 and 1.8% of patients, respectively. The incidence of hospitalizations for heart failure and hospitalizations for non-ischemic arrhythmias, as well as the incidence of thromboembolic complications and hospitalizations for transient cerebrovascular accident were similar in the two groups.

The results of the analysis of the main indicator in subgroups indicated the absence of heterogeneity in subgroups of patients with certain baseline characteristics. For CVD mortality, there was an interaction with NSAID use and no low-dose aspirin (unstandardized p <0.05 for both comparisons).

According to the planned analysis of the incidence of adverse outcomes included in the main indicator, which developed during the period of study drug administration or within 30 days after discontinuation of therapy, such outcomes in the febuxostat group and allopurinol group developed in 7.8 and 7.7% of patients respectively (risk ratio 1.00 with the upper limit of one-sided 98.5% CI 1.22).This analysis found that mortality from CVD complications was statistically significantly higher in the febuxostat group compared with the allopurinol group (hazard ratio 1.49; 95% CI 1.01 to 2.22; p = 0.047).

The results of the secondary analysis of the incidence of adverse outcomes included in the main combined indicator that developed during the period of use of the study drugs indicated a similar incidence of such outcomes in the febuxostat group and the allopurinol group (such outcomes developed in 6.2 and 6.4% of patients, respectively ; risk ratio 0.94 with the upper limit of one-sided 98.5% CI 1.17).The risk of death from any cause and the risk of death from CVD complications were higher in the febuxostat group than in the allopurinol group.

In patients with gout and concomitant severe CVD, taking febuxostat compared with allopurinol was no less safe in terms of its effect on the risk of CVD complications. Overall mortality and mortality from CVD complications were higher with febuxostat compared with allopurinol.

Questions and comments

1.What are the main findings of study
CARES
?

The CARES study found that, in general, the incidence of severe CVD complications was similar with febuxostat and allopurinol in patients with gout and concomitant CVD. However, mortality from CVD complications and overall mortality were higher in the febuxostat group than in the allopurinol group.

2. To what extent has the safety of xanthine oxidase inhibitors been studied previously?

Despite the fact that xanthine oxidase inhibitors are widely used in clinical practice in patients with gout [9], there were only limited data on the safety of their use on the impact on the risk of CVD complications, which were obtained in the course of large RCTs.In the course of the program, which included more than 5,000 patients, the incidence of CVD complications was higher in patients taking febuxostat (0.74 per 100 person-years, 95% CI 0.36 to 1.37), compared with patients who took allopurinol (0.60 per 100 person-years, 95% CI from 0.16 to 1.53) [6, 7, 10]. On the contrary, the results of observational studies suggested that there is an advantage of taking febuxostat or allopurinol in terms of the effect on the risk of CVD complications in patients with gout and concomitant CVD [11, 12].

3. How did the characteristics of patients included in this study differ from those of participants in previous studies?

Patients included in the CARES study had a significantly higher risk of CVD complications compared with participants in other studies assessing the safety of various drugs for the treatment of gout in terms of their effect on the risk of CVD complications [13, 14], and the risk of CVD complications in during the study CARES exceeded 10%.The safety indicators in this study were predetermined, and the outcomes included in such indicators were confirmed by the members of the CVD complications confirmation committee in the absence of information about the results of the allocation of patients to a specific group of tactics; therefore, the safety data obtained in the CARES study may be more reliable than data based on standardized adverse event reports.

4. Why did the CARES study increase mortality with febuxostat compared with allopurinol?

Indeed, unexpectedly for the authors of this study, mortality with febuxostat was higher than with allopurinol, which was due to an increase in mortality from CVD complications.The results were similar based on the modified analysis performed on the assumption that all patients accepted the prescribed treatment, and the planned analysis, which included data on adverse outcomes that developed during the period of study drug intake and within 30 days after discontinuation of therapy. The mechanism for this increased risk of death with febuxostat compared with placebo remains unclear. The results of preclinical studies of febuxostat showed no toxic effect on cardiac function or metabolism and an increased risk of arrhythmias [15-19].In addition, the incidence of confirmed non-fatal complications, including myocardial infarction, myocardial revascularization, and the incidence of arrhythmias or hospitalizations for heart failure were similar in the febuxostat group and the allopurinol group.

