COX inhibitors 2 mechanism of action. New generation non-steroidal anti-inflammatory drugs (NSAIDs): a review. Dosage forms of glucocorticoids

To cure a patient with rheumatoid arthritis, medications, physiotherapy, and diet are used. Initially, to stop the inflammatory process, relieve pain, non-steroidal anti-inflammatory elements (NSAIDs) are used.

Medicines in this group are not able to cure rheumatoid arthritis, improve the quality of life, do not allow the disease to spread throughout the body, affecting new joints. Preparing the body for basic therapy.

Anti-inflammatory drugs are divided into two types: cyclooxygenase inhibitors, COX-1, COX-2. Preparations of the COX-1 group have a general effect on the body, inflammation, and have a large list of side effects. Drugs of the COX-2 group represent a new generation of drugs that can act locally, entail less negative consequences of administration.

COX-1 inhibitors

Anti-inflammatory drugs of this group have a negative effect on cartilage tissue. Cope with the elimination of symptoms in rheumatoid arthritis. These medicinal products include:

COX-2 inhibitors

The group consists of anti-inflammatory nonsteroidal drugs, in terms of the quality of elimination of symptoms, exceeding COX-1 inhibitors. Medicines belonging to the group can lead to problems in the work of the patient's cardiovascular system. Drugs belonging to the group of inhibitors:

Sulfazalin is considered a good anti-inflammatory substance. The effect of taking this NSAID appears after 1.5 months from the start of regular use. The dosage is determined by the doctor, based on the clinical picture of the disease.

Prescribing principles

The main principle that guides the doctor when prescribing NSAIDs based on the clinical picture of the disease in a patient is the degree of toxicity of the agent. Frequent manifestations of toxicity are disorders of the gastrointestinal tract, including sensations of irritation, burning, and belching. Systematic irritations provoke the appearance of erosions, stomach ulcers, gastric bleeding. Initially, non-steroidal elements are selected, with the shortest time for complete assimilation, removal from the body of the active substance. Based on this, the first substance prescribed by the doctor is from the series: diclofenac, ibuprofen, movalis, ketoprofen.

The next drugs in line are picroxicam, ketorolac, indomethacin due to the longer period of complete elimination from the body. Indomethacin is able to provoke the appearance of mental disorders in people of middle, advanced age. These non-steroidal anti-inflammatory drugs are prescribed to young patients, without health problems in the liver, kidneys, gastrointestinal tract, and cardiovascular system. In this case, the likelihood of side effects from taking these NSAIDs is reduced to zero.

The next principle, on the basis of which a drug is prescribed, is the effectiveness for a particular patient. It is determined which nonsteroidal drugs are effective by trial and error. Each of the drugs is prescribed for the patient to take for a period of 7 days, during which the patient, according to his feelings, evaluates the degree of improvement after taking.

The use of selective anti-inflammatory drugs

Non-steroidal substances of the selective type differ in properties from other NSAIDs. The main difference is the excellent tolerance of the substance, the rare manifestation of side effects in combination with an effective degree of pain relief, elimination of the inflammatory process. Unlike other NSAIDs, selective during administration, it does not provoke irritation of the stomach and intestines.

If necessary, selective non-steroidal elements - Movalis, Celebrex, under the supervision of a doctor, can be taken for several years.

Correctly selected medicinal elements give a quick effect in the process of taking, the use should be continued in courses during the treatment period, up to the state of complete remission.

There are many medications aimed at improving the patient's condition, eliminating pain, stopping the inflammatory process in rheumatoid arthritis. Each patient has special properties of the body, it is impossible to draw up a treatment regimen for symptoms indicating the exact elements of NSAIDs for therapy. The selection of medicinal ingredients is carried out by a doctor.

EL. Nasonov
Department of Rheumatology MMA them. THEM. Sechenov.

Summary

The modern theory of selective COX-2 inhibitors is presented.

The pharmacodynamic properties of meloxicam and its COX-2 selectivity are described. The safety of using movalis and the absence of a negative effect on cartilage have been substantiated. Key words: selective COX-2 inhibitors, movalis.

Modern views on the selectivity of COX-2 inhibitors and pharmaco-dynamic features of Meloxicam, its COX-2 selectivity are described. The safety of Movalis application and its effect on the cartilage are validated.

Key words: selective inhibitors, COX-2. Movalis.

Non-steroidal anti-inflammatory drugs (NSAIDs) are extremely widely used in clinical practice. It is no exaggeration to say that they are among the most important "symptomatic" remedies not only for rheumatic, but also for many other diseases of the internal organs. Indeed, pain as well as fever, which are the leading symptoms of an extremely wide range of human diseases, both inflammatory and non-inflammatory in nature, are most effectively controlled by NSAIDs. Obviously, all aspects of the pharmacotherapy of pain and inflammation are far from being exhausted by the use of NSAIDs. These drugs, being "symptomatic" drugs, in many cases do not affect the fundamental pathogenetic mechanisms underlying these pathophysiological processes. Despite this, in recent years, the focus has been not so much on the creation of more effective, but on safer NSAIDs. Indeed, only gastrointestinal side effects generally develop in 34-46% of patients taking NSAIDs, and in 15% can lead to severe, potentially fatal complications (perforations, ulcers and bleeding).

In terms of studying the mechanisms of action of NSAIDs and, on this basis, creating safe drugs, the last 10 years have been particularly fruitful. This is largely due to the discovery of two isoforms of cyclooxygenase (COX), an enzyme that regulates the formation of prostaglandins (PT) from arachidonic acid. It was previously shown that COX is the main molecular target for NSAIDs! COX-1 has the functional activity of a structural (“housekeeping”) enzyme, is expressed in most cells, and regulates the production of PGs involved in ensuring the normal (physiological) functional activity of cells. COX 9 is normally absent in most tissues, however, its expression is significant. increases against the background of inflammation, mainly under the influence of "pro-inflammatory" cytokines and is suppressed by "anti-inflammatory" mediators (cortisol) and cytokines (interleukin-4). their ability to inhibit COX-2, while the most common side effects (damage to the gastrointestinal tract, kidneys, impaired platelet aggregation) - with suppression of COX-1 activity... Indeed, among the "standard" NSAIDs, drugs are more selective for COX-2 than COX-1, 3-4 times less likely to cause gastrointestinal complications th path than the less selective ones.

Particularly conclusive results were obtained during the study of meloxicam (Movalis, Boehringer Ingelheim). This drug has the same pharmacodynamic properties as the classic members of the NSAID class, but has a higher selectivity for COX-2 in vitro and in vivo. Data regarding the efficacy and safety of meloxicam are presented in detail in previous publications. Therefore, this article will only summarize the results of recent studies regarding the study of meloxicam in the light of the current teaching on the COX-dependent effects of NSAIDs.

