NSAIDs – what has changed over the past 10 years? | Tsurko V.V., Shavlovskaya O.A., Fokina N.M.

Abbreviation NSAID

- does this tell you anything? If not, then we suggest expanding your horizons somewhat and finding out what these mysterious four letters mean. Read the article and everything will become absolutely clear. We hope that it will be not only informative, but also interesting!

NSAIDs stand for non-steroidal anti-inflammatory drugs - drugs are very popular and popular nowadays, because they can simultaneously eliminate pain and relieve inflammation in a variety of organs of our body.

If until now you have never had a need to take NSAIDs, this can be considered almost a miracle. You are one of the rare lucky ones, really, your health is enviable! NSAIDs are, let’s get ahead of the next question and immediately talk about the definition of the word “non-steroidal”, which means that these drugs are non-hormonal, i.e. do not contain any hormones. And this is very good, because everyone knows how unpredictable and dangerous hormonal drugs can be.

Most popular NSAIDs

If you think that NSAIDs are drugs whose names are rarely spoken in everyday life, then you are mistaken.

Many people do not even realize how often we have to use non-steroidal anti-inflammatory drugs to cure various ailments that have accompanied the human race since the expulsion of Adam and Eve from paradise.

Read the list of such products; you probably have some of them in your home medicine cabinet. So, NSAIDs include medications such as: Aspirin, Amidopyrine, Analgin, Piroxicam, Bystrumgel, Diclofenac, Ketoprofen, Indomethacin, Ketorol, Naproxen, “Ketorolac”, “Flurbiprofen”, “Voltarengel”, “Nimesil”, “Diclofenac”, “Ibuprofen”, “Indopan”, “Iprene”, “Upsarin UPSA”, “Ketanov”, “Mesulide”, “Movalis”, “ Nise", "Nurofen", "Ortofen", "Trombo ACC", "Ultrafen", "Fastum", "Finalgel".

Yes, these are all NSAID drugs. The list, although large, is, of course, far from complete. And yet, it gives a good idea of the variety of modern non-steroidal anti-inflammatory drugs.

Some historical facts

The first primitive NSAID drugs were known to people in ancient times. For example, in Ancient Egypt, willow bark, a natural source of salicylates and one of the first non-steroidal anti-inflammatory drugs, was widely used to relieve fever and pain. And even in those distant times, healers treated their patients suffering from joint pain and fever with decoctions of myrtle and lemon balm - they also contain salicylic acid.

In the mid-19th century, chemistry began to develop rapidly, which gave impetus to the development of pharmacology. At the same time, the first studies of the compositions of medicinal substances obtained from plant materials began to be carried out. Pure salicin from willow bark was synthesized in 1828 - this was the first step towards the creation of the familiar Aspirin.

But it will take many years of scientific research before this medicine comes to light. A grandiose event took place in 1899. Doctors and their patients quickly appreciated the benefits of the new drug. In 1925, when a terrible influenza epidemic hit Europe, Aspirin became a savior for a huge number of people.

And in 1950, this non-steroidal anti-inflammatory drug was included in the Guinness Book of Records as the painkiller with the largest sales volume. Well, later pharmacists created other non-steroidal anti-inflammatory drugs (NSAIDs).

For what diseases are non-steroidal anti-inflammatory drugs used?

The range of uses of NSAIDs is very wide. They are very effective in treating both acute and chronic diseases accompanied by pain and inflammation.

Nowadays, research is in full swing to study the effectiveness of these drugs in the treatment of heart and vascular diseases. And today almost everyone knows that they can be used for pain in the spine (NSAIDs for osteochondrosis are a real salvation).

Here is a list of painful conditions in the event of which the use of various non-steroidal anti-inflammatory drugs is indicated: Fever. Headaches, migraines. Renal colic. Rheumatoid arthritis. Gout. Arthrosis. Osteoarthritis. Dysmenorrhea. Inflammatory arthropathy (psoriatic arthritis, ankylosing spondylitis, Reiter's syndrome). Postoperative pain syndrome. Pain syndrome from mild to moderate severity due to injuries and various inflammatory changes.

Classification of NSAIDs according to their chemical structure

By reading this article, you have already had the opportunity to see that there are a lot of non-steroidal anti-inflammatory drugs. To navigate among them at least a little better, let's start classifying these funds.

First of all, they can be divided as follows: a group - acids and a group of NSAIDs - non-acid derivatives.

The first include: - Salicylates (you can immediately remember about “Aspirin”). — Derivatives of phenylacetic acid (“Aceclofenac”, “Diclofenac”, etc.). - Pyrazolidines (metamizole sodium, known to most of us as “Analgin”, “Phenylbutazone, etc.). — Oxicams (“Tenoxicam”, “Meloxicam”, “Piroxicam”, “Tenoxicam”). — Derivatives of indoleacetic acid (“Sulindac”, “Indomethacin”, etc.). — Derivatives of propionic acid (“Ibuprofen”, etc.).

The second group is: - Sulfonamide derivatives (“Celecoxib”, “Nimesulide”, “Rofecoxib”). — Alkanons (“Nabumeton”).

Classification of non-steroidal anti-inflammatory drugs according to their effectiveness

The use of NSAIDs for osteochondrosis and in the treatment of other joint diseases can literally work wonders. But, unfortunately, not all drugs are equal in their effectiveness. The undisputed leaders among them can be considered: Diclofenac, Ketoprofen, Indomethacin, Flurbiprofen, Ibuprofen and some other drugs.

The listed medications can be called basic; that is, on their basis, new NSAIDs can be developed and supplied to the pharmacy chain, but under a different changed name and often at a higher price. To avoid wasting your money, study the next chapter thoroughly.

The information contained in it will help you make the right choice. What you need to pay attention to when choosing a medicine NSAIDs are, for the most part, excellent modern drugs, but when you come to the pharmacy, it is better to be aware of some of the nuances. Which ones? But read it! For example, you are faced with a choice of what is better to buy: Diclofenac, Ortofen or Voltaren. And you are trying to ask the pharmacist which of these drugs is better. Most likely, they will recommend you the one that is more expensive. But the fact is that the composition of the listed drugs is almost identical. And the difference in names is explained by the fact that they were produced by different companies, which is why the brands differ from each other.