5. How homogeneous were the data on mortality from CVD complications?

In the course of performing the corresponding analysis, heterogeneity in terms of the effect on the risk of death from CVD complications was established only in 2 subgroups: in patients with concomitant use of aspirin or NSAIDs.The use of such drugs may be associated with more frequent exacerbations of gout, which in turn may lead to an increase in the incidence of CVD complications [20]. However, it should be noted that there were no significant differences between the groups, both in the severity of the decrease in the concentration of MC in the blood, and in the frequency of exacerbations of gout. Moreover, the frequency of development of exacerbations of gout and their severity are difficult to establish accurately during clinical trials. Finally, the findings may have been random due to the large number of tests performed and the small number of adverse outcomes in each group.

6. What are the most important limitations of this study?

An important limitation of this study, according to the authors, was the large number of participants who discontinued study drugs early and participants who were not followed up until the end of the study. Early discontinuation of study drugs could lead to systematic errors in the analysis towards the null hypothesis, which could make it difficult to identify statistically significant differences between groups in the main indicator, as well as additional indicators, including the incidence of non-fatal adverse clinical outcomes.The impact of a high incidence of loss of contact with patients is more difficult to predict, since the loss of contact can be accidental. It should be noted, however, that approximately the same number of patients discontinued early participation in the study in both groups, and the baseline characteristics of such participants were similar to those of patients who were observed until the end of the study.

7. How can I summarize the main results of the study once again?
CARES
?

In patients with gout and CVD, the use of febuxostat and allopurinol generally leads to a similar incidence of CVD complications.However, in the febuxostat group compared with the allopurinol group, there was an increase in overall mortality, which was due to an increase in mortality from CVD complications.

90,000 contraindications, side effects, dosages, composition – 100 and 300 mg tablets in the drug guide

There is no current clinical data documentation for this drug that could be used to support the determination of the frequency of adverse events. Adverse events may vary in frequency depending on the dose received, as well as on the use in combination with other drugs.

The frequency categories given below assigned to adverse reactions to the medicinal product are estimates: for most reactions, no suitable data are available for calculating the frequency. Adverse reactions to a medicinal product identified during post-registration observation are considered rare or very rare.

When classifying phenomena by frequency, the following designations were used: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10,000 to <1/1000), very rare (<1/10,000), unknown (cannot be estimated based on available data).

Allopurinol-related adverse reactions in the general population of treated patients are rare and generally mild. A higher incidence is observed in the presence of impaired renal and / or liver function.

Infectious and parasitic diseases: very rarely – boil.

From the hematopoietic system: very rarely – agranulocytosis 1 , aplastic anemia 1 , thrombocytopenia 1 , granulocytosis, leukopenia, leukocytosis, eosinophilia and true erythrocytic aplasia.

From the immune system: infrequently – hypersensitivity 2 ; very rarely – angioimmunoblastic T-cell lymphoma 3 .

From the side of metabolism: very rarely – diabetes mellitus, hyperlipidemia.

Mental disorders: very rarely – depression.

From the nervous system: very rarely – coma, paralysis, ataxia, peripheral neuropathy, paresthesia, drowsiness, headache, taste perversion.

From the side of the organ of vision: very rarely – cataract, visual impairment, maculopathy.

On the part of the organ of hearing and balance: very rarely – dizziness with a feeling of rotation (vertigo).

From the cardiovascular system: very rarely – angina pectoris, bradycardia, arterial hypertension.

From the digestive system: infrequently – vomiting 4 , nausea 4 , diarrhea; very rarely – bloody vomiting, steatorrhea, stomatitis, changes in the rhythm of bowel movements; unknown – abdominal pain.

From the liver and biliary tract: infrequently – deviation of liver function tests 5 ; rarely – hepatitis (including liver necrosis and granulomatous hepatitis) 5 .

Skin and subcutaneous tissue disorders: often – rash; rarely – Stevens-Johnson syndrome / toxic epidermal necrolysis 6 ; very rarely – angioedema 7 , drug rash, hair loss, hair color change.

From the musculoskeletal system: very rarely – muscle pain.

From the urinary system: rarely – urolithiasis; very rarely – hematuria, azotemia.

From the genitals and mammary gland: very rarely – male infertility, erectile dysfunction, gynecomastia.