COX selectivity

In the mid-90s, to study the COX-selectivity of NSAIDs, various methods were developed based on the use of purified or recombinant enzymes, cultured cells expressing one or another COX isoenzyme under basal conditions (COX-1) and upon stimulation with LPS or IL-1 (COX-2), and finally, various modifications of methods using unfractionated cells (the so-called whole blood method). The latter is considered as one of the most adequate methods for assessing the COX-selectivity of NSAIDs. However, it soon became apparent that, depending on the experimental conditions (incubation time, inducers, methods for determining PG, etc.), the selectivity of NSAIDs for COX isoforms differs significantly (table 1). This makes it difficult to correctly assess the selectivity of various NSAIDs to COX-1 and COX-2. However, the high COX-2 selectivity of meloxicam compared to "standard" NSAIDs has been demonstrated using almost all existing methods, including recently developed ones based on the use of whole blood in vitro and in vivo. Importantly, according to the whole blood method, meloxicam is as selective for COX-2 as Celebrex, which belongs to the group of specific COX-2 inhibitors.

Table 1
Fluctuations in COX-2/COX-1 inhibition of NSAIDs and meloxicam (Movalis) according to different methods.

Of particular interest are the data that meloxicam exhibits higher selectivity for COX-2 not only in standard test systems, but also when using organ-specific cellular targets, such as cells of the gastric mucosa and platelets (COX-1), chondrocytes and synoviocytes. (COX-2) (Table 2).

table 2
New methods for studying the COX-selectivity of meloxicam (Movalis).

Safety

Data from the main controlled studies showing similar efficacy but higher safety of meloxicam compared to diclofenac, piroxicam and naproxen are partially summarized in Table 3.

Table 3
Tolerance of meloxicam (Movalis) in relation to gastrointestinal side effects compared with placebo and "standard NSAIDs" in RA, OA and AS 13, 20].

* p > 0.05 compared to placebo;
** R<0,02 по сравнению с мелоксикамом;
# R<0,01 по сравнению с плацебо.

It is known that NSAIDs are induced, side effects are divided into 3 main types: symptomatic (abdominal pain, nausea, dyspepsia, etc.); damage to the gastrointestinal mucosa, detected by endoscopic or x-ray studies, and severe complications (perforated ulcers and gastric bleeding). At the same time, it is often difficult to compare the results of clinical and endoscopic studies. So, for example, during endoscopic examination during treatment with NSAIDs, ulcers are detected with a very high frequency (in about 80% of patients), but ulcerative defects, as a rule, are smaller in size than those that lead to complications, and in most cases spontaneously scar . Moreover, the prognostic value of the nature of the ulcerative lesion of the gastrointestinal tract, detected during endoscopic examination during the treatment of NSAIDs in relation to the development of severe complications, requires further study. Therefore, for a correct assessment of the gastroenterological safety of NSAIDs, first of all, data are needed regarding the true frequency of severe complications.

Therefore, the results of a meta-analysis of 10 randomized controlled trials of meloxicam, which included more than 20,000 patients, are of fundamental importance. It has been established that against the background of treatment with meloxicam (compared to "standard" NSAIDs), there is a lower incidence of all the above gastroenterological side effects, including severe complications (table 4). A preliminary analysis of pharmaco-epidemiological data also showed that the use of meloxicam can significantly reduce the incidence of severe complications in patients with risk factors for NSAID-induced side effects (table 5).

Another important aspect of this problem is related to the safe use of NSAIDs in surgery. It has recently been shown that the use of meloxicam (15 mg/day) can reduce blood loss (by an average of 17.1%) during orthopedic surgery. Thus, in patients treated with meloxicam before hip surgery (n=104), blood loss during surgery averaged 354±166 ml and was significantly lower than during treatment with diclofenac at a dose of 50 mg/day (n=134, 427±224 ml) and nabumetone at a dose of 2000 mg/day (n=156, 4061209 ml) (p<0,05).

Table6face4
Results of a meta-analysis of controlled trials on the incidence of gastroenterological side effects (GAS) compared with "standard" NSAIDs (diclofenac, piroxicam, naproxen)

Table 5
Results of pharmacoepidemiological studies of meloxicam in patients with a high risk of gastrointestinal complications

*R<0,01;
**R<0,001

Effect on cartilage

It is known that some NSAIDs have a negative effect on cartilage in patients with osteoarthritis by stimulating the synthesis of pro-inflammatory cytokines or suppressing the synthesis of proteoglycan by chondrocytes. Recently, evidence has been obtained that meloxicam at therapeutic concentrations, unlike indomethacin, does not increase the synthesis of the pro-inflammatory cytokine interleukin (IL)-1 in chondrocyte culture and does not have an inhibitory effect on the formation of proteoglycan. . Thus, meloxicam, unlike many other NSAIDs, can be considered as a "chondroneutral" drug. This property may be of no small importance from the point of view of the prospects for its use in patients with osteoarthritis.

In conclusion, it must be emphasized that at present meloxicam is rightfully considered "one of the most "successful" new NSAIDs. It is registered in almost all developed countries of the world, more than 30 million patients take it. This is determined by its effectiveness and higher safety compared to "standard" NSAIDs, not only in terms of side effects from the gastrointestinal tract, but also impaired renal function, platelet aggregation and negative effects on cartilage.

LITERATURE
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13. Rainsford K.D., Ying C, Smith F.C. Effects of meloxicam, compared with other NSAIDs, on cartilage proteoglycan metabolism, synovial prostaglandin E2, and production of inter-leukin 1, 6, 8, in human and pocine explants in organ culture. J Pharm. Pharmacol., 1997, 49, 991-998.
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For citation: Nasonov E.L. The use of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors at the beginning of the XXI century // RMJ. 2003. No. 7. S. 375

Institute of Rheumatology RAMS, Moscow

P It has been more than 30 years since a group of researchers led by Jone Vane discovered the fundamental mechanism of action of non-steroidal anti-inflammatory (“aspirin-like”) drugs (NSAIDs). It is associated with a reversible inhibition of the activity of the cyclooxygenase (COX) enzyme, which regulates the synthesis of prostaglandins (PG) - important mediators of inflammation, pain and fever. This made it possible to start a purposeful synthesis of new NSAIDs. Currently, these drugs are rightfully among the most popular drugs used in clinical practice. After 20 years, a new major step was taken towards improving anti-inflammatory therapy: the discovery of two isoforms of COX - COX-1 and COX-2. The synthesis of these isoenzymes is regulated by various genes, they differ in molecular structure and have different (albeit partially overlapping) functional activities, reflecting their different roles in the implementation of the “physiological” and “pathological” effects of PG. The discovery of COX isoforms was not only of great theoretical, but also of great practical importance. First, it made it possible to explain the reasons for the effectiveness and toxicity (primarily gastroenterological) of "standard" NSAIDs, which is primarily associated with the suppression of the activity of both COX isoforms. Secondly, it provided an experimental rationale for the development of "new" NSAIDs, the so-called inhibitors (selective or specific) of COX-2, which have lower gastroenterological toxicity than "standard" NSAIDs. In the course of these studies, the mechanism of action of the “simple” analgesic paracetamol was partially deciphered, the point of application of which was another COX isoform (COX-3), predominantly localized in the cells of the cerebral cortex. This made it possible to classify non-narcotic analgesics not by their chemical properties, but by pharmacological (COX-dependent) mechanisms of action (Table 1). It should be noted that some NSAIDs with higher selectivity for COX-2 (meloxicam) were developed in the mid-80s, before the discovery of COX isoforms. The synthesis of newer drugs (the so-called coxibs) is based on data on the structural and functional heterogeneity of COX.

