What is tsog 2 how it stands for. Selective anti-inflammatory drugs: clinical efficacy, mechanism of action, side effects

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© KARATEEV A.E., 2014 UDC 615.276.036.06

SELECTIVE CYCLOOXYGENASE-2 INHIBITORS AND "PROTECTED" NON-STEROID ANTI-INFLAMMATORY DRUGS: TWO METHODS FOR THE PREVENTION OF DRUG COMPLICATIONS

Karateev A.E.

Federal State Budgetary Institution "Research Institute of Rheumatology named after N.N. V.A. Nasonova, RAMS, Moscow

Non-steroidal anti-inflammatory drugs (NSAIDs) are an indispensable tool for the control of acute and chronic pain. They are widely used in diseases of the musculoskeletal system, as well as for pain relief after injuries and surgical interventions. Unfortunately, NSAIDs can produce a number of class-specific side effects, primarily affecting the gastrointestinal tract (GIT) and the cardiovascular system (CVS). The most well-known complication is NSAID gastropathy, which manifests itself as the development of gastric ulcers and / or duodenum(DPC), bleeding, perforation and impaired patency of the gastrointestinal tract. Prevention of NSAID gastropathy relies on 2 main methods: switching to new, safer drugs or prescribing powerful antiulcer drugs together with NSAIDs.

The use of coxibs as a method of preventing gastrointestinal complications. The main advantage of "coxibs" (from the English abbreviation COX) - inhibitors of cyclooxygenase (COX) activity - is the selectivity of the effect on different forms of COX: in therapeutic doses, they practically do not affect the physiological enzyme COX-1, suppressing only its inducible variety of COX-2 . This reduces the negative impact of NSAIDs on the protective potential of the gastrointestinal mucosa and reduces the likelihood of damage.

In Russia, the coxibs family is represented by two drugs, celecoxib and etoricoxib, which have been extensively tested to prove their superiority over non-selective COX-2 inhibitors (n-NSAIDs).

The safety of celecoxib is confirmed by 2 large randomized controlled trials (RCTs) - CLASS and SUCCESS-1. In the first of these, celecoxib (800 mg/day), as well as reference drugs, diclofenac (150 mg/day) and ibuprofen (2400 mg/day), were prescribed for 6 months to approximately 8,000 patients with rheumatoid arthritis (RA) and osteoarthritis. (OA). Low-dose aspirin (NDA) (325 mg/day or less) could be prescribed as indicated, which ended up being taken by about 20% of the participants. Totally se-

Serious gastrointestinal complications occurred in 0.76% of patients treated with celecoxib and in 1.45% of patients in the active control group. This difference was not statistically significant, but it was significant in individuals who did not receive NDA: 0.44% vs. 1.27% (p< 0,05). В 3-месячное РКИ SUCCESS-1 были включены только больные ОА, которые получали целекоксиб в дозе 200 или 400 мг (n = 8800), а также диклофенак (100 мг) или напроксен (1000 мг) (n = 4394). НДА применяли гораздо реже (7,1%), поэтому результаты были однозначны: желудочно-кишечные кровотечения и перфорации язв были выявлены у 2 и 7 больных (р = 0,008).

The low risk of gastrointestinal complications with the use of celecoxib is confirmed by a meta-analysis of 31 RCTs (39,605 patients in total): dangerous gastrointestinal complications occurred more than 2 times less frequently with this drug than in controls (0.4% and 0.9 % respectively) .

The benefits of celecoxib were shown in 2 RCTs (3 and 6 months, n = 1059), which studied the dynamics of the endoscopic picture of the upper gastrointestinal tract while taking this drug (400 mg), naproxen (1000 mg) and diclofenac (150 mg/day). As a result, gastric/duodenal ulcers occurred in 4 and 25% (p = 0.001) and 4 and 15% (p = 0.001), respectively.

Recently, when assessing the negative impact of NSAIDs on the gastrointestinal tract, more and more attention is paid to the risk of developing pathology. small intestine with an increase in its permeability and chronic inflammation associated with the penetration of bacteria or their components contained in the chyme into the intestinal wall (NSAID enteropathy). This complication may present with severe bleeding, perforation, and strictures; however, its most characteristic feature is subclinical blood loss leading to the development of chronic iron deficiency anemia (IDA). The latter significantly worsens the condition of patients, reducing the oxygen capacity of the blood and resistance to stress, which ultimately determines the increased risk of cardiovascular accidents.

An integrated approach to the assessment of gastrointestinal complications was used by G. Singh et al.,

who conducted a meta-analysis of 52 RCTs (n = 51,048) comparing celecoxib with placebo and n-NSAIDs. In total, the frequency of gastrointestinal bleeding, perforation, gastric and duodenal ulcers, as well as IDA was 1.8% while taking celecoxib. This rate was not significantly higher than with placebo (1.2%), but much lower than with n-NSAIDs (5.3%, p< 0,0001) .

A summary assessment of the effect of NSAIDs on the gastrointestinal tract was carried out in the CONDOR RCT. In this study, 4481 patients with RA or OA at high risk of NSAID gastropathy, not infected with Helicobacter pylori, received celecoxib (400 mg) or diclofenac (150 mg/day) and omeprazole (20 mg/day) for 6 months. The number of serious gastrointestinal complications when using the combination of diclofenac and omeprazole was significantly higher than when using celecoxib: gastric / duodenal ulcers occurred in 20 and 5 patients, IDA - in 77 and 15, and treatment withdrawal due to complications was required in 8% and 6% of patients, respectively (p< 0,001) .

Another confirmation of the relative safety of celecoxib for the condition of the small intestine was the work of J. Goldstein et al. based on the use of the video capsule endoscopy technique. In this trial, 356 volunteers received celecoxib (400 mg), naproxen (1000 mg) plus omeprazole (20 mg) or placebo for 2 weeks. There were no differences in the effect on the state of the upper gastrointestinal tract between the groups, but the situation was different in relation to the defeat of the small intestine. In the celecoxib group, the number of patients with damage to the small intestinal mucosa was significantly less than in the naproxen group (16 and 55%, p< 0,001), хотя и больше, чем в группе плацебо (7%) .

A new confirmation of the benefits of celecoxib was the GI-REASONS study, during which the safety of this drug was evaluated in 4035 patients with OA who received it for 6 months. The control consisted of 4032 patients with OA, who were prescribed different

Celecoxib H. pylori -

Rice. 1. The incidence of serious gastrointestinal complications, including a decrease in hemoglobin level of more than 20 g/l, against the background of 6 months of taking celecoxib and traditional NSAIDs, depending on H. pylori infection: RCT GI-REASONS (n = 8067) .

personal n-NSAIDs. The features of this work were the registration of H. pylori infection (this microorganism was detected in approximately 33.6% of participants), the permission to use proton pump inhibitors (PPIs) and H2 receptor blockers (they were received by 22.4% and 23.8% of patients) and exclusion of NDA. The main safety criterion was the frequency of gastrointestinal complications, including episodes of a decrease in hemoglobin level of more than 2 g / dl, which could be associated with damage to the gastrointestinal mucosa. Clinically significant gastrointestinal complications occurred significantly less frequently when using celecoxib (1.3% and 2.4%, respectively, p< 0,001) (рис. 1).

The GI-REASONS study, like the CONDOR study, clearly demonstrates the greater safety of celecoxib compared to traditional NSAIDs, including in situations that simulate real clinical practice.

Etoricoxib, like celecoxib, was created to improve the safety of NSAID therapy. It has now become the end point of the development of the concept of selective COX-2 inhibitors: the ratio of inhibitory concentrations of COX-1 / COX-2 for etoricoxib is about 100, while for celecoxib it is only about 6.

The first studies unequivocally confirmed the high level of safety of etoricoxib. Thus, a meta-analysis of RCTs completed by 2003 that compared etoricoxib and n-NSAIDs (n = 5441) showed a significantly lower incidence of dangerous gastrointestinal complications when using the new drug. The overall incidence of bleeding, perforation and clinically significant ulcers while taking etoricoxib (60-120 mg) was 1.24%, while using comparators (diclofenac, naproxen, ibuprofen) - 2.48% (p< 0,001) .