General disorders and disorders at the injection site: very rarely – edema, general malaise, asthenia, fever 8 .

1 There are very rare reports of cases of thrombocytopenia, agranulocytosis and aplastic anemia, especially in patients with impaired renal and / or liver function, which emphasizes the need for special attention to this group of patients.

2 Serious hypersensitivity reactions, including skin reactions with flaky skin, fever, lymph node involvement, joint pain and / or eosinophilia, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare. Hypersensitivity-related vasculitis and tissue reactions can manifest in different ways, incl. hepatitis, kidney damage, acute cholangitis, xanthine stones and, very rarely, seizures.Reports of acute anaphylactic shock are very rare. If these reactions occur, which can happen at any time during the course of treatment, the use of allopurinol should be stopped immediately and permanently. Delayed disorder with multiple organ hypersensitivity (known as hypersensitivity syndrome or DRESS drug reaction with eosinophilia and systemic manifestations) with fever, rash, vasculitis, lymph node involvement, pseudolymphoma, joint pain, leukopenia, eosinophilia, hepato-splenomegaly abnormalities and the syndrome of the disappearance of the biliary tract (destruction and disappearance of the intrahepatic biliary tract) occurs in various combinations.Other organs (eg, liver, lungs, kidneys, pancreas, myocardium, and large intestine) may be affected. If these reactions develop, which can happen at any time during the course of treatment, the use of the drug Milurit ® should be stopped immediately and permanently. Patients with hypersensitivity syndrome and SJS / TEN should not be re-started to take the drug. Corticosteroids may be helpful in treating skin hypersensitivity reactions. In cases of development of generalized hypersensitivity reactions, these patients usually had impaired renal and / or liver function, especially when there was a lethal outcome.

3 Angioimmunoblastic T-cell lymphoma has been reported very rarely in post-biopsy cases of generalized lymphadenopathy. It appears to be reversible when allopurinol is discontinued.

4 Nausea and vomiting were reported in early clinical studies. More recent reports suggest that this reaction is not a significant problem and can be avoided by taking allopurinol after meals.

5 Liver dysfunctions have been described without more generalized hypersensitivity manifestations.

6 Skin reactions are the most common type of reaction and can occur at any time during treatment. They can present as an itchy, maculopapular, sometimes scaly or purpuric rash, in rare cases, exfoliative lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS / TEN). The greatest risk of developing SJS and TEN or other serious hypersensitivity reactions is observed during the first weeks of using allopurinol.The best treatment results for such reactions are achieved with early diagnosis and immediate discontinuation of all suspected drugs. If such a reaction develops, the drug Milurit ® should be canceled immediately. When returning to normal after mild reactions, the use of allopurinol can be resumed at a low dose (such as 50 mg / day), which can be gradually increased. The HLA-B * 5801 allele has been shown to be associated with the risk of developing allopurinol-dependent hypersensitivity syndrome and SJS / TEN.The use of genotyping as a screening tool for making decisions regarding treatment with allopurinol has not been introduced into practice. If a skin reaction occurs repeatedly, the use of allopurinol should be discontinued immediately and permanently, given the possibility of more severe hypersensitivity. If the presence of SS / TEN or other serious hypersensitivity reactions cannot be ruled out, allopurinol should not be resumed, due to the possibility of a severe or even fatal reaction.The basis for making a decision is the presence of a clinical diagnosis of SJS / TEN. If such reactions develop at any time during the course of treatment, the use of allopurinol should be stopped immediately and permanently.

7 The development of angioedema in combination with signs and symptoms of a more generalized hypersensitivity reaction, as well as without their presence, is described.

8 The development of fever is described in combination with signs and symptoms of a more generalized hypersensitivity reaction, as well as without their presence.

Suspected adverse reaction reports

Reports of suspected adverse reactions observed after registration of a medicinal product are of high importance. They allow you to continue to monitor the risk-benefit ratio of a given drug. Health workers are called upon to report all suspected adverse reactions in accordance with the national reporting system.

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Clinical Study Gout: Febuxostat 80 / 120mg / day, Allopurinol 100 to 600 mg / day, Colchicine, Naproxen, indipendente – Clinical Research Register

Intervention

Intervention type:

Drug

Intervention name:

Febuxostat 80 / 120mg / day

Description:

Starting dose and dose regimen of Febuxostat: the initial daily dose is 80 mg.In case the patient has the serum urate concentration> 6 mg / dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained for the duration of the study.

