Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in clinical practice and are among the most efficient symptomatic and pathogenetic drugs to relieve pain, inflammatory processes of various genes and fever. Due to the acceptable toxicity, many of them (ibuprofen, naproxen, ketoprofen, acetylsalicylic acid) are allowed to use as non-receptible drugs. We give the data recent research on communication with electrical and non-selective inhibitors of COG and cardiovascular risk.

The main consumers of the NSAID are sick elderly and senile age, which is due to the wider prevalence among people of advanced years of chronic inflammatory and degenerative diseases of the musculoskeletal system. At the same time, it is precisely in this category of patients, as a rule, a mass of concomitant diseases is observed, in particular, cardiological and gastroenterological genesis. Therefore, the conduct of NSAID therapy requires a doctor not only knowledge about the mechanism of action of these funds, but also on possible undesirable phenomena, including cardiovascular risk factors and ways to correction.

The anti-inflammatory effect of non-steroidal anti-inflammatory drugs is based on the inhibiting activity of the cyclooxygenase enzyme (COF). In the human body there are two isoforms of this enzyme. COG-1 stimulates the products of the protection of the gastrointestinal mucosa of the gastrointestinal tract, regulates the excretory function of the kidneys, the aggregation capacity of platelets. COG-2 isoenzyme stimulates the production of prostaglandins and leukotrienes, which are factors stimulating inflammatory and allergic reactions. The anti-inflammatory effect of NSAIDs is associated with the immediate oppression of COF-2. Thus, the synthesis of prostaglandins is blocked and the manifestations of inflammation are reduced: pain, swelling, hyperemia, temperature increase, function disorder.

Modern non-steroidal anti-inflammatory drugs effectively fulfill the main task - they have an anti-inflammatory effect. With the same efficiency of the NSAID, the following criterion for selecting the drug becomes its self-esteem for the patient. This is exactly what molecules synthesized over the past 30 years. Unlike traditional non-steroidal anti-inflammatory drugs, which are equally oppressed by both COF-1 and COG-2 and can cause gastrointestinal bleeding, renal function, swelling, worsen the course of arterial hypertension, heart failure, violate the activity of the blood coagulation system, modern Selective NSAIDs have fewer complications. On the other hand, large-scale studies, such as Vigor, Class, led to a ban on the use of some modern drugs or restricting their use by age, therapy duration, concomitant diseases due to the increasing risk of thromboembolic complications.

The problem of cardigabilities NSAID. International research

According to modern ideas, the positive therapeutic effects of non-steroidal anti-inflammatory drugs are associated with their ability to inhibit COF-2, while the most common side effects (damage to the gastrointestinal tract, kidneys, violation of the aggregation of platelets, etc.) - with the suppression of the activity of the CHA one. The current NSAIDs have different trophood to two types of COW. Based on selectivity to COF-1 and COG-2, the NSAIDs are divided into the following groups:

Selective COF-1 inhibitors (acetylsalicylic acid low doses);

Non-selective COF-1 inhibitors and COG-2 (indomethacin, ibuprofen, diclofenak, etc.);

Preferential COG-2 inhibitors (meloxicami, nimesulide, etodolac);

Selective COG-2 inhibitors (celecoxib, ropecoxib, validekoxib, parecoxib, rikoxib, etc.).

Recently, the focus has been attracted to the problems of the Cardiophership NSAIDs. Materials of experimental and epidemiological studies indicate the participation of COG-2 in the oncogenesis and the implementation of the inflammatory component of Alzheimer's pathogenesis. Therefore, in early 2000, several long-term controlled tests were initiated in order to assess the effectiveness of COF-2 inhibitors for the prevention of relapses of the tumors of the colon and the progression of Alzheimer's disease. In addition, a series of large-scale controlled studies of the effectiveness and safety of COX-2 inhibitors under rheumatoid arthritis (RA) and osteoarthritis was completed.

However, at the end of September 2004, the pharmaceutical company Merck and Co. Voluntarily suspended the release of the drug Ropekoxib. The formal reason for this was the intermediate results of the APROVE study (Adenomatous Polyp Prevention On Vioxx). The purpose of this study was to assess the prophylactic effect of ropecoxib for relapses of the adenomatous polyposis of the thick bowel. Analysis of 3-year results showed that in a group obtained by rofekoxib, a significant increase in the frequency of non-meaning cardiovascular complications was observed - 45 episodes (6 per 400 patients year), while in the placebo group of 25 episodes (3 per 400 patients year).

The frequency of fatal outcomes in patients receiving ropecoxib and placebo was the same. 5 patients died in the Ropeekoxib group, one of myocardial infarction (im), 4 is stated sudden death (Rhythm Violations), 1 The deadly outcome was not related to the study. In the placebo group, there were also 5 fatal exodues: 3 - from them, 1 - a sudden death and 1 - not related to the study. Although the deadly outcomes of the stroke were not registered, the frequency of dynamic violations of the cerebral circulation, in patients taking Ropecoxib, was two times higher than those who had taken placebo. Special surprise caused the fact that the increase in cardiovascular complications began to be detected only in 18 months from the beginning of the study.
Soon, for the same reasons, the ARC study was discontinued (ARC (PREVENTION WITH CELECOXIB), similar to the APPROVE study, in which a dose-dependent increase in the frequency of cardiovascular complications in patients receiving celecoxib (2.5 times - 400 mg / day was revealed. And in 3.4 times - 800 mg / day), compared with placebo. Finally, the analysis of the results of clinical trials of new koksibov - Valdecoxib and Lumiracaiba - also revealed a moderate increase in the risk of cardiovascular complications against the background of treatment with these drugs.

These data attracted great attention to the medical community to cardiovascular security not only Koksibov, but also the entire class NSAID. Ropekoxib, although it was registered, but was never actually applied in Russia, but other COF-2 inhibitors (celecoxib, meloxicams and nimesulide) take many patients in our country. It should be emphasized that the potential cardiovascular effects of Koksibov attracted close attention to themselves from the moment of the development of these drugs, which was reflected in the large number of experimental, clinical and epidemiological studies. Based on theoretical prerequisites, the vascular effects of COG-2 inhibitors are as opposed to the action of low doses of acetylsalicylic acid, namely a decrease in the COX-2 dependent synthesis of prostacyclin (PGI2) by cells of the vascular endothelium, in the absence of influence on COF-1 dependent synthesis of thromboxane (TXA2) platelet. This, as scientists believe, can lead to a violation of the balance between the synthesis of RGi2 and TXA2 towards the latter, which potentially creates a threat regarding the development of thrombotic complications.