The results of numerous large-scale controlled trials (meeting the criteria of category A "evidence-based medicine"), as well as extensive experience in the use of COX-2 inhibitors in clinical practice, indicate that the main task that was set in the development of COX-2 inhibitors is to reduce gastroenterological toxicity, solved very successfully:

• in most cases, COX-2 inhibitors are not inferior in effectiveness to "standard" NSAIDs in both acute (primary dysmenorrhea, "surgical" pain, etc.) and chronic (osteoarthritis, rheumatoid arthritis) pain;
• COX-2 inhibitors are less likely to cause severe (requiring hospitalization) gastrointestinal side effects (bleeding, perforation, obstruction) than "standard" NSAIDs.

In our previous publications and materials of other authors, modern standards of NSAID therapy are considered in detail. However, experience with the clinical use of NSAIDs, and especially COX-2 inhibitors, is rapidly expanding and improving. The purpose of the publication is to draw the attention of doctors to some new trends and recommendations regarding the rational use of NSAIDs in medicine.

General principles of NSAID treatment well known. When choosing an NSAID, you should take into account:

• the presence (and nature) of risk factors for side effects;
• the presence of concomitant diseases;
• compatibility of NSAIDs with other drugs.

During treatment, careful clinical and laboratory monitoring of side effects is necessary:

Base Study -

Complete blood count, creatinine, aspartate aminotransferase, alanine aminotransferase.

In the presence of risk factors - examination for the presence of H. pylori infection, gastroscopy.

Clinical examination -

"Black" stool, dyspepsia, nausea/vomiting, abdominal pain, swelling, difficulty breathing.

Laboratory examination -

Complete blood count once a year. Liver tests, creatinine (as needed).

Note: in the treatment of diclofenac, aspartate aminotransferase and alanine aminotransferase should be determined after 8 weeks. after the start of treatment. With the combined use of angiotensin-converting enzyme (ACE) inhibitors, serum creatinine must be determined every 3 weeks.

Treatment should begin with the least "toxic" NSAIDs (diclofenac, aceclofenac, ketoprofen, and especially ibuprofen).<1200 мг/сут). Поскольку побочные эффекты НПВП имеют зависимый от дозы характер, необходимо стремиться к назначению минимальной, но эффективной дозы. Частота случаев побочных реакций на фоне НПВП у пациентов старше 65 лет представлена в таблице 2.

• if necessary, long-term use of "standard" NSAIDs at the maximum recommended doses;
• age of patients older than 65 years;
• the presence of ulcerative complications in history;
• taking medications that increase the risk of complications (glucocorticoids, anticoagulants);
• the presence of severe comorbidities.

Obviously, over time, indications for the appointment of COX-2 inhibitors will only expand.

With the development of ulcerative lesions of the gastrointestinal tract, ideally, NSAIDs should be discontinued, which increases the effectiveness of antiulcer therapy and reduces the risk of recurrence of the ulcerative erosive process. In patients with mild pain, you can try to switch to paracetamol. However, in an effective dose (about 4 g / day), paracetamol is also unsafe in terms of the development of complications from the gastrointestinal tract and other organs. In patients with moderate/severe pain, in whom paracetamol is not known to be effective, the use of a combination of diclofenac and misoprostol, and especially COX-2 inhibitors, which, as already noted, are not inferior in effectiveness to "standard" NSAIDs, is more justified. The question of choosing the optimal tactics of antiulcer therapy is being widely studied. Currently, there is no doubt that the drugs of choice are proton pump inhibitors , which almost completely replaced H2-histamine receptor blockers (due to low efficacy) and misoprostol (due to poor tolerability) (Table 3). In addition, according to current recommendations in patients who first started taking NSAIDs, eradication H. pylori helps to reduce the risk of ulcerative bleeding during further treatment. The question of the tactics of managing patients with a very high risk of recurrence of ulcerative bleeding remains unresolved. More recently, in these patients, treatment with celecoxib has been shown to be as effective in preventing recurrent gastric bleeding as is treatment with omeprazole while on-going diclofenac. However, these patients remained at a fairly high risk of rebleeding (4.9% and 6.4%, respectively) within 6 months of therapy. This allows us to draw two fundamentally important conclusions. First, about the higher safety of COX-2 inhibitors compared to "standard" NSAIDs, even in patients at risk of severe gastrointestinal side effects. Secondly, about the inability of COX-2 inhibitors to completely eliminate the risk of severe complications in a certain category of patients. It can be assumed that the most optimal therapy in these patients will be the combined use of COX-2 inhibitors and proton pump inhibitors, but it is not known whether this strategy will completely eliminate the risk of severe gastroenterological complications.

The problem of cardiovascular safety of NSAIDs is especially relevant in rheumatic diseases, in which the systemic inflammatory process is associated with an increased risk of vascular accidents (myocardial infarction and stroke), regardless of the "classical" risk factors for atherothrombosis. Attention to this problem has increased in connection with the results of the study VIGOR (Viox Gastrointestinal Outcomes Research), an analysis of which demonstrated a higher incidence of myocardial infarction in patients with rheumatoid arthritis treated with the COX-2 inhibitor rofecoxib (0.5%) compared with the "standard" NSAID (naproxen) (0.1% ) (p<0,05) . Кроме того, было описано развитие тромбозов у 4 пациентов, страдающих системной красной волчанкой с антифосфолипидным синдромом, получавших целекоксиб . На основании мета-анализа результатов клинических испытаний рофекоксиба и целекоксиба было высказано предположение, что тромбоз является класс-специфическим побочным эффектом ингибиторов ЦОГ-2 . Теоретическим обоснованием для этого послужили данные о том, что ингибиторы ЦОГ-2 подавляют ЦОГ-2 зависимый синтез простациклина (PGI 1) клетками сосудистого эндотелия, но не влияют на продукцию тромбоцитарного тромбоксана (TxA 2) . Предполагается, что это может приводить к нарушению баланса между синтезом «протромбогенных» (тромбоксан) и «антитромбогенных» (простациклин) простагландинов в сторону преобладания первых, а следовательно, к увеличению риска тромбозов. Это послужило основанием для дискуссии о том, насколько «положительные» (с точки зрения снижения риска желудочных кровотечений) свойства ингибиторов ЦОГ-2 перевешивают «отрицательные», связанные с увеличением риска тромботических осложнений , и основанием для ужесточения требований к клиническим испытаниям новых ингибиторов ЦОГ-2. По современным стандартам необходимо доказать не только «гастроэнтерологическую», но и «кардиоваскулярную» безопасность соответствующих препаратов. К счастью, анализ очень большого числа исследований позволил установить, что риск тромбозов на фоне приема ингибиторов ЦОГ-2 (мелоксикам и др.) такой же, как при приеме плацебо или большинства «стандартных» НПВП, за исключением напроксена (именно этот препарат и применялся в исследовании VIGOR) . Предполагается, что на самом деле речь идет не об увеличении риска тромбозов на фоне приема ингибиторов ЦОГ-2, а об «аспириноподобном» действии напроксена . Действительно, напроксен в большей степени (и что самое главное - более длительно) подавляет синтез тромбоксана и аггрегацию тромбоцитов по сравнению с другими НПВП, а риск кардиоваскулярных осложнений на фоне лечения рофекоксибом не отличался от плацебо и НПВП, но был выше, чем у напроксена . Однако, по данным других авторов, прием НПВП (включая напроксен) не оказывает влияния на риск развития тромбозов . Таким образом, вопрос о том, какова связь между приемом НПВП и риском кардиоваскулярных осложнений, остается открытым.