Arm Group label:

Febuxostat 80/120 mg / day

Another name:

Adenuric

Intervention type:

Medicine

Intervention name:

Allopurinol 100 to 600 mg / day

Description:

Initial dose and dosing regimen of allopurinol: The initial daily dose of allopurinol is 100 mg, which should be increased by 100 mg every 2 weeks in patients with serum urate concentrations> 6 mg / dL.The maximum daily dose of allopurinol achievable in the study will depend on renal function and tolerability, but will not exceed 600 mg.

Arm Group label:

Allopurinol 100 to 600 mg / day

Another name:

Allopurinol

Intervention type:

Medicine

Intervention name:

Colchicine

Description:

Colchicine tablets 0.5 mg. To prevent exacerbations at the initial stages of treatment, patients will be treated with colchicine 0.5 – 1 mg once a day for at least 6 months.

Intervention type:

Medicine

Intervention name:

Naproxen

Description:

Naproxen sodium 550 mg film-coated tablets. If colchicine is intolerant, patients will be treated for at least 6 months with naproxen 550 mg twice daily and omeprazole (20-40 mg once daily) if indicated.

Another name:

Synflex

Intervention type:

Medicine

Intervention name:

indipendente

Description:

Omeprazole 20 mg capsules co-administered to patients to protect the stomach.

Another name:

Omeprazen

Eligibility

Criteria:

Inclusion criteria: 1. male or female patients 18 years of age or older; 2. History of gout, no exacerbation 4 weeks prior to study entry. 3. History of confirmed diagnosis or history of gout. according to Wallace on email. the following 12 clinical, laboratory and radiological events: 1. the maximum inflammation developed within 1 day, 2.more than one attack of acute arthritis, 3. an attack of monoarticular arthritis, 4. redness of the joints, 5. the first. metatarsophalangeal (MTP) pain or edema, 6. unilateral first attack on the MTP joint, 7. unilateral attack of the tarsal joint, 8. suspected or confirmed tofus, 9. hyperuricemia, 10. asymmetric joint edema on radiograph, 11. subcortical cysts without erosions on X ray, 12. Negative organisms on the culture of the articular fluid; 4.Naiven ULT or have previously been treated with ULT, but without ULT treatment in the last month prior to enrollment and only if the reason for the termination of the ULT is not related to safety reasons.Patients participating in the study had elevated serum urate levels> 8 mg / dL. Risk of cardiovascular disease (CVD) based on points proposed by the Joint Task Force European Society of Cardiology and other European Societies for Cardiovascular Disease prevention in clinical practice 5 to 15% (inclusive) Patients with type 2 mellitus diabetes can be included into the study if their estimated risk of cardiovascular disease is ≤7%.7. Approved concomitant medications must remain stable for the past 2 weeks. before randomization Exclusion criterion: 1. severe chronic renal failure (creatinine clearance <30 ml / min) 2. liver failure 3. active liver disease or liver dysfunction, defined as alanine aminotransferase. (ALT) and aspartate aminotransferase (AST)> 2 times the upper limit of normal. 4. type 1 diabetes mellitus 5. life-threatening co-morbidity or serious illness and / or conditions that may interfere with treatment, safety, or adherence to protocol 6.Diagnosis or treatment of malignant neoplasms (with the exception of skin cancer in basalioma) in the previous 5 years 7. Patients who have had myocardial infarction or stroke. 8. Patients with inflammatory arthritis (eg rheumatoid arthritis, etc.) 9. Patients with congestive heart failure, class III according to the classification of the New York Heart Association (NYHA). IV 10. Patients with untreated / uncontrolled thyroid function 11. Patients with clinically severe peripheral arterial disease.12. Co-administration of any of the following: azathioprine, mercaptopurine, theophylline, meclofenamate, sulfinpyrazone, trimethoprim-sulfamethoxazole, cyclophosphamide, benzbromarone, pyrazinamide, captopril and enalapril (for Allopurinol), tegafur and tacroletica. 13. hypersensitivity to any of the active substances or to any of the excipients. 14. Any contraindications to the use of febuxostat or allopurinol (with reference to the Summary of Product Characteristics). 15. Subject is unable to take any of the protocol-required prophylactic agents for exacerbated gout.medications (NSAIDs or colchicine) due to contraindications or intolerances such as hypersensitivity, active gastric ulcer, renal failure, and / or changes in liver enzymes 16. Participation in another trial of the investigational drug or device within 30 days. before screening or prior treatment with the investigational product (s) weeks after study completion, defined as a method that results in a failure rate of less than 1% per year, for example: – combined (containing estrogen and progestogen) hormonal contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal), – hormonal contraceptives containing only progestogens associated with suppression of ovulation (oral, injection, implantable), – an intrauterine device (IUD), – an intrauterine hormone release system (IUD), – bilateral occlusion of the fallopian tubes, – a vasectomized partner (provided that the partner is the only sexual partner research participant and partner who who underwent a vasectomy, received a medical assessment of surgical success), – sexual abstinence; 18.Severe mental disorders / neurological disorders. 19. Severe concomitant pathology, including incurable diseases (cancer, AIDS, etc.) 20. abuse of alcohol, analgesics or psychotropic drugs. 21. Failure or unwillingness, in the opinion of the investigator, to follow the research procedures. including, but not limited to, the ability to obtain adequate analysis of the PWV / Pulse Wave (PWA) recording. Special attention was paid to any physical abnormalities that could affect the quality of the PWV / PWA measurement: – neck area – neck flexibility and accessibility of the carotid artery, – upper arm and thigh – eliminate any deviations that could prevent adequate cuff placement; 22.Failure or unwillingness to give informed consent.