Strong evidence for the greater safety of etoricoxib came from 2 large-scale 12-week RCTs (n = 742 and n = 680) that assessed the incidence of endoscopic upper GI ulcers in patients with RA and OA treated with etoricoxib (120 mg), ibuprofen (2400 mg) , naproxen (1000 mg) or placebo. This complication while taking etoricoxib was observed in 8.1 and 7.4% of patients, i.e., more than 2 times less often than when taking n-NSAIDs (17 and 25.3%, p< 0,001), хотя и чаще, чем при использовании плацебо (1,9 и 1,4%) .

The clear line of evidence for the benefit of etori-coxib, however, was broken following the publication of the results of MEDAL, the largest RCT of NSAIDs to date. The stated goal of this study was to prove that etoricoxib is no more dangerous for the cardiovascular system than traditional NSAIDs. MEDAL enrolled 34,701 patients with OA and RA who received etoricoxib (60 or 90 mg) or diclofenac (150 mg/day) for at least 1.5 years. At the same time, patients, if indicated, could use PPIs and NDA. In total-

where the main result was achieved: the number of cardiovascular accidents (including death) when using etoricoxib and diclofenac was almost the same.

However, the data on the incidence of serious gastrointestinal complications came as an unpleasant surprise to the organizers of MIDAL. Although their total frequency with etoricoxib was significantly lower than with diclofenac (1 and 1.4%, p< 0,001), число эпизодов желудочно-кишечных кровотечений оказалось фактически равным - 0,3 и 0,32 эпизода на 100 пациентов в год. При этом одинаковая частота желудочно-кишечных кровотечений наблюдалась независимо от сопутствующего приема НДА и ИПП . Столь же трудно объяснить другой результат MEDAL. Оказалось, что частота побочных эффектов в дистальных отделах ЖКТ (таких, как кишечное кровотечение) при приеме эторикоксиба и ди-клофенака практически не различалась - 0,32 и 0,38 эпизода на 100 пациентов в год .

Nevertheless, it cannot be said that the results of MEDAL completely cross out the data of previous studies, but they make us think that we know far from all aspects of the development of gastrointestinal complications associated with the use of NSAIDs, and that when they long-term use pathogenetic factors that are not significant during their relatively short-term use may begin to act.

Thus, there are good reasons to talk about a significant reduction in the risk of serious gastrointestinal complications and better tolerability of coxibs (celecoxib and etoricoxib) compared to n-NSAIDs. The evidence for the benefit of celecoxib appears to be clearer; the drug proved to be safer in relation to complications not only in the upper, but also in the lower gastrointestinal tract.

The low risk of gastrointestinal complications with celecoxib is supported by population-based studies. At the end of 2012, a meta-analysis of 28 epidemiological studies (performed from 1980 to 2011) was published that assessed the development of gastrointestinal complications with the use of various NSAIDs. Celecoxib showed a minimal relative risk (RR) of gastrointestinal complications of 1.45; the risk was clearly higher with ibuprofen (1.84), diclofenac (3.34), meloxicam (3.47), nimesulide (3.83), ketoprofen (3.92), naproxen (4.1), and indomethacin ( 4.14). The same low risk of gastrointestinal complications, as in celecoxib, was determined by the authors of this study for one of the representatives of traditional NSAIDs - aceclofenac (1.43).

Celecoxib, for all its merits, however, is far from ideal. At high risk (particularly in patients who have had complicated ulcers or are taking NDA), it can cause serious gastrointestinal complications. In this regard, very

the data of F. Chen et al. . This study included 441 patients with rheumatic diseases who had a history of serious bleeding from upper gastrointestinal ulcers that occurred while taking NSAIDs. After successful ulcer healing and H. pylori eradication, all patients received celecoxib (400 mg/day) for 12 months either without additional prophylaxis or in combination with esomeprazole (20 mg). During follow-up, rebleeding occurred in 8.9% of patients treated with celecoxib alone and none of the patients treated with celecoxib with esomeprazole.

The main disadvantage of celecoxib and etoricoxib is that they belong to highly selective COX-2 inhibitors - the type of NSAIDs, thanks to which the world medical community learned that NSAIDs can cause cardiovascular complications.

Thus, the results of the MEDAL study, although they did not show an increase in the number of cardiovascular accidents with the use of etoricoxib, however, revealed its definitely negative effect on the progression of arterial hypertension. In addition, population studies and meta-analysis of RCTs indicate a significant cardiovascular risk associated with the use of this drug.

It should be noted that many experts consider celecoxib, unlike other coxibs, to be quite safe for CVS. This fact is confirmed by a series of population-based studies that were reviewed in a well-known systematic review (including meta-analysis) by P. McGettigan and D. Henry. The authors evaluated data from 30 case-control studies, including 184,946 patients with cardiovascular complications, and 21 cohort studies (which included more than 2.7 million patients in total) performed up to 2011. The total risk of cardiovascular complications (RR) when using celecoxib was 1.17 (1.08-1.27); it was slightly higher than against the background of naproxen 1.09 (1.02-1.16) and equal to that with ibuprofen - 1.18 (1.11-1.25). When using other NSAIDs, this indicator turned out to be worse - 1.20 (1.07-1.33) for meloxicam, 1.30 (1.19-1.41) for indomethacin, 1.40 (1.27-1.55 ) for diclofenac and 2.05 (1.45-2.88) for etoricoxib.

However, one cannot ignore a number of serious studies indicating that celecoxib can increase the risk of cardiovascular accidents. So, in 2011 S. Trelle et al. published a meta-analysis of 31 RCTs (116,429 patients in total) examining the safety of celecoxib, etoricoxib, lumirocoxib, and rofecoxib; Various n-NSAIDs and placebo served as controls. The evaluation criterion was the risk of myocardial infarction, stroke and death due to cardiovascular complications. In accordance with the data obtained, the risk of developing myocardial infarction against the background of

the intake of celecoxib was higher than that of etoricoxib (OR 1.35 and 0.75), as well as the reference drugs diclofenac (0.82) and naproxen (0.82), but lower than that of ibuprofen (1.61) . Most importantly, there was an increased risk of death with celecoxib (2.07), especially compared with naproxen (0.98). True, it was somewhat lower than with ibuprofen (2.39) and significantly lower than with diclofenac (3.98) and etoricoxib (4.07).

A slightly higher incidence of thromboembolic complications in patients receiving celecoxib was shown in a part of RCTs. Thus, in the SUCCESS-1 study mentioned above, 10 cases of myocardial infarction (0.55 per 100 patients/years) were noted in patients treated with celecoxib, and only 1 (0.11 per 100 patients/years) in those treated with naproxen or diclofenac. ; the difference is not significant (p = 0.11). In the GI-REASONS study, the incidence of cardiovascular events in patients receiving celecoxib and n-NSAIDs did not differ: 0.4 and 0.3%, however, only those who received celecoxib experienced episodes of death from cardiovascular complications (3 cases) and exacerbation of coronary heart disease, requiring revascularization (4 cases) .

Another evidence of the possible negative impact of celecoxib on the state of the cardiovascular system was a large-scale population study by G. Gislason et al. . The authors studied the relationship between NSAIDs and the risk of death in patients with myocardial infarction. The study group consisted of 58,432 patients who were successfully treated after their first myocardial infarction between 1995 and 2002. Subsequently, 9,773 patients suffered a second myocardial infarction, and 16,573 patients died. As shown by the analysis, the use of any NSAIDs was associated with a significant risk of death in patients. When using celecoxib, the danger was the greatest (with the exception of rofecoxib) - HR 2.57; for diclofenac this figure was 2.40, and for ibuprofen - 1.50.

Thus, it is clear that celecoxib is today the recognized gold standard for gastrointestinal tolerance. Nevertheless, the use of celecoxib cannot be considered a solution to the problem of the safe use of NSAIDs.

Fixed combination of non-selective non-steroidal anti-inflammatory drugs and anti-ulcer drugs. The second way to prevent NSAID gastropathy is the use of gastroprotectors designed to protect the gastrointestinal tract from the negative consequences of taking NSAIDs. The first of these was misoprostol, a synthetic analogue of PGE2, which eliminated the adverse effects of COX-1 blockade and, consequently, prevented the development of gastrointestinal complications associated with NSAIDs. The main evidence of its effectiveness was the 12-month RCT MUCOSA, which included 8843 patients with RA who received NSAIDs in combination with

zoprostol (200 micrograms 4 times a day) or placebo. Misoprostol significantly reduced the risk of gastrointestinal complications: thus, bleeding and perforation in the active therapy group occurred in 0.76% of patients, in the control group - in 1.5% (p< 0,05) .