The same can be said, for example, about “Methindole” and “Indomethacin” or “Ibuprofen” and “Brufen”, etc. To sort out the confusion, always look carefully at the packaging, because the main active ingredient of the drug must be indicated there facilities. Only it will most likely be written in small letters.

But that is not all. Or rather, it’s not that simple! Using an NSAID analogue of a drug that you are familiar with can unexpectedly cause an allergic reaction or side effects that you have never experienced before. What's the matter? The reason may lie in additional additives, which, of course, nothing was written about on the packaging. This means that you also need to study the instructions.

Another possible reason for the different results of analog drugs is the difference in dosage. Ignorant people often do not pay any attention to this, but in vain. After all, small tablets can contain a “horse” dose of the active substance. And, conversely, pills or capsules of huge sizes, it happens, consist of fillers by as much as 90 percent. Sometimes drugs are also produced in retardated form, i.e., as long-acting (prolonged) drugs. An important feature of such drugs is the ability to be absorbed gradually, due to which their effect can last a whole day. This drug does not need to be taken 3 or 4 times a day; a single dose will be sufficient. This feature of the medicine should be indicated on the packaging or directly in the name. For example, “Voltaren” in a prolonged form is called “Voltaren-retard”.

List of analogues of known drugs

We are publishing this little cheat sheet in the hope that it will help you better navigate the many beautiful pharmacy packaging. Let's say you immediately need effective NSAIDs for arthrosis to relieve excruciating pain. Take out your cheat sheet and read the following list:

Analogs of “Diclofenac”, in addition to the already mentioned “Voltaren” and “Ortofen”, are also “Diclofen”, “Dicloran”, “Diclonac”, “Rapten”, “Diclobene”, “Artrosan”, “Naklofen”.
"Indomethacin" is sold under such brands as "Indomin", "Indotard", "Metindol", "Revmatin", "Indobene", "Inteban".
Analogues of "Piroxicam": "Erazon", "Pirox", "Roxicam", "Pirocam".
Analogues of "Ketoprofen": "Flexen", "Profenid", "Ketonal", "Artrosilene", "Knavon".
The popular and inexpensive Ibuprofen is included in such drugs as Nurofen, Reumafen, Brufen, Bolinet.

Rules for taking NSAIDs

Taking NSAIDs can be accompanied by a number of side effects, so it is recommended to follow these rules when taking them:

Reading the instructions and following the recommendations it contains are mandatory!
When taking a capsule or tablet, take it with a glass of water to protect your stomach. This rule must be followed even if you are taking the most modern drugs (which are considered safer), because extra precaution never hurts;
Do not lie down after taking the drug for about half an hour. The fact is that gravity will facilitate better passage of the capsule down the esophagus;
It is better to avoid alcoholic beverages, since NSAIDs and alcohol combined together are an explosive mixture that can cause various stomach diseases.
You should not take two different non-steroidal drugs on the same day - this will not increase the positive result, but, most likely, will add up to the side effects.
If the medicine does not help, consult your doctor; perhaps the dose you were prescribed was too small.

Side effects and nonsteroidal gastropathy

Now you have to find out what NSAID gastropathy is. Unfortunately, all NSAIDs have significant side effects. They have a particularly negative effect on the gastrointestinal tract. Patients may be bothered by symptoms such as nausea (sometimes very severe). Heartburn. Vomit. Dyspepsia. Gastrointestinal bleeding. Diarrhea. Ulcer of the duodenum and stomach.

All of the above troubles are NSAID gastropathy. This is why doctors so often try to prescribe their patients the lowest possible doses of classic non-steroidal anti-inflammatory drugs. To minimize harmful effects on the stomach and intestines, it is recommended that you never take such medications on an empty stomach and only do so after a large meal.

But problems with the digestive system are not all the side effects that some NSAIDs can cause. Certain drugs can have a bad effect on the heart and also on the kidneys. Sometimes taking them can be accompanied by headache and dizziness.

Another serious problem is that they have a destructive effect on intra-articular cartilage (of course, only with long-term use). Fortunately, today there are new generation NSAIDs on the market, which are largely free from these disadvantages.

New generation non-steroidal anti-inflammatory drugs

Over the past two decades, several pharmaceutical companies have been intensively developing new modern NSAIDs, which, along with the effective elimination of pain and inflammation, would have as few side effects as possible.

The efforts of pharmacists were crowned with success - a whole group of new generation drugs, called selective, was developed. Imagine - these drugs can be taken for very long courses under the supervision of a doctor. Moreover, the time frame can be measured not only in weeks and months, but even in years.

Medicines from this group do not have a destructive effect on articular cartilage, side effects are much less common and practically do not cause complications. New generation NSAIDs are medications such as: Movalis. “Nise” (aka “Nimulid”). "Arcoxia". "Celebrex."

We will talk about some of their advantages using Movalis as an example. It is available both in traditional tablets (7.5 and 15 mg), and in suppositories of 15 mg, and in glass ampoules for intramuscular administration (also 15 mg). This medicine acts very gently, but at the same time extremely effective: just one tablet is enough for the whole day. When a patient is indicated for long-term treatment for severe arthrosis of the hip or knee joints, Movalis is simply irreplaceable.

Different forms in which NSAIDs are available

Most popular non-steroidal anti-inflammatory drugs can be purchased and used not only in the form of tablets and capsules for oral administration, but also in ointments, gels, suppositories and injection solutions. And this, of course, is very good, since such diversity makes it possible in some cases to avoid harm during treatment while simultaneously obtaining a faster therapeutic effect.

Thus, new generation NSAIDs, used in the form of injections for arthrosis, have much less effect on the gastrointestinal tract. But there is also a flip side to this coin: when administered intramuscularly, almost all non-steroidal drugs can cause a complication - necrosis of muscle tissue. This is why NSAID injections are never practiced for a long time.

Basically, injections are prescribed for exacerbation of inflammatory and degenerative diseases of the joints and spine, accompanied by severe unbearable pain. After the patient’s condition improves, it becomes possible to switch to tablets and external agents in the form of ointments.

Typically, doctors combine different dosage forms, deciding what and when can bring the greatest benefit to the patient. The conclusion suggests itself: if you do not want to harm yourself by self-treating such common ailments as osteochondrosis or arthrosis, seek help from a medical institution, that is where they will be able to help you.