The first alarming "signals" about the possibility of increasing the frequency of thrombosis in patients with RA against the background of treatment with Ropecoxib appeared in the Vioxx Gastrointestinal Outcomes Research), the results of which were published in 2000. According to the Research Protocol, the dose of rofecoxib was two times higher than the recommended (50 mg / day) and the reception of low doses of acetylsalicylic acid was not allowed. At the same time, as opposed to the results of the APPROVE study, a certain tendency to the "accumulation" of cardiovascular complications in the group of patients receiving ropecoxib began to be revealed after a month from the beginning of the test. However, in the CLASS (CELECOXIB Long-Term Arthritis Safety Study) in parallel, an increase in the frequency of cardiovascular complications in patients who took the celecoxib was not detected. In this study, the dose of celecoxib was also two times higher than the recommended (800 mg / day), but was allowed (if there were appropriate indications), the reception of low doses of acetylsalicylic acid was allowed, and the diclofenac and ibuprofen were used as "comparators".
Soon after the publication of the results of the Vigor and Class study, a group of famous American cardiologists from Cleveland, conducting its own meta-analysis of the results of clinical trials of ropecoxib and celecoxib, suggested that cardiovascular complications are a "class-specific" side effect of COX-2 inhibitors. However, the results of this meta-analysis were subjected to serious criticism, since the high basal cardiovascular risk characteristic of patients with RA was not taken into account. Subsequent meta-analyzes of materials of clinical trials of rofekoxib and celecoxib did not reveal the risk of thrombosis risk in patients taking these drugs compared to H-NPIDs.

However, these tests were not long and did not set their task as an assessment of cardiovascular complications, therefore did not allow to eliminate the possibility of increasing the risk of cardiovascular complications, especially in patients of an elderly revolution, with concomitant diseases of the cardiovascular system, inflammatory rheumatic diseases. A fundamentally important outcome of the research and discussions was the recommendation that patients with cardiovascular risk factors were planned to be treated with NSAIDs (regardless of their COG-selectivity), the preventive purpose of low doses of acetylsalicylic acid should be recommended, and the corresponding instructions for the use of ropecoxib were included. Supplements.

Based on the meta-analyzes of the results of clinical trials, Ropecoxib was suggested that an increase in the frequency of cardiovascular complications in the VIGOR study is not absolute, but relative, that is, it is not connected with the "thrombogenic" activity of rofecoxib, but with the "aspirin-like" action of naproxen. In a series of studies ("case-control"), other authors came to the conclusion of a "cardioprotective" action (compared to other NSAIDs) and other authors came. In addition, according to the data of experimental and clinical studies, the synthesis of Tha2 and aggregation of platelets than other NSAIDs, and approaches the acetylsalicylic acid, is naproxen.
At the same time, the materials of the following independent meta-analysis of the results of clinical trials of ropecoxib and epidemic studies, which were published already after the termination of the release of Ropeekoxib, indicated that the reception of this drug (at least in high doses) is associated with an absolute increase in the frequency of cardiovascular complications. . These data were not confirmed by many other authors, besides, a number of errors were revealed in a meta-analysis, when taking into account the risk of cardiovascular complications on the background of ropecoxib (compared to HPVP and placebo) became unreliable.
The situation has become even more controversial when in December 2004, the ADAPT study was pretended prematurely (Alzheimer Disease Anti-Inflammatory Prevention Trial), the purpose of which was a comparison of the prophylactic effect of the celecoxib, naproxen (and placebo) in patients suffering from Alzheimer's disease. The basis for this was an increase in the frequency of cardiovascular side effects in patients receiving naproxen, while the frequency of these complications in the group received celecoxib did not differ from placebo. Moreover, many authors have discovered a clear tendency to a moderate reduction in the frequency of cardiovascular complications in patients who received celecoxib, as compared with patients obtained by ropecoxib, and not obtained by NSAIDs.
Materials concerning the estimates of the cardiovascular effects of other COX-2 inhibitors (meloxicami, validekoxib, etc.) are few. For example, it has evidence that against the background of treatment with meloxicami risk of cerebrovascular and cardiovascular complications are somewhat lower than on the background of the reception of the celecoxib and ropecoxib. Increasing the frequency of thromboembolic complications in patients who took meloxico (compared to HPD) were noted. Moreover, there are data on the "cardioprotective" effect of meloxicam in patients with acute coronary syndrome. In this prospective randomized blind controlled study (Nut-2), 120 patients with acute coronary syndrome (without ST segment) were included, half of which against the background of standard therapy (acetylsalicylic acid and heparin) was obtained by meloxico (first intravenously, and then perrret), And half of the placebo. In patients who received meloxico, there was a significant reduction in the frequency of the recurrences of angina, they and death, as well as the need for revascularization within 30 and 90 days after the vascular disaster.
In 2004, the largest and prolonged of the previously controlled test tests of the NSAID - Target (Therapeutic Arthritis Research and Gastrointestinal Event Trial) was completed. It was compared the gastroenterological and cardiovascular security of a new "super-selective" inhibitor of COG-2 - Lumiracoxib (dose of 400 mg / day. Twice as high as recommended), naproxen (1000 mg / day) and ibuprofen (2400 mg / day) in patients with osteoarthritis. There were no reliable differences in the frequency of cardiovascular complications in compared groups of patients, although some tendency was observed for a greater absolute number of these complications (non-measure) in patients who received lumiracoxibes than naproxen.

The value of cardiovascular risk factors well demonstrates the Meta Analysis of WHITE W. and Sot. In this work, an analysis of the relative risk of cardiovascular complications of the NSAID, according to a randomized controlled test (RCI), in which the celecomb safety was compared with traditional NSAIDs (total 19,773 and 13,990 patients, respectively). Total frequency of potentially hazardous or lethal complications from the cardiovascular system was 0.96 and 1.12 patient-years. In patients without arterial hypertension (AG) complications noted with a frequency of 0.75 and 0.84, and in the presence of AG twice as much as - 1.56 and 1.78, in the absence of cardiovascular risk factors - 0.53 and 0.7, Prepare 1 risk factor 1.27 and 3.1, 2 or more factors - 2.54 and 2.9 patient-years, respectively.
The results of the work of Huang W. and Sotra are very significant. (2006 g), which studied the cohort from 9602 outpatient patients (Taiwan), received for at least 6 months. Celecoxib, meloxicam or ropecoxib. Myocardial infarction frequency, unstable angina, stroke and transient ischemia amounted to persons who did not have diagnosed cardiology diseases, 1,1, 0.6, 2 and 0.6% were more than five times higher among those who had this pathology in history - 5.0, 4.8, 6, 5.8%, respectively.
There is evidence that the risk of developing complications on the side of the cardiovascular system increases when using high (maximum permissible therapeutic) doses of NSAIDs for a long time. It is with such a prescription that an increased risk of cardiovascular complications for rofekoxib was revealed.
Thus, the question of whether the reception of the NSAID increases in general and the Koksibov in particular, the risk of thrombotic complications remains open. The evaluation of the available data is complicated due to the fact that many patients having a cardiovascular risk, simultaneously with the NSAID, take low doses of acetylsalicylic acid. According to experimental studies, some NSAIDs (ibuprofen, indomethacin) can compete with acetylsalicylic acid for binding to the active center of COX-1 and to cancel its "antiagragerant" effect. However, the interactions of other NSAIDs - ketoprophneu, diclofenac, ropecoxib and celecoxib with acetylsalicylic acid is not marked.