Later, on the basis of this gastroprotector, “protected” NSAIDs were created, such as Arthro-tec, containing 50 mg of diclofenac sodium and 200 μg of misoprostol.

Unfortunately, misoprostol is poorly tolerated and often causes dyspepsia and diarrhea. Side effects and an inconvenient regimen have significantly limited its use in real practice, especially after the advent of selective COX-2 inhibitors and the widespread use of PPIs.

PPIs quickly gained popularity as effective and convenient gastroprotectors. A series of large-scale RCTs clearly confirmed their effectiveness in the treatment and prevention of NSAID gastropathy, but nevertheless, the problem of NSAID gastropathy has not been completely resolved and one of the main reasons for this is the lack of adherence of patients to therapy.

Unfortunately, a significant proportion of patients who have serious risk factors for gastrointestinal complications and regularly use NSAIDs do not take their prescribed gastroprotective drugs. This may be due to a certain inconvenience for patients (“taking two pills instead of one”), an increase in the cost of treatment, as well as a lack of motivation when taking NSAIDs is not accompanied by any unpleasant symptoms (“why take gastroprotector if my stomach doesn't hurt?"). In addition, elderly patients may simply forget and skip taking prophylactic medications.

This problem is well illustrated by the work of American scientists J. Goldstein et al. who assessed adherence to gastroprotective therapy in a cohort of 144,203 patients with rheumatic diseases taking NSAIDs. PPIs or H2 blockers were strongly recommended in 1.8% of patients due to the serious risk of gastrointestinal complications, however, as it turned out, almost a third (32%) of patients used gastroprotectors irregularly or not at all. And this led to the most unpleasant consequences: the risk of gastrointestinal bleeding in people who did not adhere to gastroprotective therapy was 2.5 times higher than in patients who carefully followed the doctor's prescription.

The key to solving the problem of increasing patient adherence may be the use of combined drugs containing NSAIDs and an antiulcer agent. The revival of the idea of ​​"protected NSAIDs" occurred 20 years after the creation of Arthrotec, and the main reason for this was the decline in interest in selective COX-2 inhibitors after the "coxibs crisis".

Today, the main factor limiting the use of NSAIDs, many experts consider not the pathology of the gastrointestinal tract, but the risk of cardiovascular accidents. After all effective technique prevention of cardiovascular complications associated with NSAIDs, unfortunately, has not yet been developed. the only one effective method prevention of thromboembolic complications - the appointment of antithrombotic agents, such as NDA, which dramatically increases the likelihood of gastrointestinal complications.

Although the negative effect on the cardiovascular system is one of the class-specific side effects of NSAIDs, among the latter there are drugs for which the risk of developing this complication is quite low. These are traditional (non-selective) NSAIDs, and the recognized leader among them, according to numerous population and clinical research, is naproxen. This drug is followed by ibuprofen and ketoprofen, the use of which is also associated with a fairly low incidence of cardiovascular complications.

It is these drugs that are most appropriate to use to create combined drugs. As a gastroprotector, PPIs are most acceptable: they are effective, convenient to use and well tolerated. True, PPIs can give their own side effects such as a certain increase in the frequency of intestinal infections, community-acquired pneumonia, changes in the metabolism of clopi-dagrel and methotrexate. In addition, in recent years, the question of the possible negative impact of long-term PPI use on the progression of postmenopausal osteoporosis and an increased risk of osteoporotic fractures has been discussed. At the same time, their high efficiency in preventing dangerous gastrointestinal complications fully compensates for the relatively low high risk possible side effects caused by the PPIs themselves.

The idea of ​​combined use of "cardiosafe" n-NSAIDs and PPIs, which would eliminate the negative consequences of taking the first drug on the gastrointestinal tract, was implemented when creating a fixed combination of naproxen and esomeprazole (FKNE, Vimovo™) .

In order to confirm the reduction in the incidence of gastrointestinal complications with the use of the new drug, 2 large 6-month RCTs were performed (n = 854). These studies compared FCNE with conventional enteric naproxen. According to the results obtained, the incidence of gastric and duodenal ulcers that occurred while taking FCNE was 4.6% in the first study, and 8.1% in the second. In patients who received only naproxen, ulcers were detected several times more often (28.2 and 30%, respectively, p< 0,001). При этом у пациентов, получавших ФКНЭ в сочетании с НДА, язвы желудка развились лишь у 3%, а у получавших напроксен вместе с НДА - у 28,4% (р < 0,001) .

The overall tolerability of the new drug, which is largely determined by the development of dyspepsia, also turned out to be significantly better. The number of cancellations due to gastrointestinal side effects in patients taking FCNE was 3.2% and 4.8%, in those receiving only naproxen - 12% and 11.9% (p< 0,001) .

The second stage of studying the merits of FCNE was its comparison with celecoxib, a drug that, as noted above, is rightfully considered the safest among all NSAIDs in terms of the risk of developing side gastrointestinal effects.

Comparison of FCNE and celecoxib was conducted in two identically designed 12-week RCTs (n = 619 and n = 610). The study groups consisted of patients with OA who were prescribed FCNE (1 tablet 2 times a day), celecoxib (200 mg/day) or placebo. New drug was not inferior in effectiveness to the comparison drug. In terms of tolerability, it was better (not significant) when using the combination drug. Thus, the number of cancellations due to gastrointestinal complications while taking FCNE, celecoxib and placebo was 1.2, 1.6 and 2.4% in the first study, and 0.8, 3.7 and 2 in the second, five% .

Simultaneously with FCNE, another combination drug was released containing ketoprofen (at a dose of 100, 150 and 200 mg) in combination with omeprazole. In general, this project can be assessed as promising, given that ketoprofen is an effective analgesic, and a successful dosage form with a delayed release of the active substance allows you to take it once a day, however, there are still no serious clinical studies that would show the safety of the new drug, so it is still difficult to judge its merits.

the only alternative to PPI as a gastroprotector may be the H2 receptor blocker famotidine. Evidence of its effectiveness was a 6-month RCT, during which 285 patients taking NSAIDs received famotidine (80 mg, 40 mg) or placebo. By the end of the observation period, the number of gastric/duodenal ulcers was 10, 17 and 33%, respectively. This difference, however, was only significant for famotidine at a dose of 80 mg (^< 0,05) .

There appear to be no large RCTs directly comparing famotidine and PPIs for the prevention of NSAID gastropathy. Nevertheless, their effectiveness can be compared according to the results of the study by E N et al. . The study group consisted of 311 patients with coronary heart disease who were prescribed a combination of NDA and clopid-grel; In addition, during the development of acute coronary syndrome a course of enoxiparin or thrombolysis was performed. For the prevention of gastrointestinal complications for the entire period of antiplatelet therapy (from 4 to 52 weeks), patients were prescribed famotidine (40 mg/day) or esomeprazole (20 mg/day). As a result, wish

in combination with naproxen in combination with ibuprofen with esomeprazole with famotidine

Rice. 2. Results of 6-month clinical trials of fixed combinations of NSAIDs and gastroprotectors: naproxen 500 mg in combination with esomeprazole 20 mg 2 times a day (n = 854) and ibuprofen 800 mg in combination with famotidine 26.6 mg 3 times a day (n = 1382) .

gastrointestinal bleeding developed in 9 patients treated with famotidine (6.1%) and only in 1 (0.6%) patient treated with esomeprazole ^< 0,001) .

Thus, famotidine is clearly inferior to PPIs in terms of preventive effect in relation to complications associated with taking LDA. With regard to NSAID gastropathy, the situation is not entirely clear, but famotidine is unlikely to have any advantages in this case. At the same time, a number of experts consider the absence of complications inherent in PPIs to be an important advantage of famotidine, and most importantly, the negative effect on the metabolism of clopidagrel, an essential component of complex antiplatelet therapy.

Recently, the original drug Duexis® containing 800 mg of ibuprofen and 26.6 mg of famotidine appeared on the US pharmacological market. The drug should be taken 3 times a day, i.e. it is supposed to use the maximum daily dose ibuprofen - 2400 mg, in combination with a very high dose of famotidine - 80 mg / day.