Can NSAIDs be used during pregnancy?

Doctors categorically do not advise pregnant women to take NSAIDs (this prohibition especially applies to the third trimester), as well as mothers who are breastfeeding. It is believed that drugs in this group can adversely affect the gestation of the fetus and cause various malformations in it.

According to some reports, such a harmless medicine, in the opinion of many, as Aspirin, can increase the risk of miscarriage in the early stages. But sometimes doctors prescribe this drug to women according to indications (in a limited course and in minimal doses). In each specific case, the decision must be made by a medical specialist.

During pregnancy, women often have back pain and there is a need to solve this problem with the help of non-steroidal anti-inflammatory drugs as the most effective and fast-acting. In this case, it is permissible to use Voltaren Gel. But - again - its independent use is possible only in the first and second trimester; in the later stages of pregnancy, the use of this strong drug is allowed only under the supervision of a doctor.

Conclusion

We told you what we ourselves knew about NSAIDs. Decoding abbreviations, classification of medications, rules for taking them, information about side effects - this can be useful in life. But we want our readers to need medications as rarely as possible. Therefore, in parting, we wish you good, heroic health!

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs)

or
NSAIDs)
is a group of drugs that have analgesic, antipyretic and anti-inflammatory effects. Their action is based on blocking the production of prostaglandins, which are released at the site of any tissue damage. Currently, non-steroidal anti-inflammatory drugs are rightfully among the most popular drugs used in clinical practice. The most well-known NSAID is aspirin (acetylsalicylic acid). Non-steroidal anti-inflammatory drugs also include: diflunisal, lysine monoacetylsalicylate, phenylbutazone, indomethacin, sulindac, etodolac, diclofenac, piroxicam, tenoxicam, lornoxicam, meloxicam, ibuprofen, naproxen, flurbiprofen, ketoprofen, tiaprofenic acid, nabumetone, nimesulide, celecoxib, rofecoxib, mesalazine and a lot others.

The main problem with the use of non-steroidal anti-inflammatory drugs is that, being the most effective drugs in the treatment of many diseases, they also have a damaging effect on the mucous membrane of the stomach and duodenum, and both the therapeutic and damaging effects of NSAIDs are consequences of NSAID inhibition of prostaglandin production.

The main physiological functions of prostaglandins in the digestive tract are stimulation of the secretion of protective bicarbonates and mucus, activation of cell proliferation in the processes of normal regeneration and increased local blood flow in the mucous membrane. The anti-inflammatory and analgesic effects of non-steroidal anti-inflammatory drugs are due to inhibition of the enzyme cyclooxygenase (COX). There are two isoforms of COX: COX-1 and COX-2. The first of these is present in most tissues, including the gastrointestinal mucosa, and controls the production of prostaglandins, which regulate the integrity of the gastrointestinal mucosa, platelet function and renal blood flow. COX-2 plays the role of a “structural” enzyme only in some organs (brain, kidneys, bones, etc.) and is not normally found in other tissues. Its expression increases significantly under the influence of “pro-inflammatory” stimuli and, on the contrary, decreases under the influence of endogenous substances with anti-inflammatory activity. It is believed that the anti-inflammatory effect of NSAIDs depends on the blocking of COX-2, and their side effects are associated with the suppression of COX-1 (Vasiliev Yu.V.).

Nonsteroidal anti-inflammatory drugs are the cause of gastrointestinal diseases

One of the most important problems of gastroenterology is the treatment and prevention of NSAID gastropathy - diseases of the gastrointestinal tract associated with the use of non-steroidal anti-inflammatory drugs and acetylsalicylic acid.
In the late 1970s, it was found that patients with rheumatic diseases taking NSAIDs die from gastrointestinal bleeding and perforated ulcers more often than those not taking NSAIDs. Despite significant progress in the study of NSAIDs and the creation of safer drugs, modern statistics show: the risk of gastrointestinal bleeding when taking NSAIDs increases by 3-5 times, perforation - by 6, the risk of death from complications associated with damage to the gastrointestinal tract – 8 times. In 40–50% of patients hospitalized with a diagnosis of acute gastrointestinal bleeding, it is caused by taking this class of drugs. In the UK, up to 2,000 patients die annually from such complications; in the US, NSAID use is responsible for 100,000 hospitalizations and 16,000 deaths per year.

In Moscow, 34.6% of hospitalizations with a diagnosis of “acute gastrointestinal bleeding” are directly related to the use of NSAIDs. Bleeding and perforation of the ulcer are the cause of death in patients suffering from rheumatic diseases and taking NSAIDs, and account for 13.8% of the direct causes of death in patients with rheumatoid arthritis, ankylosing spondylitis and systemic lupus erythematosus (Burkov S.G.).

Clinical guidelines for the management of patients with NSAID-associated bleeding include (Russian Society of Surgeons):

All patients requiring chronic use of NSAIDs should be stratified according to the risk of bleeding complications
if there is a high risk of bleeding, it is recommended to transfer patients to selective COX-2 inhibitors in combination with the constant use of proton pump inhibitors or misoprostol
if bleeding develops, NSAIDs should be discontinued (replaced with drugs from other groups); A combination of endoscopic and drug (proton pump inhibitors) hemostasis is recommended.