Materials of epidemiological studies related to the risk of cardiovascular catastrophes in patients simultaneously taking NSAIDs and acetylsalicylic acid are not numerous and contradictory. It is obvious that the problem of drug interactions of the NSAID and acetylsalicylic acid is particularly relevant for patients suffering from rheumatic diseases. Therefore, most of them potentially show the purpose of low doses of acetylsalicylic acid. It is obvious that this particular category of patients positive and negative "cardiovascular" effects of NSAIDs and drug interactions of the NSAID and acetylsalicylic acid can be particularly clinically significant and require a special study.
In contrast to the above materials on the potentially adverse effects of the Balance of PGI2 / TXA2, under the influence of COX-2 inhibitors on the cardiovascular system, the issue of "anti-bean" action of these drugs is discussed. This is what researchers believe may be due to the suppression of the COG-2-dependent component of the inflammatory process that plays an important role in the development and progression of atherosclerotic damage to the vessels and destabilization of atherosclerotic plaques. One of the most sensitive and specific "inflammatory" cardiovascular risk markers is a C-jet protein (CRB), as well as interleukin (IL) -6. It has evidence that in patients with severe ischemic heart disease (IBS), the purpose of the celecoxib leads to a significant improvement in endothelium-dependent vasodilation, which correlates with a decrease in the concentration of the CRH and another cardiovascular risk marker - low density lipoprotein compared to patients receiving placebo.

Cardiovascular Safety of Individual Preparations

To assess the cardiovascular security of one or another NSAID, the risk of confabilization of arterial hypertension, since the persistent increase in blood pressure (AD) is one of the most important risk factors for the development of cardiovascular disasters. In addition, arterial pressure, of all possible indicators of the state of cardiovascular systems, the system is most easily amenable to instrumental control, therefore it can be considered not only important, but also a very convenient marker of the negative influence of the NSAID.
There are a number of large studies that showed the absence or minimum risk of setting the controlled ag when using celecomb. In the work of WHITE W. and Sotr., For example, the influence of 400 mg / day celexib was compared. and placebo at the level of blood pressure (according to the daily monitoring of blood pressure, SMAD) in patients, before that received an effective monotherapy with a leaser 10-40 mg / day. After 4 weeks of observation, there was no reliable negative dynamics of blood pressure both in the main and control groups: the change in the garden was an average of 2.6 ± 0.9 and 1.0 ± 1.0, and DDa 1.5 ± 0.6 and 0.3 ± 0.6 mm Hg. respectively. At the same time, the ratio of patients who, during the control, the SMAD, there was an increase in hell on average more than 5 mm Hg, turned out to be the same.
There is a major study that estimates the effect of celecoxib for blood pressure in patients with high cardiovascular risk. These are the Crescent RCCs, during which 411 patients suffering from OA, a diabetes of second type and those who had controlled AG for 6 weeks were taken by celexib 200 mg, Ropecoxib 25 mg or 1000 mg / day naproxen. At the end of the observation period, the daily monitoring of blood pressure showed the absence of the dynamics of the mean values \u200b\u200bof systolic blood pressure in patients receiving celecoxib and naproxen, but a significant increase in it in the resulting ropecoxib before / after the end of the study, respectively.

AG destabilization (average rising garden is above 135 mm Hg. Art.) Against the background of the celecoxib intake, 16% of patients were noted, while on the background of the method of naproxen in 19%, and the ropecoxib is 30%.
Extremely important data was obtained by Mamdani M. and Sot. In the course of a population retrospective cohort study regarding the risk of development or destabilization of heart failure. It was provided that the risk of hospitalization on this severe pathology in 18,908 patients receiving celecoxib did not differ from the same risk of 100 thousand people who act as control and did not accept any NSAIDs. At the same time, in 5391 patients receiving H-NPIDs, and 14,583 patients taking ropecoxib, the risk was increased by 40 and 80%.
Thus, today Zeekaloxib is the only representative of the NSAID Group, which is clearly proved the possibility of relatively safe use in patients with severe Risk and cardiovascular risk factors.

This drug can be prescribed even to patients with a significant danger of the development of complications from the upper and lower gastrointestinal departments, as well as patients with arterial hypertension and heart failure. Of course, the clinical advantages of the celecoxib do not cancel the need for careful medical control For the condition of the patient and adequate prevention of relapses of concomitant diseases. Nevertheless, so high level The evidence justifies the widespread use of celecoxib as a pathogenetic painkillers in patients with multiple comorbide pathology.

The question of cardiovascular risk for meloxicam and nimesulda remains open. According to a number of the largest epidemiological studies conducted in various parts of the globe - in particular, in the United States (Singh G. and Sotr., 15,343 patients with them, 61 372 controls) and Finland (Helin-Salmivaara A., and Sot., 33,309 patients with them, 138 949 controls), meloxicami demonstrated a slightly higher risk of developing them in comparison with the celecoxum, meloxico and ketoprofen. Similar results showed meta-analysis McGettigan P. and Henry D. (17 studies Case-control: 86 193 patients with im and 527 236 Controls and 6 cohort: C-NPID 75 520, H-NPID 375 619, 594 720 control). The total OR to them for the celecoxib was 1.06, for meloxicam - 1.25.
Data on cardiovascular risk for nimesulide is actually limited only by the work of Helin-Salmivaara A. and Sot. According to the data obtained, this drug demonstrated a frequency to them close to other NSAIDs (OR 1.69), and somewhat inferior to the celecoxile (OR 1.06).

Risk ratio and benefits of selective and non-selective inhibitors of COG

The main criterion for safe treatment of the NSAIDs should be considered to reduce the risk of developing hazardous complications, both by the head of the gastrointestinal tract (clinically pronounced ulcers of the stomach or DPK, bleeding and perforations) and the cardiovascular system (myocardial infarction and ischemic stroke). It is for this criterion that this criterion should be relying when choosing a drug for patients who have serious risk factors for medicinal complications.

Although formally numerous international studies confirm the point of view that cardiovascular complications are the "class-specific" effect of the cocksies (at least in doses above recommended), but they are often preliminary and many of them remain inaccessible for detailed independent analysis. . Not engaged experts pay attention to the fact that even approve research materials, which served as a formal basis for stopping the release of ropecoxib, are not amenable to unambiguous interpretation. With a more detailed analysis, a paradoxical decrease in the frequency of cardiovascular complications in a group of patients receiving placebo has been drawn over the past months of this test, compared with the constant level of these complications in patients receiving ropecoxib. When maintaining a similar expected dynamics of these complications in the main and control group (it is obvious that placebo can hardly have an "antithrombotic" effect), differences in the frequency of cardiovascular complications would have to be clinically not significant.

With even greater caution, it should be treated with the results of retrospective epidemiological studies based on the analysis of administrative databases, which have a number of shortcomings and restrictions and therefore can significantly disperse with the data obtained in the process of clinical studies.