Recently published data from 6-month RCTs REDUCE-1 and 2 (total 1382 patients), confirming the benefits of this drug. It should be noted that compared with the FCNE trials, patients in these studies initially had a slightly lower risk of gastrointestinal complications: mean age, 55 years, ulcerative history, 6.2%, and LDA use, 15%. According to the data obtained, the number of gastric ulcers against the background of the combined drug was 12.5%, in the control - 20.7%, duodenal ulcers - 1.1% and 5.1%.

Although the difference in the frequency of ulcers is obvious, however, they occurred more often with the combination of ibuprofen and famotidine than with FCNE (Fig. 2). Although such a comparison is not entirely legitimate, nevertheless, it clearly suggests itself, since these works had a similar structure, number and characteristics of patients.

An important disadvantage of duexis can be the inclusion of ibuprofen in its composition. There is strong data

indicating that it reduces the anti-thrombotic effect of NDA, the use of which is indicated in many patients with high cardiovascular risk. Negative interaction with NDA can significantly limit the use of a combination of ibuprofen and famotidine in elderly patients, because most of them have cardiovascular disease and require antithrombotic therapy.

In general, although the concept of combined drugs is very interesting, it has certain disadvantages. So, these drugs are inconvenient for use in short courses or in an on-demand regimen. For example, the enteric naproxen in FCNE does not begin to act until 3 hours after ingestion, which means that this drug is suitable for controlling chronic pain, but not for its emergency relief.

Another problem is that PPIs and famotidine provide protection only to the upper GI tract, without any effect on the development of NSAID enteropathy. And this pathology, as shown above, can have a very serious clinical significance.

The prevalence of this pathology is demonstrated by the results of M. Doherty et al. . The authors evaluated the effectiveness of ibuprofen and paracetamol (in monotherapy or in combination) in 892 patients with OA. The study participants consisted of 4 groups: the 1st group was prescribed paracetamol (1 g), the 2nd group - ibuprofen (400 mg), the 3rd group - paracetamol (0.5 g) and ibuprofen (200 mg), 4 th - paracetamol (1 g) and ibuprofen (400 mg); All medications were taken 3 times a day. Against the background of such treatment after 3 months, a decrease in hemoglobin levels by 1 g/l was noted in 20.3, 19.6, 28.1 and 38.4% of patients.

It can be seen that even when using ibuprofen at a dose of only 1200 mg/day, every fifth patient developed subclinical intestinal blood loss. And the use of duexis involves long-term use of 2400 mg of ibuprofen!

The same problems can probably arise while taking naproxen: after all, as shown by the study cited above by J. Goldstein et al. the majority of volunteers who received naproxen with omeprazole for 2 weeks experienced erosive changes in the small intestine mucosa.

At the same time, only real clinical experience allows us to assess the significance of a particular medical problem. In this regard, it is interesting to note that J. Goldstein et al. studied the effect of NSAIDs on the condition of the small intestine, and were among the organizers of a 6-month RCT (n = 854) that compared the safety of FCNEs and conventional naproxen. At the same time, there is no mention of the development of anemia in the participants of these studies. Similarly, there were no major problems with small bowel pathology in patients treated with FCNE when compared with celecoxib. So, in total, in two RCTs (n = 1229), against the background of a 3-month intake of a combination of naproxen and esomeprazole, a decrease in hemoglobin level was more than

Advantages and disadvantages of coxibs and a fixed combination of n-NSAIDs and a gastroprotector as a means for the prevention of NSAID-gastropathy

Indicator

Coxibs (celecoxib, etoricoxib)

n-NSAIDs + gastroprotector (Vimovo™, Duexis®, Axorid®)*

Advantages

disadvantages

Target group of patients

Fast action

Reducing the risk of developing pathology of the distal gastrointestinal tract, including chronic blood loss associated with NSAID enteropathy (proven for celecoxib)

Higher risk of cardiovascular complications compared with n-NSAIDs (at least with naproxen and ibuprofen) Combination with NDA increases the risk of gastrointestinal complications

Relatively young patients with acute and chronic pain, with risk factors for the development of gastrointestinal complications, without concomitant cardiovascular disease

Low incidence of upper gastrointestinal complications

Low incidence of gastric ulcers when combined with aspirin

Better tolerability compared to conventional NSAIDs

The n-NSAIDs included in the combined preparations are considered the least dangerous in terms of the development of cardiovascular accidents (especially naproxen)

Not suitable for acute pain relief (Vimovo™)

Do not reduce the risk of developing pathology of the distal gastrointestinal tract

Possibility of side effects associated with gastroprotective drug** May reduce the antithrombotic effect of aspirin (ibuprofen)

Older patients with chronic pain associated with rheumatic diseases, with a moderate risk of developing gastrointestinal and cardiovascular complications

Note. * - Duexis® and Axorid® preparations are not registered in Russia; ** - PPIs can increase the risk of developing intestinal infections, pneumonia, reduce the effectiveness of clopidogrel, and with long-term (long-term) use, increase the risk of progression of postmenopausal osteoporosis.

by 20 g/l was noted only in 3 patients (among those taking celecoxib - in one). In REDUCE-1 and 2, there were only 2 episodes of a decrease in hemoglobin levels of more than 20 g / l, both in patients receiving the combined drug.

In conclusion, it should be noted that the prevention of serious gastrointestinal complications in patients requiring NSAIDs is not an easy task, requiring an individual approach and careful assessment of the most important risk factors. Currently in the arsenal of the Russian doctor

Karateev Andrey Evgenievich - dr honey. sciences, head. lab. [email protected]

LITERATURE (REFERENCES)

1. Karateev A.E., Yakhno N.N., Lazebnik L.B. and other Use of non-steroidal anti-inflammatory drugs. Clinical guidelines. Moscow: IMA-PRESS; 2009.

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there are 2 effective tools to improve the safety of NSAID therapy: selective COX-2 inhibitors (coxibs) and a fixed combination of naproxen and esomeprazole. These drugs have certain advantages and disadvantages (see table), the analysis of which makes it possible to identify target groups of patients in whom their use would be most appropriate. They should not be seen as competitors - rather, coxibs and Vimovo™ will complement each other, expanding the possibilities for the treatment of chronic pain.

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10. Goldstein J., Eisen G., Lewis B. et al. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin. Gastroenterol. Hepatol. 2005: 3-13.

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14. Hunt R., Harper S., Watson D. et al. The gastrointestinal safety of the COX-2 selective inhibitor etoricoscopyoxib assessed by both end and analysis of upper gastrointestinal events. Am. J. Gastroenterol. 2003, 98(8): 1725-33.

15. Cannon C., Curtis S., FitzGerald G. et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program: a randomized comparison . Lancet. 2006; 368 (9549): 1771-81.

16 Laine L., Curtis S. P., Cryer B. et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Di-clofenac Arthritis Long-term (MEDAL) program: a randomized comparison . Lancet. 2007; 369:465-73.

17. Laine L., Curtis S., Langman M. et al. Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac . gastroenterology. 2008; 135(5): 1517-25.

18. Castellsague J., Riera-Guardia N., Calingaert B. et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). drug. Saf. 2012; 35(12): 1127-46.

19. Chan F., Wong V., Suen B. et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial . Lancet. 2007; 369:1621-6.

20. McGettigan P., Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoSMed. 2011; 8(9): e1001098.

21. Trelle S., Reichenbach S., Wandel S. et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. Br. Med. J. 2011; 342:70-86.

22. Gislason G., Jacobsen S., Rasmussen J. et al. Risk of death or rein-farction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. circulation. 2006; 113(25): 2906-13.

23. Silverstein F., Graham D., Senior J. et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 1995; 123:241-9.

24. Acevedo E., Castaneda O., Ugaz M. et al. Tolerability profiles of rofecoxib (Vioxx) and Arthrotec. A comparison of six weeks of treatment in patients with osteoarthritis. Scand. J. Rheumatol. 2001; 30:19-24.

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27. Goldstein J., Howard K., Walton S. et al. Impact of adherence to concomitant gastroprotective therapy on nonsteroidal-related gastro-duodenal ulcer complications. Clin. Gastroenterol. Hepatol. 2006; 4(11): 1337-45.