Materials for healthcare professionals addressing the damaging effects of non-steroidal anti-inflammatory drugs on the gastrointestinal mucosa

Articles and instructions

Abdulganieva D.I., Belyanskaya N.E., Nasonov E.L. Relationship between clinical manifestations of NSAID gastropathy in patients with rheumatoid arthritis and motor disorders of the upper gastrointestinal tract // Scientific and practical rheumatology. 2011. No. 3. pp. 25–28.
Vasiliev Yu.V. Proton pump inhibitors in the treatment of gastric and duodenal ulcers associated with non-steroidal anti-inflammatory drugs // Farmateka. – 2005. – No. 7. – p. 1–4.
Nasonov E.L. The use of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors at the beginning of the 21st century // Russian Medical Journal. – 2003. – Volume 11. – No. 7. – p. 375–378.
Agapova N.G. About drug-induced gastroduodenal ulcers // Journal “Mystery of Likuvannya”. Ukraine. – 2007. – 2(38).
Burkov S.G. Modern approaches to the treatment of acid-dependent diseases // Breast Cancer. – 2007. – Volume 15. – No. 6.
Guidelines for the use of non-steroidal anti-inflammatory drugs and the official instructions of Actavis Ellzabeth LCC “Diclofenac sodium extended-release tablets” for US healthcare professionals (English, pdf): “Diclofenac sodium extended-realeas tablets”.
Official instructions from the manufacturer of naproxen drugs Year Genentech, Inc. for US patients (medical guide) “What are non-steroidal anti-inflammatory drugs? EC-Naprosyn ® (naproxen extended-release tablets), Naprosyn ® (naproxen tablets), Anaprox ®/Anaprox ® DS (naproxen sodium tablets), Naprosyn (naproxen suspension)" (in English, pdf): "Medication Guide EC-Naprosyn ® (naproxen delayed-release tablets), Naprosyn ® (naproxen tablets), Anaprox ® / Anaprox ® DS (naproxen sodium tablets), Naprosyn ® (naproxen suspension).”

On the website in the literature catalog there is a section “NSAIDs and other drug-induced gastropathy”, containing articles devoted to diseases of the gastrointestinal tract caused by taking medications and their treatment.

Video

Still from video Pakhomova I.G., Novikova D.S. Management of comorbid patients in outpatient settings. Opinion of specialists: cardiologist and gastroenterologist

Still from video Bordin D.S. A simple and effective algorithm for the treatment of acid-related diseases

Still from video Uspensky Yu.P.
GERD and other acid-dependent diseases of the digestive system. Principles of rational pharmacotherapy. On the website GastroScan.ru in the “Video” section there is a subsection “For Doctors”, containing video recordings of reports, lectures, webinars in various areas of gastroenterology for healthcare professionals.

Application. Nonsteroidal anti-inflammatory drugs in the Anatomical Therapeutic Chemical Classification (ATC)

Nonsteroidal anti-inflammatory drugs are widely used in medicine for the treatment of various diseases and conditions and, therefore, they are presented in various sections of the Anatomical Therapeutic Chemical Classification (ATC), in particular, in the section “Code M. Drugs for the treatment of diseases of the musculoskeletal system
” There are two subsections of different levels containing the following positions:

M01A Non-steroidal anti-inflammatory drugs:

M01AA Butylpyrazolidones M01AA01 Phenylbutazone M01AA02 Mofebutazone M01AA03 Oxyphenbutazone M01AA05 Clofezone M01AA06 Kebuzone

M01AB Acetic acid derivatives and related compounds M01AB01 Indomethacin M01AB02 Sulindac M01AB03 Tolmetin M01AB04 Zomepirac M01AB05 Diclofenac M01AB06 Alclofenac M01AB07 Bumadizone M01AB08 Etodolac M01AB09 Lonazolac M01AB10 Fentiazac M01AB11 Acemeta cin M01AB12 Diphenpyramide M01AB13 Oxamethacin M01AB14 Proglumethacin M01AB15 Ketorolac M01AB16 Aceclofenac M01AB17 Bufexamac M01AB51 Indomethacin in combination with other drugs M01AB55 Diclofenac in combination with other drugs

M01AC Oxycams

M01AC01 Piroxicam M01AC02 Tenoxicam M01AC04 Droxicam M01AC05 Lornoxicam M01AC06 Meloxicam M01AC56 Meloxicam in combination with other drugs

M01AE Propionic acid derivatives

M01AE01 Ibuprofen M01AE02 Naproxen M01AE03 Ketoprofen M01AE04 Fenoprofen M01AE05 Fenbufen M01AE06 Benoxaprofen M01AE07 Suprofen M01AE08 Pirprofen M01AE09 Flurbiprofen M01AE10 Indoprofen M01AE11 Tiaprofen ovalic acid M01AE12 Oxaprozin M01AE13 Ibuproxam M01AE14 Dexibuprofen M01AE15 Flunoxaprofen M01AE16 Alminoprofen M01AE17 Dexketoprofen M01AE18 Naproxcinod M01AE51 Ibuprofen in combination with other drugs M01AE52 Naproxen and esomeprazole M01 AE53 Ketoprofen in combination with other drugs M01AE56 Naproxen and misoprostol

M01AG Fenamata

M01AG01 Mefenamic acid M01AG02 Tolfenamic acid M01AG03 Flufenamic acid M01AG04 Meclofenamic acid

M01AH Coxibs M01AH01 Celecoxib M01AH02 Rofecoxib M01AH03 Valdecoxib M01AH04 Parecoxib M01AH05 Etoricoxib M01AH06 Lumiracoxib

M01AX Other non-steroidal anti-inflammatory and anti-rheumatic drugs

M01AX01 Nabumetone M01AX02 Niflumic acid M01AX04 Azapropazone M01AX05 Glucosamine M01AX07 Benzidamine M01AX12 Glycosaminoglycan polysulfate M01AX13 Proquazone M01AX14 Orgotein M01AX17 Nimesulide M01AX18 Feprazone M01AX21 Diacerein M01AX2 2 Morniflumate M01AX23 Tenidap M01AX24 Oxaceprol M01AX26 Unsaponifiable compounds of avocado and soybean oils M01AX68 Feprazone in combination with other drugs

M02AA
Nonsteroidal anti-inflammatory drugs for topical use
M02AA01 Phenylbutazone M02AA02 Mofebutazone M02AA03 Clofezone M02AA04 Oxyphenbutazone M02AA05 Benzydamine M02AA06 Etofenamate M02AA07 Piroxicam M02AA08 Felbinac M02AA09 Bufexamac M02AA10 Ketoprofen M02AA1 1 Bendazac M02AA12 Naproxen M02AA13 Ibuprofen M02AA14 Fentiazac M02AA15 Diclofenac M02AA16 Feprazone M02AA17 Niflumic acid M02AA18 Meclofenamic acid M02AA19 Flurbiprofen M02AA21 Tolmetin M02AA22 Suxibuzone M02AA23 Indomethacin M02AA24 Niphenazone M02AA25 Aceclofenac M02AA26 Nimesulide M02AA27 Dexketoprofen Back to section

NSAIDs – what has changed over the past 10 years?