Floor:

All

Minimum age:

18 years old

Maximum age:

N / A

Healthy volunteers:

No

Master’s illness

Gout is a classic disease in the school literature curriculum.Turgenev suffered from her, Onegin risked her getting sick, and Pushkin himself would probably get sick if he lived a little longer. Now gout is out of fashion and is no longer found in novels, but this does not mean that we have stopped hurting it. Moreover, tens of millions of people suffer from it, and vigilant scientists warn that cases are increasing every year. We tell you where it came from, to whom it is most supportive and why we cannot get rid of it once and for all.

Sated minority

In time immemorial, the ancient Greeks believed, Dionysus seduced Aphrodite.From the union of passion and alcohol, according to the satirist Lucian of Samosata, nothing good came of it: the goddess Gout was born. Vindictive and vain, she sent illness to all who doubted her power, and did not spare the doctors, who claimed that they had found a remedy for her.

The victim noticed the touch of the goddess on the big toe, and then gradually in other joints. They swelled and reddened, covered with tophuses – bulges of irregular shape. Gout visited her chosen ones at night, bringing with it a fever and sharp pain, which gradually fettered the whole body.According to the English physician of the 17th century, the pain was so severe that a person could not bear the weight of his own clothes or the vibrations of the floor of the room when someone abruptly entered it. The attacks disappeared in a few hours, but the inflamed joints prevented the patient from walking for a long time.

No matter how strong the gout attack was at night, no matter how your nerves creaked, Kistunov nevertheless went to work in the morning and promptly began accepting applicants and clients of the bank. He looked languid, tortured, and he spoke barely, barely breathing, like a dying man.

– A. P. Chekhov, “A defenseless creature”

In the text of Lucian, Gout boasts that even the heroes do not leave her: she attributes to herself the victory over Achilles, Oedipus and Odysseus (whom the old nanny in one of the episodes identified by the characteristic scar on his leg). And although other stories about these victories are silent, the words of the goddess can be considered a subtle hint of the satirist that even popular heroes were not sinless – they already knew about what causes gout in ancient times: debauchery and gluttony.Illness was God’s punishment for the intemperate.

However, the list of gout sufferers has long resembled the Forbes list. Exceptionally rich and noble people suffered from her, her attacks tormented Tiberius and Nero, Charles V and George III, as well as 20 of 34 French kings. Gout was considered the “disease of gentlemen” – as opposed to rheumatism, the “disease of the coachmen.” She was associated with talent and high intelligence (who, if not her, ruined Beethoven, Rubens and Turgenev). Gout was proud and boasted, it became a kind of pass to high society and a measure of personal merit.