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29. Leonard J., Marshall J., Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am. J. Gastroenterol. 2007; 102(9): 2047-56.

30. Giuliano C, Wilhelm S, Kale-Pradhan P. Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis. Exp. Rev. Clin. Pharmacol. 2012; 5(3):337-44.

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32. Bezabeh S., Mackey A., Kluetz P. et al. Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors. oncologist. 2012; 17(4):550-4.

33. Ngamruengphong S., Leontiadis G., Radhi S. et al. Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am. J. Gastroenterol. 2011; 106(7): 1209-18.

34. Roberts D., Miner P. Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease. drug. Health Patient Saf. 2011; 3:1-8.

35. Goldstein J., Hochberg M., Fort J. et al. Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone. Aliment. Pharmacol. Ther. 2010, 32(3):401-13.

36. Hochberg M., Fort J., Svensson O. et al. Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials. Curr. Med. Res. Opin. 2011; 27(6): 1243-53.

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38. Taha A., Hudon N., Hawkey C. et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N. Engl. J. Med. 1996; 334:1435-9.

39 Ng F., Tunggal P., Chu W. et al. Esomeprazole compared with fa-motidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction Am. J. Gastroenterol. 2012; 107(3): 389-96.

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42. Laine L., Kivitz A., Belo A. et al. Double-Blind Randomized Trials of Single-Tablet Ibuprofen/High-Dose Famotidine vs. Ibuprofen Alone for Reduction of Gastric and Duodenal Ulcers. Am. J. Gastroenterol. 2012; 107:379-86.

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45. Doherty M., Hawkey C., Goulder M. et al. A randomized controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/ paracetamol in community-derived people with knee pain Ann. Rheum. Dis. 2011; 70(9): 1534-41.

Cyclooxygenase in two isoforms (COX-1 and COX-2) plays an important role physiological role in homeostatic and compensatory-regenerative processes through the regulation of the synthesis of prostaglandins from arachidonic acid. Both its isoforms are ubiquitous.

COX-1 prevails in the gastrointestinal mucosa, where it performs a cytoprotective function, platelets, with which their aggregant properties are associated, kidney cells, and some other organs. With insufficient activity of COX-1, a violation of the integrity of the gastrointestinal mucosa is associated with the risk of developing gastropathy, up to and including life-threatening bleeding and perforation. NSAIDs that inhibit the activity of COX-1 (non-selective) have their own side effects, primarily through this mechanism. Suppression of platelet COX-1 activity with a decrease in their aggregative abilities increases the risk of hemorrhages in blood coagulation disorders, vasculitis, but is desirable in heart diseases and a number of others pathological conditions.

COX-2 is predominant in the brain, reproductive organs, kidneys, blood mononuclear leukocytes (monocytes) and tissues (macrophages). COX-2 of mononuclear leukocytes, other cells in the foci of inflammation, induced by pro-inflammatory cytokines or growth factors, provides the synthesis of prostaglandins that mediate pain and inflammation. The synthesis of COX-2 by mononuclear cells and other cells in the focus of inflammation should be considered as a natural phenomenon. In chronic processes, inflammation often loses its protective functions and stimulation of COX-2 leads to the predominance of destructive over regenerative processes. With the blockade of NSAIDs, the COX-2 isoforms are expected to have an anti-inflammatory effect, and it is confirmed. It also becomes obvious that the achievement of the anti-inflammatory effect of NSAIDs in the absence of side effects on the gastrointestinal tract and other tissues associated with COX-1 activity is possible if only they selectively inhibit COX-2 activity. Specific COX-2 inhibitors have such properties. The mediation of inflammation and associated pain by COX-2, with the extremely important constitutional function of COX-1 and the risk of serious side effects of its suppression, strongly argues in favor of the preferred use of specific COX-2 inhibitors in the treatment.

With the isolation of two isoforms of cyclooxygenase, and now we are talking about COX-3 close to COX-2 in terms of physiological effects, establishing the significance of increased COX-2 activity in the mechanisms of inflammation and associated pain, as well as the importance of high COX-1 activity in cytoprotective processes, a revision of the pharmacodynamics of NSAIDs was carried out, when they began to be divided into non-specific and specific COX-2 inhibitors. The whole set of specific COX-2 inhibitors that existed before the targeted synthesis and launch into production, including such as meloxicam and nimesulide, to varying degrees, inhibit not only the activity of COX-2, but also COX-1. A feature of non-specific is that with an increase in the dose of the drug taken, their inhibitory activity against COX-1 increases more and more with the ensuing consequences. The only exceptions are specific COX-2 inhibitors, which exhibit inhibitory COX-1 activity at doses several times higher than those recommended for clinical use. The problem with non-specific COX inhibitors is the high risk of gastrointestinal complications. About 30% of patients complain of gastrointestinal disorders, and a third of them are forced to abandon the further use of NSAIDs. Up to 30% of hospitalizations and deaths from peptic ulcers in people over 65 years of age have been associated with NSAIDs in epidemiological studies, and this risk is dose-dependent. The likelihood of bleeding increases dramatically in smokers, alcohol abusers, oral glucocorticoids and anticoagulants, and diuretics and ACE inhibitors due to kidney disease, hypertension, and heart failure. If you do not focus on specific ones, of non-specific absolute contraindications for clinical use, indomethacin has due to its high toxicity and destructive effect on articular cartilage. Of the two known specific COX-2 inhibitors, celecoxib and rofecoxib, celecoxib lacks non-specific side effects to the greatest extent. In recommended doses, it is much easier to tolerate by patients and has significantly fewer side effects. Caution in its appointment is recommended only in patients with arterial hypertension, cardiac, moderate and severe renal and severe liver failure, it is not used in very severe renal failure and is prescribed after scarring of acute ulcers, which, however, applies to all NSAIDs. There is a well-known relationship between NSAIDs and hypertension.

COX-2 not only mediates inflammatory reactions, but is one of the regulators of other vital functions, such as sodium and water metabolism in the kidneys, renin-angiotensin and related humoral blood pressure maintenance systems.

Cyclooxygenase is an enzyme that catalyzes the conversion of arachidonic acid to prostaglandin H2 (precursor of other prostaglandins, prostacyclin and thromboxane A2).

COX-1 is constitutive, that is, it works almost constantly and performs physiologically important functions. COX-1 is inhibited by non-selective NSAIDs and this generates many side effects: bronchospasm, ulcerogenesis, ear pain, water retention in the body ...

COX-2 is inducible, that is, it begins to function in certain situations, for example, with inflammation. COX-2 is expressed macrophages, synoviocytes, fibroblasts, vascular smooth muscle, chondrocytes and endothelial cells after inducing them with cytokines or growth factors.

Inhibition of COX-2 is considered as one of the main mechanisms of anti-inflammatory activity. NSAIDs, since with selective inhibition of this cyclooxygenase, many of the side symptoms observed with inhibition of cyclooxygenase 1 can be minimized.

COX 1 and COX 2 have almost the same molecular weight - 70 and 72 kDa, respectively, the amino acid sequences match by almost 65%, the catalytic sites are also almost completely identical. An important difference from a pharmacological point of view is that COX 1 in position 523 contains a more hydrophobic amino acid - isoleucine(COX 2 in a similar position contains valine).