It is known that non-selective cyclooxygenase (COX) inhibitors, i.e. all classical NSAIDs, can increase blood pressure due to their effect on renal prostaglandins (PGs) and reduce the effectiveness of most antihypertensive drugs: β-blockers, angiotensin-converting enzyme inhibitors, diuretics (with the exception of Ca blockers). -channels). COX-2 inhibitors do not affect blood pressure and the effectiveness of drugs to lower blood pressure. Table 1 shows the classification of NSAIDs according to their selectivity for COX [5]. All representatives of the NSAID group are characterized by side effects that are a consequence of the blockade of the COX enzyme. The analgesic and anti-inflammatory effect of NSAIDs is associated with the suppression of the function of the “inducible” form of this enzyme COX-2, which is responsible for the hyperproduction of PGs, the most important mediators of pain and inflammation in the area of the pathological process. Selective COX-2 inhibitors (nimesulide, meloxicam) are inferior in the manifestation of direct effects to non-selective NSAIDs, but in their adverse reactions they are less aggressive in relation to the gastrointestinal tract. A significant risk of developing complications from the cardiovascular system (CVS) occurs in individuals taking highly selective COX-2 inhibitors (coxibs - celecoxib, etoricoxib) [6]. A serious problem, which is the subject of a pan-European discussion, remains the assessment of the real risk of developing adverse reactions with long-term use of NSAIDs, as a result of which their therapeutic value may be significantly limited [1]. Traditionally, the first place among these complications is given to NSAID gastropathy, a specific pathology of the upper gastrointestinal tract, characterized by the appearance of erosions of the mucous membrane, ulcers and gastrointestinal disasters: bleeding and perforation [7]. “NSAID-induced gastropathy” is a term used to describe lesions (erosions and ulcers) of the upper gastrointestinal tract as the most common unwanted side effect of NSAIDs [8]. This gastropathy has characteristics that distinguish it from standard peptic lesions: it is observed mainly in the antrum and prepyloric region, most often affects the elderly, in particular women, and is characterized by an asymptomatic course, representing a great danger [9]. According to data from the 1990s, patients who regularly received NSAIDs died from gastrointestinal bleeding 2–3 times more often than people who did not take any drugs of this drug group [7]. It is estimated that GI lesions occur in up to 25% of patients, causing ulcers in 40% of them and increasing the risk of bleeding, hospitalization, and death [10].

In order to avoid or minimize the negative impact of NSAIDs on the gastroduodenal mucosa, 2 approaches are used: 1) the NSAIDs themselves are improved in order to make them safer; 2) combine NSAIDs with antisecretory agents (proton pump inhibitors (PPIs)) or synthetic analogues of PG (Table 2) [11]. According to the recommendations of the American Rheumatological Association (2002), if there is a high risk of damage to the mucous membrane of the gastroduodenal zone while taking NSAIDs (2 or more risk factors, complications in history), it is necessary to prescribe selective COX-2 inhibitors in combination with PPIs instead of classical (non-selective) NSAIDs , if there is 1 risk factor, you can limit yourself to only a selective COX-2 inhibitor, and if the risk is low (there are no risk factors), you can use classic NSAIDs [8]. In recent years, fundamental importance in assessing the safety of NSAIDs has been given to the risk of developing dangerous complications from the cardiovascular system: myocardial infarction, sudden coronary death and ischemic stroke (cardiovascular accidents). The vast majority of episodes of serious gastrointestinal complications that occur while taking NSAIDs are observed in patients with so-called risk factors, the most important of which are: advanced age (over 65 years), a history of ulcers, especially complicated ulcers, taking high doses of NSAIDs or concomitant use NSAIDs and angioplatelet agents and/or anticoagulants, severe concomitant diseases, etc. In this case, the assessment of risk factors is carried out taking into account their gradation for each patient individually (Table 3, 4).

A large-scale study was conducted to assess the incidence of gastrointestinal complications with the use of NSAIDs for the period 2001–2008. in the Friuli – Venezia – Giulia area (Italy) [13]. Purpose of the study: information on the risk of developing complications from the upper gastrointestinal tract in patients taking nimesulide, the most common NSAID in Italy. As part of the monitoring of the drug nimesulide by European regulatory authorities, the risk associated with the use of nimesulide and other NSAIDs was assessed in comparison with the risk in patients not taking these drugs. The study included 588,827 patients with a total of 3,623,341 NSAID prescriptions, and nimesulide was found to be the most popular drug. The incidence rate of upper gastrointestinal lesions decreased by 50% from 2001 to 2008: 4.45 cases per 1 thousand patient-years in 2001 versus 2.21 cases per 1 thousand patient-years in 2008. B the study presented data on the relative risk (RR) of developing lesions when using NSAIDs, which averaged 3.28; for drugs such as rofecoxib, celecoxib, nimesulide RR <2; for the drugs ibuprofen, diclofenac, etoricoxib and meloxicam – 5>OR>2; for the drugs ketoprofen, piroxicam – RR≥5. The incidence rates of upper gastrointestinal lesions in the Friuli-Venezia-Giulia region decreased by approximately 50% between 2001 and 2008. Thus, it was concluded that nimesulide has a low or medium range of RR values.

Unlike most NSAIDs, nimesulide selectively inhibits the “pro-inflammatory” isoform of COX-2 and has a lesser effect on the “physiological” COX-1 [7]. It is the first selective COX-2 inhibitor synthesized (Table 1) [14]. Simultaneous inhibition of COX-1 and COX-2, characteristic of other NSAIDs, significantly narrows the range of their use due to possible side effects from the gastrointestinal tract. Another advantage when prescribing nimesulide is its non-acidic origin (in the nimesulide molecule the carboxyl group is replaced by sulfonanilide), which provides an additional protective effect on the gastrointestinal mucosa. The main advantage of oral administration of nimesulide is its better tolerability compared to other NSAIDs [5]. In particular, when using nimesulide, side effects associated with the gastrointestinal tract developed much less frequently, which is most likely due to its selectivity to COX-2. Nimesulide has anti-inflammatory, analgesic, antipyretic effects. A significant safety factor for nimesulide is the presence of antibradykinin and antihistamine effects, which are as important in the postoperative period as the anti-inflammatory effect [15]. Table 5 presents data on the frequency of damage to the gastrointestinal mucosa identified in patients at the Institute of Rheumatology of the Russian Academy of Medical Sciences for the period 2000–2005. [16].