Another aspect of this problem, no less important from a practical point of view, is related to combined use of NSAIDs and acetylsalicylic acid . Obviously, the need for such therapy can be very high, given the elderly age of patients who are the main "consumers" of NSAIDs, and the high risk of cardiovascular accidents in patients with inflammatory rheumatic diseases. Since taking low doses of acetylsalicylic acid in itself can cause the development of severe complications from the gastrointestinal tract, a natural question arises, what are the real advantages of COX-2 inhibitors over "standard" NSAIDs in patients forced to take low doses of acetylsalicylic acid. Indeed, according to research CLASS a significant decrease in the frequency of severe gastroenterological side effects during treatment with celecoxib (compared to "non-selective" NSAIDs) was found only in patients who did not receive low doses of acetylsalicylic acid. However, a recent meta-analysis of trial results for celecoxib shows a clear trend towards a reduction in both symptomatic side effects and severe GI complications with COX-2 inhibitors compared with "standard" NSAIDs. The incidence of severe gastrointestinal complications in patients treated with low doses of acetylsalicylic acid was 51% less with celecoxib than with NSAIDs.

When choosing NSAIDs, it must be taken into account that some of them (for example, ibuprofen and indomethacin) have the ability to cancel the "antithrombotic" effect of low doses of acetylsalicylic acid, while others (ketoprofen, diclofenac), as well as "selective" COX-2 inhibitors do not show this effect. More recently, it has been found that while taking ibuprofen, there is an increase in the risk of cardiovascular accidents compared with taking other NSAIDs. Thus, patients with cardiovascular risk factors while taking NSAIDs (regardless of their COX selectivity) should be given low doses of acetylsalicylic acid. The most optimal drugs in patients taking low doses of acetylsalicylic acid are probably COX-2 inhibitors.

Lung pathology

Approximately 10-20% of patients with bronchial asthma have hypersensitivity to acetylsalicylic acid and NSAIDs, manifested by a severe exacerbation of asthma. This pathology was previously called "aspirin sensitive bronchial asthma" and is now "aspirin-induced respiratory disease" (aspirin exacerbated respiratory disease). It has been established that COX-2 inhibitors (nimesulide, meloxicam, celecoxib, rofecoxib) do not have cross-reactivity with acetylsalicylic acid and NSAIDs regarding the induction of asthma exacerbation and are the drugs of choice in this category of patients.

Fracture repair

In recent studies, it was found that "standard" NSAIDs and COX-2 inhibitors equally have a negative effect on fracture consolidation in laboratory animals. This drew attention to the problem of rational analgesia and patients with skeletal fractures, including osteoporotic ones. Clinical data on the effect of NSAIDs on the healing of skeletal fractures are extremely scarce. Preliminary results indicate a negative effect of "standard" NSAIDs on the healing of vertebral fractures and the absence of such in COX-2 inhibitors. Until more evidence is available, it should still be recommended to limit the use of NSAIDs for analgesia to the extent possible in patients with bone fractures.

In conclusion, it must be emphasized that the treatment of NSAIDs continues to be a difficult part of the pharmacotherapy of human diseases. The appearance of COX-2 inhibitors, on the one hand, made the treatment safer, on the other hand, it drew attention to a number of new aspects of anti-inflammatory and analgesic therapy of NSAIDs (Table 4). We hope that the presented data will allow doctors to provide more qualified assistance to patients with pain of various nature and avoid mistakes that can lead to undesirable consequences for the health and even life of patients.

a) irreversible COX inhibitors

1. Pr-ny salicylic acid - salicylates:acetylsalicylic acid (aspirin), lysine acetylsalicylate

b) reversible COX inhibitors

2. Pyrazolidins:Phenylbutazone (Butadione), analgin

3. Indomethacin (Metindol), Sulindac (Clinoril), Etodolac (Elderin)

4. Diclofenac sodium (Voltaren, Ortofen), potassium (Rapten-Rapid)

5. Oxycams:Piroxicam (Felden), lornoxicam (Xefocam), meloxicam (Movalis)

II. selective COX-2 inhibitors

1. S-va containing a sulfonamide group:nimesulide, celecoxib

By activity and chemical structure

Acid derivatives:

with pronounced anti-inflammatory activity:

Salicylates: Acetylsalicylic acid, lysine monoacetylsalicylate, diflunisal (Dolobit), methyl salicylate

Pyrazolidins: Phenylbutazone (Butadione)

Derivatives of indolacetic acid: Indomethacin (Metindol), Sulindac (Clinoril), Etodolac (Elderin)

Derivatives of phenylacetic acid: Diclofenac sodium (Voltaren, Ortofen), potassium (Rapten-Rapid)

Oxycams: Piroxicam (Felden), lornoxicam (Xefocam), meloxicam (Movalis)

With moderate anti-inflammatory activity

Propionic acid derivatives: Ibuprofen (Brufen, Nurofen), Naproxen (Naprosyn), Ketoprofen

Anthranilic acid derivatives: Mefenamic acid, flufenamic acid

NSAIDs with pronounced anti-inflammatory activity Non-acid derivatives

Alcanones: Nabumeton (Relafen)

Sulfonamide derivatives: Nimesulide (Nimesil, Nise), Celecoxib (Celebrex), Rofecoxib (Viox)

NSAIDs with weak anti-inflammatory activity = analgesics-antipyretics

Pyrazolones: Metamizole ( Analgin),Aminophenazone ( Amidopyrine)

Para-aminophenol (aniline) derivatives: Phenacetin, Acetaminafen ( Paracetamol, perfalgan, panadol, efferalgan, calpol)

Derivatives of heteroarylacetic acid: Ketorolac (Ketorol), Tolmetin

Mechanism of action non-steroidal anti-inflammatory drugs(NSAID) is associated with competitive inhibition of COX. Blockade of COX by non-steroidal anti-inflammatory drugs leads to disruption of the synthesis of prostaglandins E 2 and 1 2 and the development of three main effects:

Anti-inflammatory;

analgesic;

Antipyretic.