According to experts, in the heat of turbulent, not always correct controversy about the disadvantages of COF inhibitors undeservedly moved to the second plan of their dignity associated with higher gastroenterological safety. Part of the specialists are confident that excessive limitations of the use of NSAIDs and COF-2 inhibitors (in the absence of an alternative) or a long procedure for testing and registration of "new" NSAIDs reduce the quality of medical care to patients suffering from acute and chronic pains of different nature. At the same time, of course, the need for special controlled long-term tests aimed at estimating the cardiovascular effects of COX-2 inhibitors in groups of high cardiovascular risk is no doubt.

Thus, as in relation to the NSAID Gastro-Paray, the problem of the drug pathology of the cardiovascular-co-trial system is primarily determined by you-juice comorbidity among patients in need of long analgesic therapy. At the same time, in real clinical practice, the presence of both the gastrointestinal tract and cardiovascular risk factors that are often combined with each other are to be taken into account.
A fundamental approach to the adequate prevention of NSAID-associated complications is a clear assessment of the probability of complications and the appointment of the safest drugs. This choice is quite complicated, which is primarily due to the lack of generally accepted criteria for the safety of therapy, especially when prescribing one or another drug, having serious risk factors.
It should be noted that the concepts of "good tolerance" and "security" medicinal preparation Often mixed. However, this is far from the same thing, and the situation with NSAIDs clearly shows this difference. The fact is that under "good tolerance", first of all, refers to the low rate of development of subjective negative sensations, clearly connected with the moment of drug intake. For NSAIDs, it is dyspepsia - various unpleasant symptoms from the heading of the gastrointestinal tract (gastralgy, the feeling of gravity, "burning" in the epigastrium, nausea), the appearance of which is more determined by the contact irritant effect of drugs. Dyspepsia is the most frequent complication of the reception of the NSAID: it occurs in 10-30% of patients who regularly host these drugs, and often becomes the cause of interruption of therapy, transition to other drugs or appointments of "gastroprotectors". Although this is a very serious problem, it should be remembered that the NSPID associated dyspepsia is not a life-threatening state.
The conclusion of the safety of a particular drug should be based not in the opinion of individual experts, but only on the basis of serious evidence obtained in the course of well-organized prospective studies, as well as according to a serious retrospective analysis of the results, its use in real clinical practice. The tool for such an assessment is randomized controlled tests (RCCs), long-term observation of large cohort of patients and epidemiological studies, in which the risk of certain complications ("case-con-trol") is estimated. Therefore, not all NSAIDs, which are traditionally considered more secure, correspond to this criterion. For example, very popular "traditional" NSAIDs ibuprofen and ketoprofen have good subjective tolerance, which allows a number of experts to recommend these drugs as a means of you-bo-ra, including patients with factors of rice. However, in fact, the advantage of these drugs is limited only by "good tolerance".

If we evaluate the results of prospective studies, the absolute frequency of serious and lethal complications on the side of the cardiovascular system (myocardial infarction, ischemic stroke, sudden coronary death) undoubtedly exceeds similar indicators of hazardous medicinal pathology of the gastrointestinal tract. This situation is clearly confirmed by the data of the largest NSAID safety research - Medal program. In the course of Medal 34 701 with osteoarthritis (OA) patient or rheumatoid arthritis (RA) for 18 months. She took the selective NSA Verikoxib in a dose of 60 and 90 mg, or diclofenac 150 mg / day. According to the data obtained, the total frequency of hazardous reaches, such as clinically pronounced ulcers, bleeding, perforations, against the background of the intake of orcoxiba amounted to 1.0%, diclofenac - 1.4%. At the same time, cardiovascular complications were noted in 1.9 and 1.9%, and cerebrovascular - in 0.53 and 0.48%, respectively.
As in the case of the NSAID gastropathy, the overwhelming majority of cardiovascular catastrophes against the background of taking NSAIDs occurs in patients with specific risk factors. For cardiovascular complications such are the presence of diagnosed cardiological diseases, excess body weight, smoking, lipid metabolic disorders, diabetes, thrombosis of peripheral vessels, as well as arterial hypertension. According to many authoritative rheumatologists and specialists from other areas of medicine (including cardiologists), the benefits of the application, registered in Russia of COG-2 inhibitors, exceeds the risk associated with cardiovascular side effects. Nevertheless, experts advise adhere to the following recommendations:

In detail to inform patients about potential cardiovascular side effects of all drugs with characteristics of COX-2 inhibitors;
- to assign NSAIDs with special caution in patients with risk of cardiovascular complications;
- to conduct careful "monitoring" of cardiovascular complications (especially blood pressure) throughout the reception time;
- not exceed the recommended dose, since it is impossible to exclude that the cardiovascular risk increases with long-term reception of drugs in high doses;
- if necessary, prescribe low doses of acetylsalicylic acid, although the effectiveness of this therapy to prevent cardiovascular complications in patients taking NSAIDs has not been proven;
- When choosing drugs to keep in mind that some NSAIDs (naproxen - 500 mg / 2 times in day and celecoxib 200 mg / day) show higher cardiovascular safety than other NSAIDs (Ropecoxib, Valdecoxib, diclofenac, ibuprofen).

In general, to improve the safety of the use of selective and specific COF-2 inhibitors, it is necessary to carefully evaluate the ratio of possible benefits and risk of side effects, take into account contraindications and comply with particular caution in solving the question of the appointment of these drugs to patients with the pathology of the cardiovascular system and kidneys.

Paracoxib (dynastate) elevaton () relaphen)

VIII. Others

Nammaton (Rodanol s) Benzidamine (tantaum)

* Analgesic antipyretics, (practicallydo not possess anti-inflammatory action

Classification for action mechanism

I Selective COF-1 inhibitors

Acetylsalicylic acid at low doses (0.1-0.2 per day)

II non-selective COF-1 inhibitors and COF-2

Acetylsalicylic acid in high doses (1.0-3.0 per day or more) Phenylbutazone ibuprofen ketoprofen nifloum nifloumic acid Pyroxiks Lornoxicam diclofenac

Indomethacin and a number of other NSAIDs

III Selective COF-2 Inhibitors

Meloxicam

Nimesulid

Nammaton

IV high-selective COF-2 inhibitors

Kesetoxib

Paracoxib

V Selective COF-3 inhibitors (?)

Acetaminophen

Metamizoll

The use of NSAIDs for the treatment of a person has several millennia. Celsius (1 century BC) described 4 classic signs of inflammation: hyperemia, temperature rise, pain, edema and used willow cortex extract to facilitate these symptoms.

IN 1827. Glycoside Salicin was isolated from Willow's bark.

IN 1869 Company employeeBayer (Germany) Felix Hofman synthesized acetylsalicylic acid (at the request of a father suffering from heavy rheumatism) with a more acceptable taste than an extremely bitter extract of willow bark.

IN 1899 Bayer began commercial production aspirin.

IN currently there are more than 80 non-steroidal anti-inflammatory drugs. Preparations received a common name.non-steroidal anti-inflammatory,because different from

steroid anti-inflammatory glucocorticoids in chemical properties and mechanism of action. Every year, more than 300 million people take the NSAIDs in the world, of which 200 million preparations are purchased without a doctor's prescription.