A characteristic feature of nimesulide is the low risk of developing gastropathy compared to traditional NSAIDs [17]. A.E. Karateev et al. [5] conducted a retrospective analysis of the frequency of erosive and ulcerative complications of the gastrointestinal tract when taking diclofenac and COX-2 selective NSAIDs in patients with rheumatic diseases who received inpatient treatment at the Institute of Rheumatology of the Russian Academy of Medical Sciences in the period from January 2002 to November 2004. A less frequent occurrence of multiple erosions and ulcers when taking COX-2 selective NSAIDs, especially if there is a history of ulcers. Most rarely, gastrointestinal lesions developed when taking nimesulide [18].

So, nimesulide, a selective NSAID with a good safety profile, has become the leader among prescribed NSAIDs in Russia over the past 10 years. Numerous domestic and foreign studies have shown that when using nimesulide, there is a low risk of developing side effects from both the gastrointestinal tract and the cardiovascular system. Today, the search for “safe” NSAIDs remains relevant. The annual cost of treating GI lesions is approximately $134 for patients not treated with NSAIDs, $180 for occasional NSAID users, and $244 for chronic NSAID users (as of 1996); Excessive costs to the health care system caused by the adverse effects of NSAIDs reached almost $500 million (as of 1998) [10]. The findings suggest that when determining the true cost of NSAIDs, costs associated with the treatment of gastric and duodenal lesions should also be taken into account [10].

In order to increase the safety of NSAIDs, molecules of active substances containing an NO group were created. An attempt to reduce the number of side effects of NSAIDs on the gastrointestinal tract and cardiovascular system was to bind NSAIDs to a donor of nitric oxide (NO), which inhibits COX. NO ensures the preservation of the gastric mucosa and maintains cardiovascular homeostasis [19]. Interest in NO in connection with the prescription of NSAIDs is due to the physiological properties of this small molecule, which has a wide range of diverse effects on organs and tissues [8]. The effects of NO are associated with the processes of slowing platelet aggregation and migration of neutrophils through the vascular wall, relaxation of smooth muscle cells of the vascular intima, neoangiogenesis, neoneurogenesis, etc. In the field of inflammation and tissue damage, NO can act in a “negative” role as a pain mediator, causing sensitization and direct stimulation of nociceptors [20]. For the gastric mucosa, NO acts as a fundamental protective factor, which “duplicates” the protective properties of PG and has a unidirectional effect with them. NO stimulates mucus secretion, regulates microcirculation, and inhibits the adhesion of leukocytes to the endothelium. NO is an essential component of the endogenous system of the mucous membrane of the stomach, duodenum and small intestine, protecting against damage, maintaining the integrity of the structure and function of the gastrointestinal tract by increasing mucus production, bicarbonate secretion, blood flow and reducing pro-inflammatory activation of cellular composition. The stimulating effect of NO on mucus secretion is an important process that ensures restoration of the gastric mucosa when damage to its surface develops [21].

The use of the protective properties of NO to improve the safety of NSAIDs served as the basis for the creation of the drug amtolmetin guacil (AMG), which has gastroprotective properties, based on the non-selective NSAID tolmetin. AMG is a product of combinatorial chemical technology that combines tolmetin with the amino acid glycine and guaiacol, which, by inhibiting COX-1 and COX-2, disrupts the metabolism of arachidonic acid and reduces the formation of PG (including at the site of inflammation) [22]. Due to the mechanisms of COX inhibition, AMH has anti-inflammatory, analgesic, antipyretic, and desensitizing effects [23]. The protective effect of AMH on the gastric mucosa is realized by stimulating capsaicin receptors (vanilloid receptors) present in the walls of the gastrointestinal tract. AMH contains a vanillin group [24], due to which it stimulates capsaicin receptors, indirectly causing the release of gastrointestinal peptides, including calcitonin gene-encoded peptide (CGRP), which leads to an increase in NO synthesis [25]. The pharmacological advantages of the drug AMG (drug Nizilat®), unlike other NSAIDs, are determined by an increase in the activity of NO in the gastrointestinal mucosa. The structure of AMH itself contains a protective effect for the gastroduodenal mucosa, which compensates for the weakening of protection by reducing the level of endogenous PGs when inhibiting COX [8].

The results of the analysis indicate that AMH is characterized, along with a better tolerability profile compared to other NSAIDs, and the potential for cost savings. The first analysis showed that, regardless of the severity of the lesions and the comparator drug considered, the use of AMH allows the use of fewer healthcare resources, which leads to cost savings [10]. The registered advantage of AMG over other NSAIDs is also explained by the fact that the use of AMG helps prevent the occurrence of severe lesions (grade 4), as a result of which patients require hospital treatment. A meta-analysis of early (before 1999) results of randomized controlled clinical trials that reported gastric tolerability of AMH compared with other NSAIDs in the treatment of OA, rheumatoid arthritis (RA) and pathogenetically related diseases showed no data on the development of toxic changes in stomach or kidneys (in animal models), and, conversely, evidence of a protective effect on the gastric wall has been obtained [26]. The results of the presented systematic review of the literature regarding the tolerability of AMH in comparison with other NSAIDs, including the most commonly used drugs in this group, show that the incidence of adverse reactions and early discontinuation of treatment is significantly lower in patients who took AMH than in those who used other NSAIDs.