Mechanism d-I:

Anti-inflammatory:

Suppression of PgE production 2 and PgI 2 associated with inhibition of COX 2 (in low doses);

Inhibition of neutrophils associated with an effect on the associated G-protein (at high doses)

Reducing the formation and inactivation of inflammatory mediators;

Inhibition of lipid peroxidation

Stabilization of lysosomal membranes (which prevents the release of lysosomal enzymes and prevents damage to cellular structures);

· Inhibition of the processes of formation of macroergic compounds in the processes of oxidative phosphorylation (violation of the energy supply of the inflammatory process);

Suppression of chemokine secretion

Suppression of the synthesis and expression of cell adhesion molecules and, accordingly, the locomotor function of leukocytes;

Inhibition of adhesion of neutrophils and interaction with receptors (the release of inflammatory mediators from them is disturbed, inhibition of synthesis);

Analgesic effect (after 20-40 minutes in moderate doses)

Peripheral Component:

Reduce the number of receptors, stabilizing membranes

Increase in the threshold of pain sensitivity of receptors;

Decreased activity of proteolytic enzymes

· Limitation of exudation (after 5-7 days) with a subsequent decrease in compression of pain endings by exudate in closed cavities (joints, muscles, periodontium, meninges).

Central

· Reducing the formation of Pg-E 2 in the structures of the spinal cord and brain involved in the conduct and perception of pain;

Inhibit COX-2 and PGE synthesis in the CNS, where it is involved in the conduction and perception of pain

Reduce hyperalgesia as a result of: blockade of the synthesis of PG and prostacyclin, which potentiate irritating. effect of IL-1, TNF-α, histamine, serotonin, bradykinin and neurokinins on pain receptors.

Violate the conduction of pain impulses along the conduction pathways of the spinal cord, inhibit the lateral nuclei of the thalamus.

Stimulate the release of endorphins and therefore enhance the inhibitory effect of the periaqueductal gray matter on the transmission of nociceptive impulses

Antipyretic effect (after 20-40 minutes)

1. Inhibit the synthesis of endogenous pyrogens in the periphery (IL-1) in Mon/Mf

2. By inhibiting COX, they reduce the synthesis of PG-E 1 and PG-F 2, HA and serotonin in the central nervous system

Restore the balance of the centers of heat production and heat transfer in the neurons of the preoptic region of the hypothalamus.

Dilate skin vessels and increase perspiration

Inhibition of energy production in the focus of inflammation

Biochemical reactions underlying inflammation are highly energy-consuming: synthesis of inflammatory mediators, chemotaxis, phagocytosis, connective tissue proliferation

NSAIDs disrupt ATP synthesis (suppress glycolysis and aerobic oxidation, uncouple OP)

Effect of NSAIDs on proliferation processes

NSAIDs inhibit the formation of connective tissue (collagen synthesis):

1. Reduce fibroblast activity

2. Violate the energy supply of proliferative processes

The greatest antiproliferative effect is possessed by: indomethacin, diclofenac sodium, aceclofenac, piroxicam, lornoxicam, meloxicam

Antiaggregatory effect of TxA 2 /PgI 2

· By inhibiting COX 1 in platelets, they inhibit the synthesis of the endogenous proaggregant thromboxane.

Selective COX 2 inhibitors do not have an antiaggregatory effect.

Immunotropic action of NSAIDs: Inhibit the activation of transcription factor (NF-kB) in T-lymphocytes

Inhibit the synthesis of cytokines (IL-1,6,8, interferon-β, TNF-α), rheumatoid factor, complement and adhesion molecules

Reduce overall immunological reactivity

Inhibit specific reactions to antigens

Indications for NSAIDs: Acute rheumatic. diseases- gout, pseudo-fallagra, exacerbation of osteoarthritis . Chron. rheumatic diseases- rheumatoid arthritis, spondyloarthropathy, osteoarthritis . Acute non-rheumatic diseases- injuries, back pain, postoperative pain, renal colic, dysmenorrhea, migraine, etc. Other diseases - pleurisy, pericarditis, erythema nodosum, colon polyposis; prevention - thrombosis, colon cancer.

Acetylsalicylic acid- a derivative of salicylic acid, irreversibly blocks COX due to acetylation of the active center of the enzyme. It has a significantly greater affinity for COX-1 than for COX-2. BUT analgesic, antipyretic, anti-inflammatory, antiaggregatory.

1. Inhibits cyclooxygenase (COX-1 and COX-2) and irreversibly inhibits the cyclooxygenase pathway of arachidonic acid metabolism, blocks the synthesis of PG (PGA 2, PGD 2, PGF 2alpha, PGE 1, PGE 2, etc.) and thromboxane. Reduces hyperemia, exudation, capillary permeability, hyaluronidase activity, limits the energy supply of the inflammatory process by inhibiting ATP production.

2. Affects the subcortical centers of thermoregulation and pain sensitivity. A decrease in the content of PG (mainly PGE 1) in the center of thermoregulation leads to a decrease in body temperature due to the expansion of skin vessels and increased sweating.

3. The analgesic effect is due to the effect on the centers of pain sensitivity, as well as the peripheral anti-inflammatory effect and the ability of salicylates to reduce the algogenic effect of bradykinin.

4. A decrease in the content of thromboxane A 2 in platelets leads to an irreversible suppression of aggregation, somewhat dilates blood vessels. Antiplatelet action persists for 7 days after a single dose. A number of clinical studies have shown that significant inhibition of platelet adhesion is achieved at doses up to 30 mg. Increases plasma fibrinolytic activity and reduces the concentration of vitamin K-dependent coagulation factors (II, VII, IX, X). Stimulates the excretion of uric acid, as its reabsorption in the tubules of the kidneys is disturbed.

5. F/kinetics: T 1/2 of acetylsalicylic acid is no more than 15–20 minutes. It circulates in the body (by 75–90% due to albumin) and is distributed in tissues in the form of salicylic acid anion. Cmax is reached after about 2 hours. Acetylsalicylic acid practically does not bind to blood plasma proteins. During biotransformation in the liver, metabolites are formed that are found in many tissues and urine. Excretion of salicylates is carried out mainly by active secretion in the tubules of the kidneys in unchanged form and in the form of metabolites.

6. Application: an effective antiplatelet agent in doses of 100-150 mg per day for the prevention of coronary thrombosis in coronary heart disease, for the prevention of ischemic stroke. Treatment of acute and chronic rheumatic diseases; neuralgia, myalgia, joint pain.

Contraindications: Hypersensitivity, incl. "aspirin" triad, "aspirin" asthma; hemorrhagic diathesis (hemophilia, von Willebrand disease, telangiectasia), dissecting aortic aneurysm, heart failure, acute and recurrent erosive and ulcerative diseases of the gastrointestinal tract, gastrointestinal bleeding, acute renal or hepatic failure, initial hypoprothrombinemia, vitamin K deficiency, thrombocytopenia, thrombotic thrombocytopenic purpura , deficiency of glucose-6-phosphate dehydrogenase, pregnancy (I and III trimester), breastfeeding, children and adolescents under 15 years of age when used as an antipyretic (risk of Reye's syndrome in children with fever due to viral diseases).