Eating Hungry GIF from Eating GIFs

The King from the animated series “Disappointment” lays on sausages in the hope of earning the same impressive gout as the neighboring autocrat

And this was not the only reason why the townspeople of the 16th-18th centuries could dream about gout. It was believed that in addition to social status, she could bestow enviable health on the owner. They said that it was incompatible with other diseases – tumors and paralysis, fever and melancholy.Doctors could even recommend that their patients go to the resort to catch a long-awaited ailment there. Finally, gout has been called an excellent aphrodisiac. God’s punishment became a kind of blessing. The lives of those whom it touched, in the words of Jerome Cardan, a physician of the 16th century, was “happy in everything except pain.”

Path of the Aristocrat

Getting sick with gout, however, is not so easy. Food and a dissolute lifestyle are not enough here, you need to know exactly what to show intemperance in.

The English name for the disease – gout – comes from the Latin gutta, “drop”. It was once believed that a swollen joint accumulates excess vital juices, bodily fluids, which drain into the legs through the vessels. In fact, the reason is exactly the opposite: a hard crystal grows in the joint cavity.

Crystals of uric acid

Beale, Lionel S./ CC0

The true culprit for gout is uric acid, C 5 H 4 N 4 O 3 . It is formed when cells digest foreign DNA and RNA from food during the breakdown of purines (which include the nitrogenous bases adenine and guanine). The acid enters the bloodstream, then the kidneys must remove it from the body. But this is not always possible – if there is too much of it, then the kidneys do not have time to cope with it.And since uric acid is poorly soluble, as soon as its concentration grows a little, a crystalline precipitate begins to form. Therefore, including gout attacks, usually occur at night – in the cold, the solubility of uric acid is lower, and crystals are formed more often.

Like other types of arthritis, gout attacks the joints – this is where uric acid crystals begin to grow. Following them, immune cells enter the joint, and inflammation begins, which gradually destroys the articular surfaces of the bones.If enough uric acid remains in the blood, it can be deposited in other tissues of the body, for example, in the thin capillaries of the kidneys. And impaired renal function together with chronic inflammation is fertile ground for the development of hypertension and other problems of the cardiovascular system

“The Origin of Gout”, 19th century caricature

Henry William, 1815

There are several ways to saturate your blood with uric acid.For starters, you can inherit certain variants of genes that are responsible for the absorption of uric acid in the kidneys. The better receptors on the walls of the renal tubules bind to it, the more it will return from urine back into the blood. Therefore, the tendency of rulers to gout could be genetically determined – especially when you consider the inheritance of the crown and frequent closely related marriages within royal dynasties.

Another option is to artificially disrupt the kidneys. For example, poisoning with lead.There have been many reasons for this in history, starting with Ancient Rome, where grape syrup was boiled in lead pots, and ending with Europe, where up to the 19th century, wine and port were stored in lead barrels. So the disease of gentlemen to some extent could be just a symptom of lead poisoning, and that, in turn, – a consequence of addiction to alcohol.

Source: Martina Scholtens / CMAJ, 2008

If you did not get the “aristocratic genes”, and alcohol only comes in glass, then you can bet on the saturation of purines, leaving the cells to organize the excess of uric acid in the blood.Since the main source of purines is DNA and RNA, gout can be provoked by food, where there are relatively many of them, that is, products of animal origin (in plant foods, most of the volume is occupied by carbohydrate cell walls). First of all – meat and seafood. But dairy products or vegetables rich in purines do not come close to gout, at least according to modern estimates (there are still fewer cells in milk than in meat, and the concentration of purines in vegetables is not so high).

There is also a roundabout way for vegetarians.The release of uric acid is caused by a single carbohydrate, fructose. At the same time, purines are not included in fructose, but in order to digest it, the cell spends its “energy currency” – ATP, during which a “production waste” of AMP is formed, which already contains adenine (and this is already purine). That is why sugary drinks, which contain a lot of fructose, affect the development of gout.

Ethanol also has a similar property – to start the production of uric acid inside cells, and it works according to the same principle.Therefore, alcohol abuse could cause gout even in those aristocrats whose kidneys were working properly. However, alcohol and alcohol are different: it is known that beer, for example, has a greater “goutiness” than wine – probably due to the fact that it contains more yeast and, accordingly, nucleic acids.