In a number of randomized preclinical studies on experimental models (rats, mice), the effectiveness of AMH and its metabolites was assessed, the mechanisms of influence on the mucous membrane of the stomach and duodenum were studied, and gastroprotective effects were shown. Thus, in histological studies on rats [23, 27–29], it was demonstrated that tolmetin, unlike classical NSAIDs, does not cause hemorrhagic or necrotic damage even when administered intragastrically in doses 6 times higher than the doses required to reduce the intensity of cutaneous inflammation. AMG has very low gastrotoxicity due to the unique mechanism of action of the drug. In addition to a significantly lower ulcerogenic effect when taking doses that have an anti-inflammatory effect, AMH protects the gastric mucosa from the irritating effects of ethanol. It is believed that the gastroprotective effect mainly depends on the production of NO in the gastric mucosa due to the activation of the inducible isoform of NO synthase [23]. The gastroprotective properties and mechanisms of AMH and its metabolites (MED15) in mice were assessed [30]. To create a biological model and evaluate gastroprotective properties in experimental animals, damage to the gastric mucosa was caused by ethanol. In the experiment, animals in groups selected by randomization took AMH in doses of 75, 150 and 300 mg/kg, respectively, tolmetin - 90 mg/kg, the control group was without drug load. Using electron microscopy, using biochemical methods, the content of NO, malondialdehyde, NO synthetase and superoxide dismutase, and tissue homogenates were measured in the gastric mucosa. With repeated administration of AMG (75, 150 and 300 mg/kg) for 7 days, no damage to the gastric mucosa induced by ethanol was detected; there were no significant differences from the control group; in the tolmetin group (90 mg/kg), on the contrary, noticeable damage to the gastric mucosa was noted compared to the control group. The authors of the study concluded that when administered AMH (150 and 300 mg/kg), not only did superoxide dismutase activity significantly increase, but also the content of malondialdehyde in mouse stomach homogenates apparently decreased.

In another study in biological models (rat), the purpose of which was to determine whether pre-treatment with AMH affects changes in lipid peroxidation (LPO) and antioxidant enzyme and non-enzyme defense systems, which are considered to be one of the causes of colon and gastric damage caused by use indomethacin, ethanol and 2,4,6-trinitrobenzenesulfonic acid (TNBS) [28]. The drugs used in the study were AMH, tolmetin, diclofenac, indomethacin and celecoxib. According to the protocol, animals received orally AMH (100 mg/kg), tolmetin (60 mg/kg), diclofenac (10 mg/kg), celecoxib (40 mg/kg) or indomethacin (20 mg/kg) - all in the form of a suspension in 1% carboxymethylcellulose; Trinitrobenzenesulfonic acid (TNBS) (30 mg/kg) was dissolved in 0.25 ml of 30% ethanol. The study concluded that AMH was effective in improving TNBS-induced changes in LPO and antioxidant defense systems in the gastric and colon mucosa. Additionally, unlike tolmetin, AMH was associated with improvements in antioxidant defense systems. The beneficial effects of AMH on oxygen free radical-induced pathology raise the possibility that antioxidant activity may be involved in this mechanism [28].

One of the clinical studies [31] provided a comparative assessment of the effectiveness and safety of AMG and celecoxib in patients with RA. The study included 235 patients with RA (180 of them completed the study): patients in the main group (n=85) received AMH at a dosage of 600 mg twice a day, patients in the comparison group (n=95) received celecoxib 200 mg/day for 24 weeks The effectiveness of RA therapy was assessed using the American College of Rheumatology index. The drugs had comparable effectiveness when assessing the dynamics of indicators at the 4th, 12th and 24th weeks. treatment. In the compared groups, no significant differences were obtained when analyzing data from endoscopy, ECG, clinical blood and urine tests, or when assessing side effects and gastrointestinal symptoms. Thus, this study demonstrated equal efficacy and safety (especially for the gastrointestinal tract) of both AMH and the selective COX-2 inhibitor celecoxib.

Controlled randomized clinical trials have shown that the anti-inflammatory and analgesic effects of AMH are equivalent to the effects of other NSAIDs, such as diclofenac, naproxen, piroxicam, tolmetin and other drugs for the treatment of osteoarthritis, RA. Thus, one of the studies [9] assessed the effectiveness of the use of AMG in comparison with diclofenac in elderly women (average age - 60 years) with various pathologies of the osteoarticular system (coxarthrosis, gonarthrosis, RA, etc.). The study included 50 patients, 25 of whom received AMH and 25 received diclofenac. The course of treatment was 30 days. Dosage regimen: AMG - in the first 3 days, 1 tablet (600 mg) every 12 hours on an empty stomach, in the remaining 27 days - 1 tablet on an empty stomach; diclofenac – 3 tablets (50 mg) after meals. Analysis of the data confirmed a slight improvement in the mucous membrane on the 30th day of the study in the group of patients taking AMH, while in the group taking diclofenac there was an increase in the Graham index (assessment of the negative effect on the gastric mucosa). In general, when taking AMH, there was a more significant improvement in the condition (in percentage terms) compared to diclofenac: 79% versus 54.2%, respectively.

Conclusion Over the past 10 years, nimesulide, a selective NSAID with a good safety profile, has become the leader among prescribed NSAIDs in Russia. Numerous domestic and foreign studies have shown that when using nimesulide, there is a low risk of developing side effects from both the gastrointestinal tract and the cardiovascular system. Thus, patients without risk factors can be treated with non-selective NSAIDs, while patients with risk factors should be treated with selective NSAIDs (in combination with a PPI if there is more than one risk factor). However, it is worth remembering that the risk of developing NSAID gastropathy also exists in the group of patients without risk factors for the development of gastrointestinal pathology, but with other provoking factors, for example, smoking, irregular diet, stress, Helicobacter pylori, alcohol consumption.

To increase the safety of NSAIDs, the protective properties of NO were used, which served as the basis for the creation of an AMH drug based on the non-selective NSAID tolmetin. Experimental studies have shown that AMG does not have ulcerogenic activity and has a direct protective effect on the stomach wall. The presence of vanilla fragments in the AMH molecule (unlike other NSAIDs) induces a gastroprotective effect, which opens up new possibilities for using the drug in the long-term treatment of inflammatory diseases.