8. Specific side effects of acetylsalicylic acid are irritation and ulceration of the gastric mucosa, bronchospasm - aspirin asthma. Bronchospasm is caused by activation of the lipoxygenase pathway of arachidonic acid metabolism.

9. Poisoning: headache, ringing in the ears, visual disturbances, mental disorders; nausea, vomiting, diarrhea, epigastric pain; respiratory alkalosis or metabolic acidosis.

Diclofenac sodium - a derivative of phenylacetic acid. The drug is one of the most commonly used anti-inflammatory drugs with a pronounced analgesic and antipyretic activity. It has pronounced analgesic properties, antipyretic activity. Possesses low toxic activity.

Lornoxicam is a non-selective COX inhibitor. It has pronounced analgesic and anti-inflammatory effects. The antipyretic effect occurs only when taking large doses.

Indiscriminately inhibits cyclooxygenase (COX-1 and COX-2). Reduces the production of PG, leukotrienes, affects the gastric mucosa, platelet function and renal blood flow. It inhibits the release of reactive oxygen species, the kinin system.

It mainly affects the exudative and proliferative phases of the inflammatory response. When administered to patients with rheumatoid arthritis, it exhibits a pronounced analgesic effect, reduces the duration of morning stiffness, the Richie articular index, the number of inflamed and painful joints; in some patients reduces ESR.

Indications: analgesic for inflammatory processes: osteoarthritis, rheumatoid arthritis) + postoperative period + pain associated with tumors. Enter 2-3 times a day. When taken orally, it is rapidly and completely absorbed, bioavailability approaches 100%. The time to reach C max is about 2 hours (with i / m administration - 15 minutes). In plasma, almost all of it binds to proteins. It is hydroxylated in the liver and converted into a pharmacologically inactive metabolite. T1 / 2 - 4 hours. About 30% of the dose is excreted in the urine, mainly in the form of metabolites, the rest - with bile. Of the side effects, frequent reactions from the gastrointestinal tract should be noted.

Ibuprofen - phenylpropionic acid, which is used for pain caused by inflammation.

pharmachologic effect .

Non-selectively inhibits COX-1 and COX-2, reduces the synthesis of PG. The anti-inflammatory effect is associated with a decrease in vascular permeability, an improvement in microcirculation, a decrease in the release of inflammatory mediators (PG, kinins, LT) from cells, and a suppression of the energy supply of the inflammatory process.

The analgesic effect is due to a decrease in the intensity of inflammation, a decrease in the production of bradykinin and its algogenicity. In rheumatoid arthritis, it mainly affects the exudative and partly proliferative components of the inflammatory response, has a rapid and pronounced analgesic effect, reduces swelling, morning stiffness and limited mobility in the joints.

A decrease in the excitability of the heat-regulating centers of the diencephalon results in an antipyretic effect. The severity of the antipyretic effect depends on the initial body temperature and dose. With a single dose, the effect lasts up to 8 hours. With primary dysmenorrhea, it reduces intrauterine pressure and the frequency of uterine contractions. Reversibly inhibits platelet aggregation.

Since PGs delay the closure of the ductus arteriosus after birth, COX suppression is believed to be the main mechanism of action of ibuprofen in IV use in neonates with patent ductus arteriosus.

Analgesic effect compared with anti-inflammatory develops when prescribing smaller doses. In pain syndrome, the onset of action of the drug is noted after 0.5 hours, the maximum effect is after 2-4 hours, the duration of action is 4-6 hours. The drug is well and quickly absorbed when taken orally, it penetrates well into the synovial fluid, where its concentration reaches more higher values ​​than in blood plasma. t is 2 hours.

Ibuprofen is characterized by all the typical side effects of NSAIDs, while it is considered (especially in the US) safer than diclofenac and indomethacin.

The drug is contraindicated in the risk of angioedema, with bronchospastic syndrome.

Celecoxib is a selective COX-2 inhibitor. It mainly inhibits the activity of the enzyme, which is formed in the focus of inflammation.

pharmachologic effect- anti-inflammatory, analgesic, antipyretic.

Selectively inhibits COX-2 and blocks the formation of pro-inflammatory PGs. At therapeutic concentrations, it does not inhibit COX-1. In clinical trials in healthy volunteers, celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for 7 days (above the recommended therapeutic doses) did not reduce platelet aggregation or increase bleeding time. Suppression of PGE 2 synthesis can lead to fluid retention due to increased reabsorption in the thick ascending segment of the loop of Henle and possibly other distal parts of the nephron. PGE 2 inhibits water reabsorption in the collecting ducts by interfering with the action of antidiuretic hormone.

Tc does not affect aggregation, because COX-2 is not formed in platelets. Found activity to prevent the development of tumors and polyposis of the colon and rectum.

When ingested, it is rapidly absorbed, C max is reached after about 3 hours. Eating food, especially rich in fats, slows down absorption. The degree of binding to plasma proteins is 97%. The equilibrium concentration is reached by the 5th day. It is evenly distributed in tissues, penetrates through the BBB. It is biotransformed in the liver mainly with the participation of the CYP2C9 isoenzyme of cytochrome P450. T 1/2 - 8-12 hours, total clearance - 500 ml / min. It is excreted in the form of inactive metabolites, mainly through the gastrointestinal tract, a small amount (less than 1%) of unchanged celecoxib is found in the urine.

Indications: Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriatic arthritis.

Side effects of NSAIDs

Karateev A.E. (State Research Institute of Rheumatology RAMS, Moscow)

Non-steroidal anti-inflammatory drugs (NSAIDs)- a unique class of drugs that combine a wide range of therapeutic effects, ease of use and relatively low cost. NSAIDs are used for therapeutic and prophylactic purposes in a very wide range of diseases and pathological conditions, being the most commonly used group of drugs in clinical practice and everyday life. Unfortunately, the use of NSAIDs is limited by their undesirable effects, primarily by the development of pathological changes in the gastrointestinal tract (GIT) associated with taking these drugs. The central place in this problem is given to the so-called NSAID-induced gastropathy - lesions of the upper gastrointestinal tract, characterized by the development of damage to the mucous membrane (erosion, ulcers and their complications). The search for ways to prevent NSAID-induced gastropathy, which is a very serious medical and social problem, has become one of the priority areas of scientific research in recent years.

The creation of a new class of NSAIDs - selective inhibitors of cyclooxygenase 2 (COX-2) has opened a new direction in the population prevention of NSAID-induced gastropathy. Currently, it has been proven that serious gastroduodenal complications (ulcers of the upper gastrointestinal tract, gastrointestinal bleeding (GI) and ulcer perforation) occur significantly less frequently when taking selective COX-2 inhibitors than with the use of "classic" NSAIDs. At the same time, the anti-inflammatory and analgesic effects of these drugs were satisfactory and comparable to those of "classic" NSAIDs. , which makes it possible to recommend selective COX-2 inhibitors for widespread use in clinical practice.