I pray: “Leave me, Lord,
My honorable disease,
I am a nobleman for it!”
Not by your mean sickness,
Not hoarse, not hernia –
Noble disease
What can be found
At the top officials in the empire,
I’m sick, man!
Yes, it’s called!
To get it –
Champagne, Burgon,
Tokay, Hungarian
You have to drink for thirty years…

– N. A. Nekrasov, “Who lives well in Russia”

Round trip

In the 19th century, every self-respecting literary hero suffered from gout. Today, only fans of classic novels and the series “Disappointment” remember about her. The disease of the aristocrats is no longer on hearing, and not because the aristocrats were crushing. Rather, they began to live even better: reliable remedies appeared from attacks of pain, and inflamed joints ceased to be a sentence.

The first drugs for gout appeared in ancient times.Until the end of the 19th century, one of the main medicines was colchicine – a poisonous plant alkaloid, with which, according to legend, Medea poisoned her victims. As it turned out later, this had its own logic – colchicine blocks the assembly of the intracellular skeleton. Therefore, in large doses, it is poisonous, and in small doses it inhibits the activity (including division and movement) of immune cells, thereby slowing down the development of inflammation in the joint.

In the 19th century, doctors turned their attention to another anti-inflammatory agent – salicylates, which were later replaced by aspirin.And then George Hitchings and Gertrude Elion came up with the idea of ​​treating gout with allopurinol, for which, among other things, they received the Nobel Prize. This synthetic analogue of purine blocks enzymes in cells that break down real purines, thereby stopping the production of uric acid.

In the village, happy and horned,
Would wear a quilted robe;
I would really know life,
I would have gout at forty,
Drank, ate, bored, got fat, grew weak.
And finally, in his bed
Died in the midst of children,
Whiny women and doctors.

– A. Pushkin, “Eugene Onegin”

However, the disease itself has not gone anywhere. Moreover, it only gets bigger. According to a recent survey, the incidence of gout in the world has increased by 5.5 percent over the past 30 years, and in total it affects more than 41 million people. Most often it is found in Australia and North America, less often in Europe and Asia (in Russia, according to data for 2008, 341 thousand people suffer from it, that is, 0.31 percent of the adult population), and even less often in Africa and Latin America.In the 21st century, aristocratic gluttony and closely related marriages of royal dynasties have fallen out of practice, but gout remains a “privileged” disease that plagues wealthy white men.

It is less common in women. This is probably due to the action of estrogens (thanks to them, more uric acid remains in the urine and leaves the body). However, this gender inequity is a little smoothed out after 65 years: before that time, the ratio of men to women among patients was 4: 1, after – 3: 1.This is due to the fact that women go through menopause and the concentration of estrogen drops. In addition, women live longer on average, and therefore their proportion among patients is growing.

So, in a way, gout can be considered an age-related disease (despite the fact that in men it can appear after 30). The further, the worse the kidneys work and the more uric acid remains in the bloodstream. And other pathologies that accumulate with age – for example, obesity and changes in the tissue of the joints – only provoke the deposition of crystals.

Therefore, it is not surprising that gout is gaining ground every year. Over the past decades, we have begun to live longer and eat more (including purines in meat and sugary drinks). But along with the advantages of world domination, we got the close attention of the goddess, who still does not forgive gluttony. And this is hardly worth rejoicing: there is still no medicine that would relieve us of gout once and for all (and would not compensate for the symptoms).

Human friend

Generally speaking, the problem with an excess of uric acid in the blood could be solved very simply – get yourself an enzyme that breaks it down. Most animals have one, it is called uricase and does an excellent job with the problem. Therefore, they rarely suffer from gout, although even one tyrannosaurus is known, on the bones of which traces of characteristic damage were found. Apparently, he also succeeded in life.

Tyrannosaurus rex bones with traces of gout

Bruce M.Rothschild et al. / Nature, 1997

In humans, like some other primates, uricase does not work. The gene that encodes it broke down long ago and turned into a pseudogene. This is partly why it is rather difficult to trace how it has changed over time: it has many point substitutions that distinguish it from the corresponding gene of other mammals, but it is not clear whether they appeared before the breakdown or after.