Specific cyclooxygenase-2 inhibitors and osteoarthritis

Cyclooxygenase and osteoarthritis

Cyclooxygenase in two isoforms (COX-1 and COX-2) plays an important physiological role in homeostatic and compensatory-restorative processes through the regulation of prostaglandin synthesis from arachidonic acid. Both of its isoforms are ubiquitous, but not equally distributed in various organs and tissues and functionally differ. COX-1 prevails in the gastrointestinal mucosa, where it performs a cytoprotective function, platelets, with which their aggregant properties are associated, kidney cells, and some other organs. The constitutional properties of COX-1 are explained by its control over the synthesis of thromboxane A2, prostaglandin E2 and prostacyclin. With insufficient activity of COX-1, a violation of the integrity of the gastrointestinal mucosa is associated with the risk of developing gastropathy, up to and including life-threatening bleeding and perforation. NSAIDs that inhibit the activity of COX-1 (non-selective) have their own side effects, primarily through this mechanism. Suppression of the activity of COX-1 platelets with a decrease in their aggregative abilities increases the risk of hemorrhages in blood clotting disorders, vasculitis, but is desirable in heart disease and a number of other pathological conditions. COX-2 is predominant in the brain, reproductive organs, kidneys, blood mononuclear leukocytes (monocytes) and tissues (macrophages). In the kidneys, it acts as one of the important enzymes for controlling the reabsorption of water and sodium and, through it, other functions. COX-2 also affects blood circulation through stimulation of the synthesis of vasodilator prostacyclin-I2. The latter, acting on juxtaglomerular cells, causes the release of renin, enhances the synthesis of angiotensin and the release of aldosterone, however, with hypovolemia. Aldosterone enhances the reabsorption of water and sodium, the excretion of potassium. The release of renin and angiotensin results in an increase in blood pressure. When COX-2 is inhibited, arachidonic acid is metabolized through an alternative pathway involving cytochrome P450. Its products may have renal vasoconstrictive effects with induction of hypertension. In the light of these data, suppression of COX-2 activity cannot be directly associated with increased edema and increased blood pressure, which was subsequently confirmed by targeted studies of selective NSAIDs. COX-2 of mononuclear leukocytes, other cells in the foci of inflammation, induced by pro-inflammatory cytokines or growth factors, provides the synthesis of prostaglandins that mediate pain and inflammation. It is associated with the progression of inflammatory processes of a very different nature, among which OA is a particular phenomenon. Taking into account that inflammation is considered as a protective compensatory-adaptive recovery reaction to damage, selected by evolution, providing replacement of lost structures connective tissue, and is constructive in most diseases of an inflammatory nature, the synthesis of COX-2 by mononuclear cells and other cells in the focus of inflammation should be considered as a natural phenomenon. In chronic processes, which include OA, inflammation often loses its protective functions and stimulation of COX-2 leads to a predominance of destructive over regenerative processes. With the blockade of NSAIDs, the COX-2 isoforms are expected to have an anti-inflammatory effect, and it is confirmed. It also becomes obvious that the achievement of the anti-inflammatory effect of NSAIDs in the absence of side effects on the gastrointestinal tract and other tissues associated with COX-1 activity is possible if only they selectively inhibit COX-2 activity. Specific COX-2 inhibitors have such properties. The analgesic effect of COX-2 inhibitors should be associated not only with their local anti-inflammatory action, when pain receptors of the tissues involved in the inflammatory process in OA are preserved, but also with the effect on the activity of COX-2 in the brain, which plays an important role in the perception and formation of pain. The mediation of COX-2 inflammation and associated pain syndrome, with the extremely important constitutional function of COX-1 and the risk of serious side effects of its suppression, strongly argues in favor of the preferred use of specific COX-2 inhibitors in the treatment of OA.

Cyclooxygenase-2

The enzyme cyclooxygenase (COX) catalyzes the first step in the synthesis of prostaglandins in the arachidonic acid cycle. Under the action of COX, arachidonic acid released from membrane phospholipids is converted into prostaglandin PGG 2, which is then metabolized into prostaglandin PGH 2, and that into other eicosanoids (prostaglandins, thromboxanes, prostacyclins) (Fig. 7).

Prostaglandins (PGs), the best known cellular mediators of inflammation, are derivatives of polyunsaturated fatty acids. Initially, it was believed that PGs are formed only in the prostate gland, but later it turned out that they are synthesized in almost all organs and tissues. Depending on the structure of prostaglandins (there are about 20 of them in total), they are divided into several types, denoted by the letters of the Latin alphabet: A, B, C, D, E, F, etc. PGs of each type are divided into 1st, 2nd and 3rd series according to the number of double bonds in the side chains of the molecule. Depending on the type and series, prostaglandins are designated: PGE 2, PGD 1, PGH 2, etc.

Prostaglandins are short-lived compounds. The half-life of some of them is calculated in seconds. The rapid destruction of PGs determines the locality of their effects - prostaglandins act mainly at the site of their synthesis. Metabolism of prostaglandins, leading to their rapid inactivation, is carried out in all tissues, but is especially active in the lungs, liver and kidneys.

In addition to being well-recognized mediators of inflammation, PGs mediate a wide range of other positive and negative functions for the body. The positive ones include the participation of PGs in the regulation of a number of physiological processes - hemostasis, platelet aggregation, maintenance of smooth muscle tone, secretion of gastric juice and regulation of its acidity, as well as participation in the activity of the reproductive, excretory, endocrine systems and the implementation of the pain / inflammatory response. Violation of the biosynthesis of PGs can cause the development of severe pathological conditions.

To the negative aspects of the activity of prostaglandins (in particular prostaglandin PGE 2), in addition to participating in the development of pathological inflammation and allergic reactions, include: 1) participation in the implementation of dysplastic and neoplastic processes (tumor growth), namely, in the suppression of apoptotic cell death, pathological neoangiogenesis and invasion, and 2) mediation of immunosuppressive functions.

There are two main varieties (two main types) of cyclooxygenase, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Despite the similarity of enzymatic activities, in contrast to the COX-1 isozyme, which is constitutively expressed in almost all mammalian tissues, the COX-2 isoenzyme is almost never found in normal (non-transformed) cells. At the same time, like other products of early response gene expression, COX-2 is rapidly and transiently activated in response to the action of pro-inflammatory mediators and mitogenic stimulators: cytokines, endotoxins, growth factors, tumor promoters. (42) and some oncogenes (v- src, v- Haras, HER2/neu, wnt) (47, 104, 128) . The genes encoding these isoenzymes are also characterized by different properties and expression parameters. (46) .

It is known that one of the main cytokines that induce the corresponding (cytokine-dependent) signaling cascade is tumor necrosis factor a (TNFa), which activates proapoptotic receptor-mediated signaling pathways at high concentrations; stops the processes of cell division and causes physiological cell death, and in small doses acts as a survival factor and cell proliferation. The COX-2 isozyme involved in the biosynthesis of prostaglandins PGE 2 and PGF 2a belongs to a large group of proteins whose expression is increased as a result of activation of this signaling cascade.

Since, as we have already noted, prostaglandin PGE 2, in addition to being an inflammatory mediator, mediates a number of other biological functions associated with pathological hyperplastic and neoplastic processes, the inducible COX-2 isozyme mediating its synthesis is reasonably considered one of the key molecular targets in antitumor “targeted” therapy and prevention. The basis for this conclusion is the results of numerous epidemiological, experimental and clinical studies, in which it was found that an elevated level of COX-2 is associated with carcinogenic processes in many organs and tissues, including the prostate gland. (36) .At the same time, a decrease in the frequency of recurrence of many tumors, on the contrary, was noted when taking non-steroidal anti-inflammatory drugs (NSAIDs) - COX-2 inhibitors (46) .

To date, a fairly large number of NSAIDs are used in clinical practice. According to the mechanism of COX-2 inhibition, they are divided into:

1) simple competitive (Ibuprofen, Piroxicam),

2) competitive reversible (Indomethacin, Diclofenac) and

3) competitive irreversible (Aspirin).

However, all these compounds, together with the inhibition of the conditionally “bad” inducible isozyme COX-2, also (or even to a greater extent) suppress the activity of the constitutive “good” isozyme COX-1, and, consequently, negatively affect the implementation of physiological processes in the body. Hence the undesirable side effects that often occur when they are taken (especially for a long time): complications from the gastric mucosa up to the appearance of gastrointestinal bleeding and ulcerative lesions, worsening of wound healing, suppression of physiological inflammation. According to 1998 statistics, in the United States, complications arising from the use of NSAIDs annually cause 100,000 emergency hospitalizations and 16,500 deaths. (106) .

To cure a patient with rheumatoid arthritis, medications, physiotherapy, and diet are used. Initially, to stop the inflammatory process, remove 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 are medicines new generation, capable of acting locally, entail less negative consequences of the introduction.

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 clinical picture diseases.

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 drug. 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 can cause mental disorders in middle-aged and elderly people. 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 the feeling of 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.

Non-steroidal anti-inflammatory drugs of the new generation, without exaggeration, are the most popular drugs in the world.

There is not a single medical industry where, for a particular disease, a representative of this group would not be registered in the standard of treatment.