30 million people are forced to take them constantly

MECHANISM OF ACTION

INFLAMMATION

The main components of inflammation

Alteration, -Gypemistry, --Scuding -Proliferation.

The combination of these phenomena underlieslocal signsinflammation: -propness, -Aspection of temperature, -Tell, -Bol,

Violation of the function.

IN the result of generalization of the process, along with local changes, develop andgeneral -intoxication, -lichery, - delectocytosis,

The reaction of the immune system.

By the nature of the flow, inflammation may beacute and chronic. Acute inflammationlasts from several days to several weeks. It is characteristic of:

The bright severity of signs of inflammation and-project or alteration, or vascularly exudative phenomena.

Chronic inflammation- This is a more sluggish, long-term process. Dominate:

Dystrophic and -proliferative phenomena.

IN inflammation process under the influence of various damaging factors

(microbes, their toxins, enzymes lysosomes, hormones)

includes "Cascade" of arachidonic acid

(With inflammation, arachidone acid is released from membrane phospholipids). 1) phospholipase is activated2, which from phospholipids of cell membranes frees arachidonic acid.

Arachidonic acid is predecessor of prostaglandins (GHG) - mediators of inflammation. 2) Prostaglandinsin the focus of inflammation, they participate in the development of the system, -gyperemia, and chores.

3) Arachidone Acid is involved in the metabolism process: cycloxygen and lipoxygenase.

With the participation of cyclooxygenasearachidonic acid turns into mediators of inflammation - cyclic endoperoxides1 -Prostaglandins2 -Statsiklins -Tromboxanes 3

With the participation of lipoxygenase

Arachidone acid turns into leukotrienes - mediators allergic reactions Immediate type and inflammation mediators.

Cyclooxygenase (COF) -key enzyme arachidonic acid metabolism.

This enzyme catalyzes two independent reactions:

1) cyclooxygenase

the addition of oxygen molecules to arachidonic acid molecule with the formation of PGG2

Inflammation is a pathological reaction that occurs in the body in response to damage. This protective process is a cascade of complex biochemical and biological reactions, one of the steps of which is the activation of specific enzymes - cyclooxygenases. What is cyclooxygenase and what their role in the development of inflammation will be discussed in our article.

To understand how cyclooxygenase works, it is necessary to disassemble the stages of the formation of the inflammatory process..

In response to various damage in the human body, inflammation is developing. This process is characterized by redness, increasing temperature, pain and edema. Symptoms of inflammation occur under the action of so-called inflammation mediators. These include prostaglandins, leukotrienes, biologically active substances, lysosomal enzymes.

The main symptoms of inflammation occur under the action of prostaglandins.

Reference. Prostaglandins are proteins that contribute to the exit of fluid from the vessels in the intercellular space, which causes tissue edema. They also provoke irritation of nervous endings, due to which pain appears during inflammation. Also, under the action of prostaglandins, local blood flow enhances and redness and temperature increase occurs.

It is important to know that prostaglandins perform not only the function of inflammation mediators. They have a number of effects and perform many essential functions in various organs and systems. Prostaglandins contribute to the expansion of bronchi, decrease in vascular resistance, increase the secretion of mucus in the stomach, decrease in the acidity of gastric juice, etc.

Prostaglandins appear in the human body in the process of exposure to cyclooxygenases (COF-1 and COF-2) on arachidone acid. What is COF-1 and COF-2, consider below.

What is cyclooxygenase

Cyclooxygenase - these are enzymes that are large protein molecules with high molecular weight. Their main task is to catalyze the synthesis, i.e., accelerate the composting of the prostaglandins from arachidonic acid.

There are several types of oxygenases: COF-1, COF-2 and COF-3.

COF-1.

The first-type cyclooxygenase is the so-called basic cyclooxygenase. This enzyme is normally synthesized in the body and turns arachidone acid into prostaglandins, which participate in the development of normal biological reactions. These prostaglandins are not mediators of inflammation. They contribute to the formation of the gastric mucosa, impede the respiratory spa, reduce the voltage of the vascular wall, adjust the normal activity of platelets.

COF-2.

Second-type cyclooxygenase - specific enzymewhich works only in response to inflammation. It is with the activities of this oxygenase that the main clinical manifestations of inflammation are associated, namely pain, redness, swelling, temperature rise.

COF-3.

Until recently, it was believed that there are only 2 types of cyclooxygenase. However, at the end of the 20th century, the results of studies of American scientists were published, which prove the existence of another, third, such oxygenase.

This species is mainly the tissues of the central nervous system. And during inflammation increases the sensitivity of the thermoregulation center, which provokes activation of several regulatory mechanisms and an increase in human body temperature. Other effects, in addition to increasing the body temperature, this enzyme does not have.

Inhibitors of cyclooxygenase

Inhibitors of cyclooxygenases are chemicals that block prostaglandin synthesis From arachidonic acid by turning off cyclooxygenase. They are selective and non-selective.

Non-selective inhibitors block the activity of not only pro-inflammatory cyclooxygenase (COX-2), but also base - COF-1. All the negative side effects of this type of chemical compounds are connected with this.

In addition to reducing the inflammatory process in the human body, the synthesis of "good" prostaglandins is also suspended. The protective forces of the stomach mucosa barrier are reduced, which provokes the formation of ulcers and erosive gastritis. Reducing the number of prostaglandins can cause spasm of smooth muscles of respiratory tract and provoke a suffocation.

Due to the lack of prostaglandins in the bloodstream, spasm of vessels And sections of ischemia are formed (with insufficient oxygen intake), and then necrosis (cell die). Such areas are formed in any human body, which significantly reduces its function.

Moreover, prostaglandins are responsible for the normal functioning of platelets. With their lack of platelets lose their ability to aggregation (gluing among themselves), which can lead to the formation of hematomas and bleeding.

Reference. Selective cyclooxygenase inhibitors act selectively. They block only the pro-inflammatory variety of COF. This reduces the number of side effects, since the "good" prostaglandins are synthesized in the same mode, the synthesis of only inflammation mediators stops.

Medications

Main pharmacological group of drugswhose anti-inflammatory effect is based on inhibition (slowdown) of cycloxienesis activity - these are nonsteroidal anti-inflammatory funds (NSAID).

Injective cyclooxygenase inhibitors include such drugsAs "Aspirin", "", "", "Ibuprofen", "" and others. These drugs in varying degrees inhibit COX-1 and COF-2, therefore, the above-listed effects, they are also caused to varying degrees.

Selective cyclooxygenase inhibitors include such drugslike "Celecoxib", "Meloxicam", "Nimesulid" and others. These drugs minimally inhibit COF-1. Their mechanism of action is associated with blocking the activities of COG-2, therefore, when applied, unwanted adverse reactions show themselves to the minimum.

Attention! The most non-selective is considered "aspirin". This drug has the most prior reactions. That is why, if necessary, it is necessary to constantly monitor the integrity of the mucous membrane of the stomach, the hemostasis system, the state of other organs and systems.