The most important area of ​​application of selective COX-2 inhibitors may be their use in patients with so-called risk factors for the development of NSAID-induced gastropathy, primarily in patients with a history of ulcerative disease. It is known that the use of "classic" NSAIDs by patients with a history of ulcers or multiple erosions (ME) of the mucous membrane of the upper gastrointestinal tract significantly increases the risk of recurrence of this pathology and such dangerous complications as perforation and gastrointestinal tract. This group of patients, constituting 15-20% of those with indications for long-term use of NSAIDs, is the most difficult in terms of selecting adequate anti-inflammatory therapy.

At the same time, there is no convincing evidence that the use of selective COX-2 inhibitors in patients with a history of ulcers will be safer than the use of classical NSAIDs. There is only one study on this issue, conducted according to the standards of evidence-based medicine and devoted to the study of gastroduodenal tolerance of specific COX-2 inhibitors (celecoxib) in patients with a high risk of developing severe gastroduodenal complications. This is a study by F. Chan et al. (2002) , which compared the incidence of recurrence of gastrointestinal bleeding in patients with rheumatic diseases who had a history of this complication after 6 months of taking celecoxib 400 mg / day or diclofenac 100 mg / day in combination with omeprazole 20 mg / day. The recurrence rate was 4.9% in the main group and 6.4% in the control group (the difference is not significant).

In our country, the situation with the prevention of NSAID-induced gastropathy remains very serious. The practice of monitoring the undesirable effects of drugs has not been developed, approaches to the safe therapy of NSAIDs have not been systematized, and there are no clear recommendations on the use of selective and specific COX-2 inhibitors in clinical practice. Therefore, the study of gastroduodenal tolerance of selective COX-2 inhibitors in patients with a history of ulcers seems interesting and timely.

For this study, we chose nimesulide (Nimesil; Berlin Chemie). This drug is a typical representative of the group of selective COX-2 inhibitors, widely used in Russia, has stable anti-inflammatory and analgesic effects, and a good profile of gastroduodenal tolerance. The dosage form of Nimesil (soluble) can significantly reduce the time of contact with the mucous membrane of the upper gastrointestinal tract and, to a certain extent, reduce the risk of developing contact damage.

Target The present study consisted in assessing the safety of nimesulide in patients with rheumatic diseases with a history of ulcers or ME of the mucous membrane of the stomach and / or duodenum (DU).

Materials and methods

The study group consisted of 42 patients with chronic rheumatic diseases aged 22 to 73 years who took NSAIDs for a long time (at least 6 months).

Inclusion criteria were: the presence in history (according to endoscopy), within a period of not more than 6 months before the start of the study, ulcers or ME (n>10) of the stomach or duodenum, which significantly arose while taking NSAIDs, and the need to continue taking NSAIDs for at least , 3 months.

Exclusion Criteria were: presence of an open ulcer or more than 5 erosions of the upper gastrointestinal tract at the time of study entry, severe functional impairment, severe comorbidity, history of gastrointestinal bleeding (within the last 12 months) or perforation of the ulcer, history of an allergic reaction to study drugs and current use inclusion in the study of proton pump inhibitors (PPIs) or misoprostol.

The patients included in the study were randomly divided into 2 groups. Key demographics of patients are presented in table 1. Among them, middle-aged and elderly women predominated, mostly patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The vast majority of patients in both groups at the time of inclusion in the study were taking diclofenac, about a third received glucocorticosteroids (GCS) at doses of 5 to 15 mg/day and cytotoxic drugs (mainly methotrexate). There were no statistically significant differences in demographic indicators and the nature of therapy for the underlying disease in patients in the study groups.

The initial pathology of the gastrointestinal tract in the studied groups is presented in Table 3. Ulcers localized in the stomach prevailed, which, in general, corresponds to the population structure of NSAID-induced gastropathy. Less common were duodenal ulcers or ME of the gastric mucosa. There were no statistically significant differences in the nature of the ulcer history in patients in the study groups.

Patients in group 1 were prescribed nimesulide at a dose of 200 mg/day for 2 doses, patients in group 2 received diclofenac 100 mg/day. For a more adequate comparison of the study drugs used in different dosage forms, and to exclude the contact effect of NSAIDs in the control group, diclofenac was prescribed in the form of suppositories 50 mg 2 times a day. Patients of groups 1 and 2, if necessary (in the event of gastralgia and dyspepsia), took antacids (up to 4 times a day). All patients in group 2 were prescribed ranitidine 150 mg/day.

EGDS was performed before and 12 weeks after the start of the study. In the presence or ME at the first EGDS, standard antiulcer therapy (omeprazole 40 mg/day for 2-4 weeks) was carried out, and after ulcer scarring confirmed by EGDS, the patients were included in the study program.

The safety of NSAIDs was assessed based on the data of repeated endoscopy (after 12 weeks) according to the frequency of relapses of NSAID-induced gastropathy. The recurrence of NSAID-induced gastropathy was considered to be the re-detection of ulcers (local damage to the mucous membrane with a size of at least 0.5 cm, having a distinct visible depth) and ME of the mucous membrane of the stomach or duodenum.

In addition, the dynamics of subjective sensations from the gastrointestinal tract (gastralgia and dyspepsia) was assessed. In some patients, in the event of severe gastralgia and dyspepsia, EGDS was performed ahead of schedule.

Mathematical processing of the obtained data was carried out using standard statistical programs. Statistical significance of differences between groups was assessed using Student's t-test, c2, and Fisher's exact test.

Research results

1. Repeated EGDS was performed in 18 patients of group 1, incl. 2 patients ahead of schedule - after 6 and 10 weeks from the start of the study, respectively. In 3 patients, endoscopy was not performed due to the interruption of Nimesil intake in the early stages (less than 2 weeks from the start of the test), 1 patient dropped out of observation (did not appear for the study at the control dates).
2. Repeated EGDS was performed in 18 patients of group 2, incl. 1 patient ahead of schedule, after 6 weeks from the start of the study. 2 patients dropped out of observation (did not appear for the study in the control period).
3. Recurrence of gastric ulcer was noted in 1 patient of group 1 (5.6%). Relapses of NSAID-induced ulcers and erosions were registered in 6 patients of group 2 (33.3%): 4 had gastric ulcers, 1 had ME, and 1 had a duodenal ulcer (p = 0.0424; figure).
4. The presence of gastralgia and dyspepsia was noted in 7 of 19 patients of group 1 (36.8%) and in 4 of 18 patients of group 2 (22.2%; p = 0.0539), and in 1 patient of group 2 severe gastralgia caused early conducting EGDS.
5. The therapeutic effect of Nimesil was rated as "good" by 8 patients (38.1%), "satisfactory" - by 9 (42.9%), "unsatisfactory" - by 4 (19.0%), and in 2 patients the unsatisfactory effect was the cause interruption of therapy in the early stages. The evaluation was performed in 21 patients of group 1.
6. The therapeutic effect of diclofenac was assessed as "good" by 7 patients (36.8%), "satisfactory" - by 10 (52.6%), "unsatisfactory" - by 2 patients (10.5%). The evaluation was performed in 19 patients of group 2.
7. Adverse reactions (not associated with the occurrence of erosive and ulcerative changes) that occurred in patients in groups 1 and 2 are presented in table 4. Most often, dyspeptic symptoms appeared in patients, and in patients of group 1 more often (not statistically significant) than in group 2.