Nevertheless, there is a suspicion that it broke down for a reason. In the human genome, there are two more genes associated with the metabolism of uric acid: these are genes for transporter proteins that are responsible for its reabsorption in the kidneys. Recently, scientists have noticed that they, too, have accumulated a number of substitutions in comparison with other mammals. Moreover, these replacements are arranged in a cunning way: some of them increase the “craving” of proteins for uric acid, while others, on the contrary, weaken. Apparently, there was a two-stage adjustment of the transporter proteins – as a result, they bind to uric acid just enough to maintain its maximum concentration in the blood, at which it does not yet precipitate.Thus, this concentration turned out to be 5-10 times higher than in other mammals, and in every fifth person it is literally on the verge of precipitation (this condition is called hyperuricemia ).

If uric acid accumulates in our blood, it means that there is some benefit to the body as a whole. What it consists of, we still do not know for sure. Some researchers, for example, believe that uric acid is structurally similar to caffeine and other neurostimulants, which means it can spur our brain activity.This is how they proposed to explain the prevalence of successful and talented people among patients with gout (apparently, at some point, their uric acid concentration went out of control).

Besides insanity, he had stomach catarrh, gout and many other diseases; he had to prescribe a diet and keep starving, but he ate and did not eat with the same pleasure, was proud of his illnesses, and even thanked Dr. Shevyrev for gout and shouted loudly at the patients who were building a snowy mountain all that day: he vaguely imagined that he was a general, appointed to oversee the construction of a formidable fortress.

– L. N. Andreev, “Ghosts”

Others believe that hyperuricemia can protect us from something. The 16th-18th century beliefs that gout reduces the risk of developing tumors or works as an aphrodisiac have not yet been confirmed. However, mice in which the uricase gene is artificially disabled and the concentration of uric acid is elevated live longer than usual, respond better to stress and tolerate brain injury. These findings are consistent with a third hypothesis for the benefits of hyperuricemia, which suggests that uric acid may act as an antioxidant, protecting neurons from stress and damage.This is probably why multiple sclerosis and Parkinson’s disease are less common among patients with gout.

One way or another, hyperuricemia and its companion gout will remain with us for a long time. At one time, uric acid crystal deposition was idealized and considered a symbol of nobility. Today, gout remains predominantly a disease of the wealthy and successful gluttons, but no longer works as a gateway to the upper strata of society. Now we have to console ourselves with the fact that this is in some way a symbol of the superiority of humans over other mammals.Uric acid has made a man out of a monkey, and perhaps will still make a superman – if only we do not allow the solution to become oversaturated.

Polina Loseva

Organization and implementation of certification of specialists with secondary medical and pharmaceutical education

Specialist certificate is a single sample document confirming the compliance of specialist training with state educational standards.

Certificate of a specialist is issued on the basis of postgraduate professional education (postgraduate study, residency), or additional education (advanced training, specialization), or a screening test conducted by the commissions of professional medical and pharmaceutical associations, on the theory and practice of the chosen specialty, legislation in the field protection of the health of citizens.

The obligation of every practicing specialist to have a certificate is defined in article 100 of the Federal Law of November 21, 2011.N 323-FZ “On the basics of protection
health of citizens in the Russian Federation “

Federal Law of November 21 2011 . N 323-FZ

“On the basics of protecting the health of citizens in the Russian Federation” (extract)

Article 100. Final provisions

1. Before January 1, 2016:

1) persons who have received higher or secondary medical education in the Russian Federation in accordance with federal state educational standards and have a specialist certificate have the right to carry out medical activities in the Russian Federation;

2) the right to engage in pharmaceutical activities in the Russian Federation belongs to persons who have received a higher or secondary pharmaceutical education in the Russian Federation in accordance with federal state educational standards and have a specialist certificate, as well as persons who have the right to
engaging in medical activities and having received additional professional education in the retail trade of medicinal products, provided they work in rural settlements in which there are no pharmacy organizations, separate subdivisions of medical organizations (outpatient clinics, paramedics and paramedic-obstetric points, centers (departments) general medical (family) practice) licensed to carry out pharmaceutical activities;

3) persons who have received medical or pharmaceutical education, who have not worked in their specialty for more than five years, may be admitted to medical activity or pharmaceutical activity in accordance with the acquired specialty after completing training in additional professional educational programs (professional retraining) and in the presence of a certificate specialist;

2.