There is also a selective COF-3 inhibitor. This drug is called Paracetamol. It stops the work of COG-3 and reduces the temperature of the human body. However, it does not have other anti-inflammatory effects - does not remove swelling, does not reduce pain and redness. This is due to the fact that COG-3 does not participate in the development of reactions, respectively, the blocking of the connection will not lead to their decrease.

Conclusion

Inflammation is defensive reaction The body is on the actions on the part of a foreign damaging agent. It is accompanied by the development of unpleasant clinical manifestations that prevent us in everyday life. In order to return to active life, NSAIDs are used - cyclooxygenase inhibitors.

Do not forget that in addition to the basic effect (reduction of inflammation), there are also side. Do not self-medicate. Take the preparations of this group only by appointment of a doctor.

Cyclooxygenase in two isoforms (COF-1 and COG-2) plays an important physiological role in homeostatic and compensatory reducing processes through the regulation of the synthesis of prostaglandins from arachidonic acid. Both of its isoforms are represented everywhere.

COF-1 prevails in the gastrointestinal mucosa, where it performs a cytoprotective function, platelets, with which their aggregative properties, kidney cells, some other organs, are associated with thrombocytes. With the insufficient activity of COF-1, a violation of the integrity of the gastrointestinal mucosa with the risk of gastropathy development is connected to life-threatening bleeding and perforations inclusive. NSAIDs, which suppress the activity of COG-1 (non-selective), have their own side effects, primarily on this mechanism. The suppression of the activity of the COG-1 platelets with a decrease in their aggregative abilities, increases the risk of hemorrhages in violations of blood coagulation, vasculitis, but turns out to be desirable for diseases of the heart and a number of other pathological conditions.

COG-2 prevails in the brain, reproductive organs, kidneys, mononuclear leukocytes of blood (monocytes) and tissues (macrophages). COG-2 mononuclear leukocytes, other cells in inflammation foci inducing by pro-inflammatory cytokines or growth factors, provides synthesis of prostaglandins, mediated pain and inflammation. The synthesis of COF-2 mononuclears and other cells in the focus of inflammation should be considered as a natural phenomenon. In chronic processes, inflammation often loses the protective functions and stimulation of COF-2 entails the predominance of destructive over recovery processes. With the blockade of the NSAIDs of Isoforms of COF-2, they expect their anti-inflammatory effect, and it is confirmed. It also becomes obvious that the achievement of the anti-inflammatory effect of the NSAID in the absence of side effects on the tract and other associated with the activity of COX-1 tissue is possible, unless they selectively inhibit the activity of COF-2. Specific COF-2 inhibitors have such properties. The mediation of inflammation and associated pain COX-2 pain under the extremely important constitutional function of COG-1 and the risk of serious side effects of its suppression, convincingly indicate the preferred use in the treatment of specific COX-2 inhibitors.

With the release of two cyclooxygenase isoforms, and now it is also close to COX-2 on the physiological influences of COX-3, establishing a value in the mechanisms of inflammation and related pain increasing the activity of COX-2, as well as the importance of high activity of COF-1 in cytoprotective Processes, the Pharmacodynamics of NSAIDs was carried out, when they began to divide them on nonspecific and specific COX-2 inhibitors. All sets that existed to targeted synthesis and launch into the production of specific COF-2 inhibitors, including those such as meloxicams and nimesulide, are in varying degrees not only the activity of COX-2, but also COF-1. The peculiarity of non-specific is that with an increase in the dose of the received drug, their inhibitory activity relative to COX-1 with the ensuing consequences is increasingly growing. The exception is only specific COG-2 inhibitors that exhibit the overwhelming COF-1 activity in doses, several times higher than those recommended for clinical use. The problem of nonspecific COF inhibitors is in the existence of a large risk of complications by the gastrointestinal tract. About 30% of patients make complaints about the trades of the gastrointestinal tract, and one third of them are forced to abandon the further use of the NSAID. In accordance with the data of epidemiological studies in people aged more than 65 years, up to 30% of hospitalization and death on peptic ulcers are associated with the reception of the NSAID, and this risk is dose-dependent. The probability of bleeding increases sharply in smokers, abusing alcohol, when using oral glucocorticoids and anticoagulants, as well as when receiving diuretics and aPF inhibitors In connection with the diseases of the kidneys, arterial hypertension and heart failure. If not accentuated on specific, from non-specific absolute contraindications of clinical use has indomethacins due to its high toxicity and destructive effect on the articular cartilage. The side effects of nonspecific to the greatest degree of two known specific inhibitors of COX-2 celecoxib and roofecoxib are deprived of celecoxib. In the recommended doses, it is significantly easier for patients and has significantly less side effects. Caution When it is appointed, it is recommended to show only in patients with arterial hypertension, cardiac, medium and severe renal and heavy liver failure, it is not used with very severe renal failure and is prescribed after scarring of acute ulcers, which, however, concerns all NSAIDs. The connection of the reception of NSAIDs and arterial hypertension is known.

COG-2 not only mediate inflammatory responses, but is one of the regulators and other vital functions, such as the exchange of sodium and water in the kidneys, renin-angiotensin and interacting with her humoral systems to maintain blood pressure.

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

COF-1 is constitutive, that is, it works almost constantly and performs physiologically important functions. COF-1 is inhibited non-selective NSAID And it generates many side effects: bronchospasm, ulterogenesis, ears pain, water delay in the body ...

COF-2 is inducible, That is, it begins to function at certain situations, for example, when inflammation. COF-2 is expressed macrophages, synovocytes, fibroblasts, smooth vascular muscles, chondrocytes and endothelial cells after inducing by cytokines or growth factors.