Literature 1. Shavlovskaya O.A. Advantages of NSAIDs and selective COX-2 inhibitors in the treatment of pain // Handbook of a polyclinic physician. 2014. No. 3. pp. 46–49. 2. Pakhomova I.G., Pavlova E.Yu. Non-steroidal anti-inflammatory drugs: focus on safety when choosing a drug // Consilium medicum. Neurology (app.). 2014. No. 1. P. 30–34. 3. Coleman S., Briffa KN, Carroll G. A randomized controlled trial of a self-management education program for osteoarthritis of the knee delivered by health care professionals // Arthritis Res Ther. 2012. Vol 14 (1): R21. Published online 2012 January 27. DOI: 10.1186/ar3703. 4. Tsurko V.V. Osteoarthrosis: a geriatric problem // Breast Cancer. 2005. No. 24. pp. 1627–1631. 5. Karateev A.E., Barskova V.G. Criteria for choosing a non-steroidal anti-inflammatory drug // Handbook of a polyclinic doctor. 2007. T. 5. No. 5. P. 13–17. 6. Pizova N.V. Back pain: focus on the thoracic region // Handbook of a polyclinic doctor. 2014. No. 4. pp. 44–48. 7. Karateev A.E. Nimesulide: myths and reality // Directory of a polyclinic doctor. 2013. No. 4. pp. 56–61. 8. Shavlovskaya O.A. Amtolmetin guacil: experience of use in clinical practice // Handbook of a polyclinic doctor. 2014. No. 7. pp. 54–58. 9. Tavella A., Ursini G. Studio clinico sull'attivita antiinflamatoria e sulla tollerabilita gastro-enterica di amtolmetineguacil, un nuovo FANS, in confronto a diclofenac su pazienti anziani con patologie osteoarticolari // Clin. Ter. 1997. Vol. 148. R. 543–548. (Tavella A., Ursini J. Clinical study of anti-inflammatory activity and gastrointestinal tolerability of Amtolmetin guacil (a new NSAID) compared with diclofenac in elderly patients with pathologies of the osteoarticular system // RMJ. 2013. No. 32. C 1678–1682. Translated by N.G. Lyutov). 10. Belisari A., Mantovani LG Cost-benefit analysis of amtolmetin-guacil // Clin Drug Invest. 2001. Vol. 21(1). R. 47–58. 1173-2563/01/0001-0047/$22.00/0. 11. Lapina T.L. Ways to reduce gastrointestinal risk when prescribing non-steroidal anti-inflammatory drugs // Consilium medicum. Adj. Neurology. 2013. No. 2. P. 50–52. 12. Karateev A.A., Yakhno N.N., Labeznik L.B. etc. Use of non-steroidal anti-inflammatory drugs. Clinical recommendations. M., 2009. 13. Castellsague J., Pisa F., Rosolen V. et al. Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti-inflammatory drugs in Friuli Venezia Giulia, Italy // Pharmacoepidemiology and Drug Safety. 2012. Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3385. 14. Balabanova R.M. Nimesulide is an anti-inflammatory drug with selective inhibition of COX-2 // Breast Cancer. 2001. T. 9. No. 7–8. pp. 291–294. 15. Shavlovskaya O.A. Therapeutic spectrum of use of the drug Nise (Nimesulide) // Russian Medical Journal. 2013. T. 21. No. 10. P. 512–518. 16. Karateev A.E. Nimesulide: advantages outweigh disadvantages // Difficult patient. 2012. No. 4. pp. 42–49. 17. Shavlovskaya O.A. Nimesulide in the treatment of pain // Consilium medicum. Adj. Neurology. 2013. No. 1. pp. 12–15. 18. Karateev A.E., Alekseeva L.I., Bratygina E.A. and others. Assessment of the incidence of side effects with long-term use of Nimesulide in real clinical practice // RMZh. 2009. No. 21. P. 1466-1472. 19. Bijlsma JW, Berenbaum F., Lafeber FP Osteoarthritis: an update with relevance for clinical practice // Lancet. 2011 Jun 18. Vol. 377 (9783). R. 2115–2126. DOI: 10.1016/S0140-6736(11)60243-2. 20. Karateev A.E. On the way to creating a new generation of non-steroidal anti-inflammatory drugs: amtolmetin guacil // Modern rheumatology. 2014. No. 2. pp. 72–78. 21. Pasechnikov V.D. Mechanisms of protection of the gastric mucosa and NO-releasing non-steroidal anti-inflammatory drugs // Consilium medicum. 2013. T. 15. No. 9. pp. 79–81. 22. Coruzzi G., Bertaccini G. Gastric effects of the novel non-steroidal anti-inflammatory drug amtolmetin guacyl // Nutrition. 1999. Vol. 15. No. 4. R. 325–326. 23. Coruzzi G., Coppelli G., Spaggiari S. et al. Gast roprotective effects of amtolmetin guacyl: a new non-steroidal anti-inflammatory drug that activates inducible gastric nitric oxide synthase // Digest Liver Dis. 2002. Vol. 34. R. 403–410. 24. Tubaro E., Luisella B., Mezzadri CM The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal anti-inflammatory drug // European Journal of Pharmacology. 2000. Vol. 387. R. 233–244. 25. Coruzzi G. New safer non-steroidal anti-inflammatory drugs? // DDT. 2000 Jan. Vol. 5. No. 1. R. 35–37. 26. Marcolongo R., Frediani B., Biasi G. et al. A meta-Analysis of the tolerability of amtolmetin guacil, a novel, effective nonsteroidal anti-inflammatory drug, compared with established agents // Clin Drug Invest. 1999 Feb. Vol. 17(2). R. 89–96. 1173-2563/99/0002-0089/$04.00/0 27. Bertaccini G., Coruzzi G. Amtolmetin guacyl: a new antiinflammatory drug devoid of gastrolesive properties // Naunyn Schmiedeberg's Arch. Pharmacol. 1998. Vol. 358 (Suppl. 1). R. 366. 28. Kirkova M., Kesiova M., Konstantinova S. et al. In vivo effects of amtolmetin guacil on lipid peroxidation and antioxidant defense systems in different models of gastrointestinal injury // Autonomic & Autacoid Pharmacology, 2007. No. 27. R. 63–70. 29. Karabatas L., Pastorale C. Inhibition of nitric oxide generation in mononuclear splenocytes from multiple-low-dose-streptozotocin diabetic mice // JMED Research. 2013. Vol.2013 Article ID 256606, DOI: 10.5171/2013.256606. 30. Li YH, Li J, Huang Y et al. Gastroprotective effect and mechanism of amtolmetin guacyl in mice // World J Gastroenterol. 2004 Dec 15. Vol. 10 (24). R. 3616–3620. 31. Jajic Z., Malaise M., Nekam K. et al. Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis // Clinical and Experimental Rheumatology 2005. Vol. 23. R. 809–818.