The discussion of the results

While taking Nimesil at a dose of 200 mg/day for 3 months, relapses of NSAID-induced ulcers and ME occurred significantly and significantly less frequently than while taking diclofenac in the form of suppositories of 100 mg/day. Thus, (as far as we know), for the first time in a domestic study, reliable data were obtained on the possibility of using selective COX-2 inhibitors in patients with a high risk of developing NSAID-induced gastropathy. Of course, the small size of the study groups, the relatively short observation period, and the open nature of the study do not allow us to draw global conclusions about the prospects for the widespread use of selective COX-2 inhibitors in patients with a history of ulcers. At the same time, our study can serve as a "starting point" for more long-term, multicenter studies on this issue.

Recurrence of gastric ulcer was noted only in 1 patient who took nimesulide. This fact once again confirms that the use of selective and specific COX-2 inhibitors significantly reduces, but does not completely eliminate the risk of developing serious gastroduodenal complications. Thus, the frequency of serious gastroduodenal complications while taking meloxicam and diclofenac, demonstrated in one of the largest studies (MELISSA), did not differ significantly (5 and 7 cases, respectively). We have shown the possibility of developing ulcers in patients taking meloxicam , it should be noted that most of them had an ulcer history. The combination of celecoxib and antiplatelet doses of aspirin significantly increases the risk of developing gastroduodenal complications, making it equal to the risk of developing this pathology while taking "classic" NSAIDs (CLASS).

It should be noted that the group of patients with serious risk factors for gastropathy seems to be the most difficult in terms of adequate anti-inflammatory and analgesic therapy. It is on this group that the attention of many research groups dealing with the problem of NSAID-induced gastropathy is focused. .

The occurrence of relapses in a third of patients in the control group seems to be quite natural. So, according to a large special study conducted in the United States, relapses of gastric ulcer associated with taking NSAIDs developed even more often - in 49% of cases. . The control group imitates a very common in Russia tactics of managing patients with rheumatic diseases with a history of NSAID-induced gastropathy. The use of candlestick forms, as we have shown earlier and confirmed in this work, does not avoid recurrence of ulcers and ME of the upper gastrointestinal tract. The leading in the pathogenesis of NSAID-induced gastropathy is the systemic negative effect of NSAIDs on the mucous membrane, while the contact action is more responsible for the development of dyspeptic phenomena. Ranitidine is still widely used by Russian doctors for NSAID-associated pathology of the upper gastrointestinal tract due to its relatively low cost and good tolerability. However, there is no doubt that this drug cannot currently be considered as an effective prophylactic against relapses of NSAID-induced ulcers and gastric erosions. .

A special discussion requires a relatively high frequency of adverse reactions not associated with recurrence of ulcers and erosions that occurred in patients taking Nimesil compared with patients in the control group. First of all, this is due to the fact that almost all patients had taken diclofenac for a long time (at least 6 months) before the start of the study. Therefore, when prescribing diclofenac in suppositories to patients who had previously taken this drug orally and tolerated it well enough, it was difficult to expect any adverse reactions. Moreover, the use of the suppository form of the drug in combination with an H2 blocker made it possible to significantly reduce the frequency and severity of dyspepsia in patients in the control group. It should be noted that the most well-known comparative studies of the tolerability of selective COX-2 inhibitors (such as meloxicam) and "classic" NSAIDs did not show significant differences in the frequency of dyspepsia when using them. Thus, the incidence of gastralgia and dyspepsia in patients taking meloxicam was 13%, and in patients taking diclofenac - 19% (MELISSA) . Severe dyspeptic symptoms are among the most common complications that occur while taking celecoxib. In the CLASS study the overall incidence of gastrointestinal symptoms while taking celecoxib was 29.9% (in the control group - 35.6%). Subjective symptoms were the reason for discontinuation of the drug in 8.0% of patients (in the control group — 10.1%). Only a large number of patients included in these studies made the differences in the subjective tolerance of these drugs (compared to the "classic" NSAIDs) statistically significant.

A persistent increase in blood pressure in 2 patients of the main group is quite natural, since they suffered from arterial hypertension for a long time and received appropriate antihypertensive therapy. In general, arterial hypertension is a fairly common and typical undesirable effect of NSAIDs, probably due to a negative effect on the kidney vessels. So, in the study of F. Chan et al. manifestations of nephropathy (which included arterial hypertension, edema and impaired renal function) while taking celecoxib occurred in 24.3% of patients. Obviously, the possibility of developing such adverse events should be taken into account when prescribing nimesulide to patients with arterial hypertension.

An episode of reduced visual acuity in one patient should be considered taking into account her multiple comorbidities (arterial hypertension, diabetes mellitus, glaucoma, cataracts). Undoubtedly, such a complication may not be associated with the intake of Nimesil, however, it chronologically coincided with the time of the study and therefore should be classified as an adverse reaction. It should be noted that episodes of reduced visual acuity also belong to the possible, although relatively rare, non-specific adverse reactions that occur while taking NSAIDs.

The relatively high frequency of adverse reactions that occurred while taking Nimesil is determined by the characteristics of the study group, which included patients with severe chronic articular pathology who received a complex of antirheumatic drugs. Nevertheless, the main goal of the study seems to have been achieved, since the main problem with the use of NSAIDs in rheumatological practice is precisely serious gastroduodenal complications associated with the development of ulcers or ME.

conclusions

Nimesil can be considered as a safer remedy than the "classic" NSAIDs in relation to the development of serious gastroduodenal complications in patients with rheumatic diseases with a history of ulcers. The data obtained allow us to consider Nimesil as the drug of choice if it is necessary to continue taking NSAIDs in patients with a history of NSAID-induced gastropathy.

Indications for the use of selective COX-2 inhibitors (Nimesil)

• General indication

  the need for anti-inflammatory and analgesic therapy.

• Additional indications

  at first appointment

  1. a history of gastric ulcer or duodenal ulcer;
  2. the presence of additional risk factors for the development of NSAID-induced gastropathy (age over 65 years, severe comorbidity - coronary artery disease, diabetes mellitus, etc., the need for concomitant intake of high doses of corticosteroids, anticoagulants, antiplatelet doses of aspirin);
  3. the presence of dyspeptic phenomena in the absence of an ulcer history ("non-ulcer dyspepsia") and gastroesophageal reflux.

  at secondary appointment(in patients who have been taking non-selective COX-2 inhibitors for a long time):

  1. a history of NSAID-induced ulcer or ME of the gastric mucosa or duodenum;
  2. development against the background of taking non-selective COX-2 inhibitors of dyspeptic syndrome in the absence of erosive and ulcerative changes in the mucosa (“NSAID-associated dyspepsia”).

Note: the question of the need to prescribe additional drug prophylaxis with antiulcer drugs while taking selective COX-2 inhibitors (Nimesil) should be decided individually in the presence of a combination of risk factors for gastropathy.

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