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

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

Celecoxib is the first specific inhibitor of cyclooxygenase-2 Non-steroidal anti-inflammatory drugs (NSAIDs), which regularly takes the overwhelming majority of patients with rheumatic diseases, are among the most widely used in the clinical practice of medicines. However, despite the undoubted clinical efficacy, modern NSAIDs have certain disadvantages. Even short-term reception of these drugs in low doses can lead to the development of adverse reactions, first queue to development ulcerative-necrotic lesions of the gastrointestinal tract, (Gastrointestinal tract) that may be a serious threat to patient health. The risk of complications of drug therapy NSAIDs in individuals of the elderly and senile age, which are the main "consumers" of NSAIDs. Therefore, in recent years, special attention has been attracted to the development of new generation drugs that preserve all positive (high-inflammatory, analgesic and antipyretic activity) of the quality of modern NSAIDs, but less toxic. Forms of cyclooxygenase The main mechanism of the NSAID action associated with in the inhibition of cyclooxygenase activity (COW) - enzyme regulating the formation of prostaglandins (GH), was deciphered about 30 years ago. Great progress in this area was achieved in the early 1990s due to the discovery of two isoforms of the COF: structural enzyme (COF-1) which regulates PG products involved in providing normal (physiological) cell functional activity, and enzyme induced (COF-2) participating in the synthesis of PG in the inflammation zone. These data allowed us to suggest that those listed above the therapeutic effects of NSAID are associated with their ability to inhibit COX-2, While the most common side effects (lesion of the gastrointestinal tract, kidneys, disturbance of platelet aggregation) - with the suppression of the activity of COF-1 . Indeed in the process of studying pharmacological properties Modern NSAIDs have been shown that all drugs inhibit both isoforms of the COF, although in a specifically degree. When comparing the results of experimental (in the inhibition of COF in vitro) and clinical and epidemiological (relating to the prevalence of NSAID gastrophropathies) studies found that the NSAIDs, the more strongly overwhelming activity of COF-1 (aspirin, indomethacin, pyroquin), more often cause the tract of the tract Preparations exhibiting equivalent inhibitory activity with respect to both isoforms (diclofenac, ibuprofen, etc.) and especially often compared with NSAIDs, more selective for COX-2 (meloxico, etc.). These results, in combination with deciphering the three-dimensional spatial structure of COF-1 and COG-2 and the kinetics of the interaction of the NSAID with the active centers of these enzymes, served as the basis for the development of new drugs, selectively overwhelming the activity of COG-2. First specific inhibitor COF-2, implemented in clinical practice, is undoubtedly the drug celecoxib, which in the chemical structure is 4-gasoline sulfonamide). Kesetoxib Currently registered and allowed to clinical use for the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) in the United States and some other countries, including in Russia. It should be especially emphasized that the results of experimental studies zeanetoxib actually served first reliable confirmation of the hypothesis that inhibition of COF-2, in the absence of suppression of COF-1, allows you to control the development of prostaglandin-dependent inflammation and pain . In Vitro experiments, it was found that the introduction zeanetoxib Rats with adjuvant arthritis by 80-85% reduces the severity of inflammatory edema and hyperalgesia. This is equivalent to the effect of a complete therapeutic dose of non-selective inhibitor COF-1 and COG-2 indomethacin and slightly inferior to dexamethane, which blocks COX-2 at the level of expression of the IRNA of this isoenzyme. In vitro experiments, it was shown that, depending on the test method, the drug is about 10-3,000 times selective to COX-2 than COF-1 and significantly exceeds the traditional NSAIDs. It is also shown that the purpose of the celecoxib does not lead to the exacerbation of aspirin bronchial asthma and hidden heart failure. Prospects for use inhibitors COF-2. In recent years, the research of researchers has been attracted to the study of the role of COG-2-dependent synthesis of PG and the COF-2 itself in the development of a wide range of pathological conditions emerging beyond inflammation (oncopathology, the bone of the central nervous system and the cardiovascular system, disruption of bone metabolism, etc.) . According to epidemiological studies, in patients treated with NSAIDs, in 40-50% of cases noted reducing the frequency of colon cancer. Believe that antitumorianand antiproliferative action NSAID It may be indirect to the effect on the COX-2-dependent regulation of angiogenesis and apoptosis of tumor cells. In recent studies, it was shown that celecoxibus suppresses growth and induces apoptosis of in vitro and in vivo tumor cells. Thus, along with improving the safety of the treatment of inflammatory diseases, the introduction of highly selective inhibitors COF-2 (including celecoxib) opens up new perspectives in the prevention of malignant neoplasms. COF-1 is constitutiveThat is, it works almost constantly and performs physiologically important functions. COF-1 is inhibited non-selective NSAID And it generates many side effects: bronchospasm, ulterogenesis, ears pain, water delay in the body ... The above-described side effects are due to the fact that in inhibition of cyclooxygenase-1 is observed, first, a vacuum predominance lakeotrienovsecondly, an increase in the synthesis of leukotriene (leukotrienes C4, D4, E4 is a slowly reacting substance of anaphylaxis, MPSA, generating bronchospasm; prostaglandins Perform a protective role in the mucous membrane of the stomach, therefore the decrease in their synthesis generates ulcergenesis). The vacuate predominance of leukotrienes is due to the fact that against the background of reduced synthesis of prostaglandins, leukotrienes become prevailing substances. An increase in leukotriene synthesis is due to the fact that when blocking cyclooxygenase is unchangeable arachidonic acid Pratically fully expended on the synthesis of leukotrienes (at the time, in physiological conditions, arachidonic acid is evenly distributed between the synthesis of prostaglandins and leukotrienes). The lack of prostaglandins in the renal tissue, observed when blocking COF-1, violates local autore regulatory mechanisms. Cyclooxygenase 2. COF 2 in a complex with a selective inhibitor Designations Symbols COF 2, (eng. Cox. 2 ) Nm_000963. Other data Cipher kf 1.14.99.1 Lock 1st XP., 1Q25.2. -25.3 COF-2 is inducible, That is, it begins to function at certain situations, for example, when inflammation. COF-2 is expressed macrophages, synovocytes, fibroblasts, smooth vascular muscles, chondrocytes and endothelial cells after inducing by cytokines or growth factors. Inhibition of COG-2 is considered as one of the main mechanisms of anti-inflammatory activity NSAIDSince, with selective inhibition of this cyclooxygenase, many side symptoms observed with cyclooxygenase inhibitations can be minimized. COF 1 and COF 2 have almost the same molecular weight - 70 and 72 kDa, respectively, the amino acid sequences correspond to almost 65%, the catalytic sites are also almost completely identical. Important from a pharmacological point of view, the difference is that COX 1 in 523 position contains a more hydrophobic amino acid - isoleucine (COF 2 in the same position contains valin).