They are highly effective, but their use in most countries is limited to prescriptions, since self-administration of this group of drugs can be harmful.

What drugs are non-steroidal anti-inflammatory drugs (NSAIDs)

There are slightly more than 30 representatives of this group, however, about 10 medicines are widely used.

The group of NSAIDs includes drugs that inhibit the enzyme cyclooxygenase, it is involved in the synthesis of inflammatory markers: prostaglandins, thromboxanes and prostacyclins. These substances are involved in the process of fever and pain. There are three types of enzyme (isoforms) of cyclooxygenase, which have different functions.

Cyclooxygenase type 1 is constantly present in the body, it is involved in the synthesis of prostaglandins and similar substances that protect the stomach, kidneys, and regulate microcirculation processes.

Cyclooxygenase type 2 - is formed in the body during inflammation, is present inconsistently. Synthesizes substances involved in the processes of inflammation and cell division.

Cyclooxygenase type 3 - receptors for this enzyme are mainly located in nervous system, the third isoform is involved in the processes of temperature increase and plays a role in the appearance of pain syndrome.

According to the fact that there are 3 types of enzyme, there are 3 groups of NSAIDs.

1. Selective (selective) COX-1 blockers - the most popular representative of all NSAIDs - aspirin.
2. Non-selective (non-selective) blockers of COX 1 and COX 2 - most NSAIDs: diclofenac, indomethacin, ketoprofen, ketorolac, piroxicam.
3. Selective inhibitors of COX 2 - nimesulide, meloxicam, rofecoxib, celecoxib.
4. Selective inhibitors of COX 3 - paracetamol, analgin.

Selective COX-1 inhibitors and non-selective COX-1, 2 inhibitors are the "old" generation of this group of drugs. Aspirin is widely used in small doses as an antiplatelet agent (blood thinner) in the prevention of cardiovascular events.

COX 3 inhibitors are a separate group, and it should be noted that analgin (metamisole sodium) is not approved for use in most countries, in our country it is approved for use. And paracetamol is widely used as an anesthetic drug in Europe and the United States.

New generation of COX inhibitors, mechanism of action

COX 2 inhibitors are non-steroidal drugs of the so-called "new" generation, they are mainly used in the practice of a modern doctor.

COX 2 inhibitors are divided into:

• Drugs with predominant inhibition of COX 2 - nimesulide, meloxicam. They still have a slight inhibitory effect on COX 1, especially with long-term use.
• Highly selective COX 2 inhibitors - celecoxib, rofecoxib.

Mechanism of action of COX 2 inhibitors (nimesulide, meloxicam)

In the process of inflammation, an isoform of cyclooxygenase 2 is formed, when taking a COX 2 inhibitor, it is rapidly absorbed from the digestive tract, 89% of the active substance enters the blood. Once in the bloodstream, the drug replaces the receptors that are receptors for COX 2, thus reducing the number of inflammatory markers (prostaglandins).

In addition to the blockade of these receptors, competitive replacement of COX 1 receptors also partially occurs, especially it increases with prolonged use of drugs of this group or when the therapeutic dosage is exceeded.

A feature of this group is a decrease in selectivity with prolonged use or the use of the drug in high doses. Which accordingly increases the frequency of side effects, since under these conditions COX 1 may appear - dependent undesirable effects of drugs.

Mechanism of action of highly selective COX-2 inhibitors (celecoxib, rofecoxib)

When ingested, the drug is absorbed from the digestive tract, entering the systemic circulation, competitively blocks COX 2 receptors. In standard therapeutic concentrations, it does not affect COX 1.

What is the difference between "old" inhibitors and "new" drugs?

Unlike selective COX-1 inhibitors and non-selective inhibitors COX 1 and 2, selective and highly selective inhibitors of the cyclooxygenase 2 isoform during treatment are not inferior in effectiveness to the "old" generation, and the frequency of damage to the digestive system is four times lower compared to non-selective inhibitors, in some, for example, celecoxib, seven times.

Also, the difference from COX 1 inhibitors is the lack of action on the blood coagulation system (this is COX 1 - a dependent effect), therefore, the frequency of a side effect - in the form of an increase in blood coagulation, is much less common in drugs of this group.

With the use of COX 2 inhibitors, the effects of bronchospasm, worsening of bronchial asthma or heart failure occur less frequently. Safer use in the elderly has also been noted.

Modern research opens NSAID COX 2 inhibitors on the other hand as possible antitumor agents. In laboratory studies, celecoxib has shown antiproliferative and antitumor effects.

General contraindications and indications for the use of selective COX 2 inhibitors

Indications for taking NSAID inhibitors are very extensive. In the official instructions for the use of this group of drugs, various diseases of the joints and the spinal column mainly prevail, since the vast majority of studies have been performed in this area and this is the most common cause of pain.

Indications

• Pain syndrome.
• Joint diseases: rheumatoid arthritis, arthritis, osteoarthritis, trauma consequences, gout, etc.
• Pain syndrome in neurological practice.
• Toothache.
• Menstrual pain.
• Headache.
• As an anesthetic in the postoperative period.

Contraindications

All contraindications are combined medicines this group:

• "aspirin triad": bronchial asthma, intolerance to aspirin, polyposis of the nose and paranasal sinuses;
• ulcerative lesions of the digestive tract in exacerbation;
• hemorrhage in the brain;
• severe heart failure;
• severe renal failure;
• hemophilia;
• period after coronary artery bypass surgery;
• pregnancy and lactation;
• drug addiction and alcoholism.

Features of the use of COX 2 inhibitors

Although the side effect of this group of drugs is much less pronounced than with the use of non-selective COX inhibitors, most of the side effects of COX 2 blockade are still present. Therefore, taking a COX 2 inhibitor should be at least half an hour after a meal, if there is an ulcer in any part of the gastrointestinal tract, then taking a COX 2 inhibitor is combined with prophylactic administration of a proton pump blocker (omeprazole, pantoprazole, etc. .), and the reception per day should be two times.

It is acceptable to take this group of drugs for a long time, however, it should be remembered that in this case the risk of developing undesirable effects increases in direct proportion to the duration of therapy.

Some representatives of the "new" nonsteroidal drugs

Celecoxib

It is a highly selective inhibitor of COX 2. When taken orally, it is easily absorbed, reaching a maximum concentration after 3 hours in the blood. The drug is used after meals, when taken together with fatty foods, the absorption of the drug is significantly slowed down.

According to official instructions, celecoxib is used for rheumatoid arthritis, osteoporosis, psoriatic arthritis, ankylosing spondylitis. The most common side effect is headache, dyspepsia. Celecoxib is taken orally at a dose of 200 mg x 2 times a day, the maximum allowable dose is 400 mg x 2 times a day.

Meloxicam

When taken orally, it is rapidly absorbed from the gastrointestinal tract, the maximum level is reached after 5 hours, while 89% of the drug is in the plasma. According to the instructions, meloxicam is used for inflammatory processes in the joints, arthritis, arthrosis, and unspecified joint diseases.

The drug is available in the form of tablets, injections, rectal suppositories. Meloxicam is given once a day. It is recommended to take the drug during meals. The most common undesirable effect of taking Meloxicam is dyspepsia, headache. With prolonged use of meloxicam or use above therapeutic doses, its selectivity decreases.

Nimesulide

The most frequent selective inhibitor of COX 2. The maximum value is reached in blood plasma after 1.5 - 2 hours from ingestion, with simultaneous ingestion of food, the absorption time increases significantly. The indications for the use of this drug, unlike other representatives, includes pain caused by various reasons.

Most frequent unwanted effects: diarrhea, nausea, vomiting, increased liver transaminases. The drug is taken orally, there are water-soluble forms, a maximum of 200 mg of nimesulide per day is possible.

Why are these drugs prescribed by prescription?

It would seem that there are fewer side effects, you can take it for a long time and for any reason, so why is this group dispensed by prescription in some pharmacies? For each medicine, there are certain indications that only a doctor can set.

It is impossible to take new generation NSAIDs for a minor reason, since this group has many severe individual side effects, for example, sudden acute renal failure, drug-induced hepatitis, etc., which can occur suddenly in a young, healthy person and lead to his death.

Also, a large number of people have a low threshold of pain sensitivity, and they tend to take painkillers for any minor pain syndrome, and addiction to the NSAID group occurs over time, the body can no longer function normally without the next dose of the drug, this is due to the adaptation of cyclooxygenase receptors to inhibition of NSAIDs.

Also, a layman who is not associated with medicine will not be able to assess all the risks of taking the drug simultaneously with other drugs. For example, taking COX-2 blockers reduces the effect of some blood pressure medications. Therefore, the independent use of these drugs cannot be justified in any case.

Preferanskaya Nina Germanovna
Associate Professor of the Department of Pharmacology of the Educational Department of the Institute of Pharmacy and Translational Medicine of the Multidisciplinary Center for Clinical and Medical Research of the International School "Medicine of the Future" of the First Moscow State Medical University. THEM. Sechenov (Sechenov University), Ph.D.

Recurrent pain leads to disability in up to 80% of patients. In patients older than 50 years, in 17% of cases, the pain syndrome is caused by chronic diseases in the lumbar region, including degenerative lesions of the intervertebral cartilage discs, in 57% of cases, degenerative-dystrophic changes in the spine are detected, 28% suffer from osteoarthritis, 6% from spondylolisthesis (displacement of the vertebrae relative to each other ), 1% - rheumatoid arthritis.

Selective NSAIDs have a pronounced anti-inflammatory, anti-edematous and analgesic (analgesic) effect.

The main indications for the use of selective NSAIDs are: osteoarthritis, rheumatoid arthritis, acute arthritis in non-rheumatic diseases, ankylosing spondylitis, acute and chronic pain in the lower back, exacerbation of chronic joint diseases, as well as diseases of extra-articular and soft tissues.

They are indispensable for various sprains, bruises, arthrosis, they are effective in chronic pain against the background of inflammation, pain in the postoperative period, cramping pain and associated with dysmenorrhea.

Under the conditions of the development of the inflammatory process, the induction of synthesis and enzymatic activity occurs. cyclooxygenase-2(COX-2). With the help of this enzyme, an excess amount of inflammatory mediators (histamine, kinins) is formed in the focus of inflammation, which dilates blood vessels, increases the permeability of the vascular wall, and sensitizes nociceptors to bradykinin and histamine. The main mechanism of action of selective NSAIDs is the selective inhibition of the COX-2 enzyme, which belongs to inducible (adaptive, regulated) enzymes.

At therapeutic doses, selective cyclooxygenase inhibitors predominantly inhibit the inflammation-induced COX-2 isoform and have little or no effect on the other COX-1 isoform. COX-2 begins to function only during inflammation under the influence of immune mediators (cytokines). When it is inhibited, the synthesis of prostaglandins involved in inflammation, cell proliferation and destruction is suppressed. Prostaglandins and related biologically active compounds (eicosanoids) and other inflammatory mediators affect kidney hemodynamics, water-salt and fat metabolism, stimulate the movement of leukocytes to the area of ​​inflammation and phagocytosis of foreign compounds, etc. Nerve cell receptors receive less irritating signals and pain recedes , decreases.

The main undesirable side effects when using selective NSAIDs are: dizziness, drowsiness, headache, fatigue, increased heart rate (tachycardia), slight shortness of breath, dry cough, indigestion, the appearance of protein in the urine, increased activity of liver enzymes and skin rash (spot).

It should be noted that these drugs show less undesirable side effects from the gastrointestinal tract (vomiting, belching, diarrhea, bleeding, mucosal ulceration, ulcerogenic effect): active substance is in a special shell - film-coated capsules or tablets are made from substances that do not dissolve in the acidic environment of the stomach. These coatings are enteric-soluble and begin to break down only when they enter the intestine, which can significantly reduce the irritating effect of drugs on the gastric mucosa.

Due to the decrease in the activity of histamine, bradykinin, the manifestations of allergic reactions are reduced. The drugs reduce the function of the urinary system to a lesser extent, which in turn reduces the occurrence of edema and increased blood pressure.

New generation drugs - highly selective NSAIDs - do not have a destructive effect on cartilage tissue and are chondroneutral. With their use, it was possible to minimize the effect on the blood coagulation system and platelet function.

As a result of the foregoing, the tolerability of the use of selective NSAIDs improves and, with their long-term use, unwanted side effects occur much less frequently. All this increases the adherence of patients to the use of selective NSAIDs, creates high compliance and the patient's willingness to strictly follow the doctor's recommendations.

Classification of non-steroidal selective agents of reversible action of NSAIDs:

1. Highly selective reversible COX-2 inhibitors"TOoxybs"

• fluorinated derivative of benzenesulfonamide - Celecoxib (Celebrex);
• chlorinated pyridine derivative of phenylsulfone - Etoricoxib (Arcoxia).

2. Predominantly selective reversible COX-2 inhibitors"Oxycams"

• thiazole derivative of benzothiazinecarboxamide - Meloxicam (Movalis, Mirloks).

3. Selective reversible COX-2 inhibitors

• methanesulfonamide derivative: Nimesulide (Nise, Nimulide).

Celecoxib (Celecoxib, substance) - TN "Celebrex" (caps. 100 mg, 200 mg), TN "Dilaxa" (caps. 200 mg), TN "Roukoxysib-Routek" (caps. 200 mg) - a highly selective inhibitor of COX-2, a fluorinated derivative of benzenesulfonamide - effectively relieves pain in degenerative pathologies of the joints. The mechanism of analgesic action is based on inhibition of the synthesis and production of prostaglandins E 1 and E 2 , which play an important role in the development of the inflammatory process, suppresses the exudative and proliferative phases of inflammation and increases the sensitivity of pain receptors. At therapeutic concentrations, it does not inhibit COX-1. As a result of the suppression of the synthesis of PGE 2, fluid retention is possible, because increased reabsorption of the thick ascending segment of the loop of Henley, as well as other distal parts of the nephron. In addition, it is known that PGE 2 can inhibit water reabsorption in the area of ​​the collecting ducts, preventing the action of antidiuretic hormone. The drug does not inhibit the excretory ability of the kidneys, even in patients with chronic kidney failure. Celecoxib (until it is eliminated from the body) temporarily reduces the rate of sodium excretion. With prolonged use in high doses, its selectivity decreases. Equilibrium plasma concentration is reached by the fifth day of taking the drug.

Important! The drug is contraindicated for use in children and adolescents under 18 years of age.

Particular caution must be observed in people who are diagnosed with heart failure, as the drug increases the susceptibility to fluid retention.

Be wary appoint during pregnancy and lactation.

During treatment, you should refrain from activities that require increased attention and quick reaction, as accommodation may be disturbed.

Etoricoxib (Etoricoxib) - TN "Arcoxia" (table. 30 mg, 60 mg, 90 mg, 120 mg), TN "Costarox" (table. 60 mg, 90 mg, 120 mg) is a highly selective inhibitor of COX 2, a chlorinated pyridine derivative of phenylsulfone. NSAIDs inhibit the activity of COX-2 by a selective mechanism, preventing the biosynthesis of prostaglandins and other inflammatory mediators. There is a decrease in the severity of the symptoms of the inflammatory process, while the substance does not affect the functional activity of platelets and does not damage the mucous membrane of the digestive tract. The degree of inhibition of COX-2 is dose-dependent. The agent does not affect COX-1 if the daily dosage does not exceed 150 mg.

Patients with diseases of the musculoskeletal system with the help of the drug get rid of morning stiffness, there is an improvement in joint mobility, the intensity of inflammation decreases, the pain syndrome is perfectly stopped. The therapeutic effect after taking occurs within half an hour. Active substance the drug is perfectly absorbed from the bloodstream and has a high bioavailability, which is 100%.

The drug has the ability to reduce the excitability of the thermoregulation center in the diencephalon and have an antipyretic effect.

After oral administration, the substance is quickly absorbed in the digestive tract and penetrates into the blood. After taking Etoricoxib, 120 mg, its maximum concentration in the blood is observed after 60 minutes. Eating reduces the maximum concentration by 35%, and the time to reach it increases to 2 hours.

Important! Metabolism proceeds with the participation of microsomal liver enzymes, forms inactive metabolites. The drug overcomes the BBB and the placental barrier, which must be taken into account when prescribing to women during breastfeeding. It is not prescribed to patients with diseases of the cardiovascular system and urinary tract, pregnant women and children under 12 years of age.