Specific cyclooxygenase-2 inhibitors and osteoarthritis

Cyclooxygenase and osteoarthrosis

Cyclooxygenase in two isoforms (COF-1 and COG-2) plays an important physiological role in homeostatic and compensatory reducing processes through the regulation of the synthesis of prostaglandins from arachidonic acid. Both of its isoforms are represented everywhere, but are not equally distributed in various organs and tissues and are functionally different. COF-1 prevails in the gastrointestinal mucosa, where it performs a cytoprotective function, platelets, with which their aggregative properties, kidney cells, some other organs, are associated with thrombocytes. The constitutional properties of COG-1 are explained by controlling it synthesis of thromboxane A2, Prostaglandin E2 and Prostacyclin. With the insufficient activity of COF-1, a violation of the integrity of the gastrointestinal mucosa with the risk of gastropathy development is connected to life-threatening bleeding and perforations inclusive. NSAIDs, which suppress the activity of COG-1 (non-selective), have their own side effects, primarily on this mechanism. The suppression of the activity of the COG-1 platelets with a decrease in their aggregative abilities, increases the risk of hemorrhages in violations of blood coagulation, vasculitis, but turns out to be desirable for diseases of the heart and a number of other pathological conditions. COG-2 prevails in the brain, reproductive organs, kidneys, mononuclear leukocytes of blood (monocytes) and tissues (macrophages). In kidney, it protrudes one of the important enzymes for controlling the reabsorption of water and sodium and, through it, other functions. The blood circulation of COG-2 also affects the stimulation of the synthesis of vasodileor prostacyclin-I2. The latter, acting on Yuchstaglomelar cells, causes the release of renin, enhances the synthesis of angiotensin and the liberation of aldosterone, however, in hypovevolemia. Aldosterone enhances the reabsorption of water and sodium, the excretion of potassium. The liberation of renin and angiotensin has a consequence of an increase in blood pressure. When inhibiting COX-2, arachidonic acid is subjected to metabolism on an alternative path with the involvement of cytochrome P450. Its products may have renal vasoconstrictive effects with hypertension induction. In the light of these data, the suppression of COG-2 activity cannot be directly associated with increased edema and an increase in blood pressure, which is subsequently confirmed by targeted studies of selective NSAIDs. COG-2 mononuclear leukocytes, other cells in inflammation foci inducing by pro-inflammatory cytokines or growth factors, provides synthesis of prostaglandins, mediated pain and inflammation. With her, the progression of the inflammatory processes of the most different nature, OA among which is private phenomenon. Taking into account that inflammation is considered as a protective compensatory and adaptive rehabilitation reaction to damage, ensuring the replacement of the structures connective tissue, and is constructive in most inflammatory nature diseases, the synthesis of COF-2 mononuclears and other cells in the focus of inflammation should be considered as a natural phenomenon. In chronic processes to which OA and the inflammation relates often to protective functions and stimulation of COF-2 entails the predominance of destructive over restorative processes. With the blockade of the NSAIDs of Isoforms of COF-2, they expect their anti-inflammatory effect, and it is confirmed. It also becomes obvious that the achievement of the anti-inflammatory effect of the NSAID in the absence of side effects on the tract and other associated with the activity of COX-1 tissue is possible, unless they selectively inhibit the activity of COF-2. Specific COF-2 inhibitors have such properties. The anesthetic effect of COG-2 inhibitors should be associated not only with their local anti-inflammatory effect when pain receptors involved in the inflammatory process with OA tissues, but also by the effect on the activity of the COX-2 brain, playing an important role in the perception and formation of pain. Conducting inflammation and associated sophisticated COG-2 syndrome with an extremely important constitutional function of COX-1 and the risk of serious side effects of its suppression, convincingly indicate the preferred use in the treatment of OA specific COF-2 inhibitors.

Cyclooxygenase-2

The cyclooxygenase enzyme (Cox) catalyzes the first stage of the synthesis of prostaglandins in the arachidonic acid cycle. Under the action of the reservoir released from membrane phospholipids, arachidonic acid turns into prostaglandin PGG 2, which is then metabolized into prostaglandin PGH 2, and that - to other eikosanoids (prostaclines, thromboxanes, prostacyclines) (Fig. 7).

Prostaglandins (PGS) are the most famous cell mediators of inflammation - are derivatives of polyunsaturated fatty acids. It was originally believed that pgs are only in prostate gland, However, it later it turned out that they are synthesized in almost all organs and tissues. Depending on the structure of the prostaglandins (about 20, they are known in total) are divided into several types of latin alphabet letters: A, B, C, D, E, F, etc. The PGS of each type is divided into 1st, 2nd and 3rd series in accordance with the number of double bonds in the side chains of the molecule. Taking into account the type and series of prostaglandins designate: PGE 2, PGD 1, PGH 2, etc.

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

In addition to the fact that PGS are generally accepted inflammatory mediators, they mediate wide spectrum Others, positive and negative for the body, functions. PGS is positive in the regulation of a number of physiological processes - hemostasis, platelet aggregation, maintaining a tone of smooth muscles, isolating the gastric juice and regulating its acidity, as well as participation in the activities of reproductive, excretory, endocrine systems and the realization of pain / inflammatory response. Violation of the PGS biosynthesis can cause the development of severe pathological conditions.

To the negative parties of the activities of prostaglandins (in particular, 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 neoagiogenesis and invasion, as well as 2) mediation of immunosuppressive functions.

Two basic varieties are known (two main types) of cyclooxygenase - cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Despite the similarity of enzymatic activity, in contrast to the Izima COX-1, the constitutively expressive in almost all mammalian tissues, the COX-2 isoenzyme in normal (untransformed) cells is almost never detected. At the same time, similar to other expression products of early response genes, Cox-2 quickly and transitally activated in response to the action of pro-inflammatory mediators and mitogenic stimulants: cytokines, endotoxins, growth factors, tumor promoters (42) and some oncogenes (V- sRCV- Ha-Ras., HER2 / Neu., Wnt) (47, 104, 128) . Different properties and parameters of expression are characterized by genes encoding data (46) .

It is known that one of the main cytokines induced by the corresponding (cytokine-dependent) signal cascade is a tumor necrosis factor A (TNFA), which in large concentrations activates pro-apoptotic receptor-indirect signal pathways, i.e. Stops the processes of cell division and causes the physiological death of cells, and in small doses act as a factor of survival and cell proliferation. The PGE 2 and PGF 2A, participating in the biosynthesis of PGE 2 and PGF 2A, bezen COX-2 enters the numerous protein group, the expression of which increases as a result of the activation of this signal cascade.

Since, as we have already noted, prostaglandin PGE 2, besides what is a mediator of inflammation, mediates a number of other biological functions associated with pathological hyperplastic and neoplastic processes, mediated by its synthesis induibial isozim COX-2 reasonably considered one of the key molecular targets in antitumor "targeted" therapy and prophylaxis. The basis for such a conclusion is the results of numerous epidemiological, experimental and clinical studies, which found that the elevated level of COX-2 is conjugate with carcinogenic processes in many organs and tissues, including in prostate gland (36) .B The same time reducing the frequency of recurrences of many tumors, on the contrary, was noted when taking non-steroidal anti-inflammatory drugs (NSAIDs) - COX-2 inhibitors (46) .

Today in clinical practice, a sufficiently large number of NSAIDs is applied. According to the mechanism of inhibiting SAC-2, they are divided into:

1) simple competitive (ibuprofen, pyroxics),

2) competitive reversible (indomethacin, diclofenac) and

3) Competitive irreversible (aspirin).

However, all these compounds, together with inhibition of the conditionally "bad" inducible Izima Ka-2, the same (or even more) suppress the activity of the constitutive "good" isozima Ki-1, and, consequently, negatively affect the implementation of physiological processes in the body. From here, unwanted side effects, often arising from their admission: complications from the gastric mucosa right up to the appearance of gastrointestinal bleeding and ulcerative lesions, worsening of the wound pressure, suppressing physiological inflammation. According to statistics of 1998, in the US, complications arising from the reception of NSAIDs are the cause of 100 thousand cases of emergency hospitalization and 16.5 thousand deaths. (106) .

Citation:Nosov E.L. Celecoxib is the first specific inhibitor of cyclooxygenase-2 // RMW. 1999. №12. P. 580.

Non-steroidal anti-inflammatory drugs (NSAIDs), which regularly takes the overwhelming majority of patients with rheumatic diseases, are among the most widely used in the clinical practice of medicines. However, despite the undoubted clinical efficacy, modern NSAIDs have certain disadvantages. Even short-term reception of these drugs in low doses can lead to the development of adverse reactions, primarily to the development of ulcerative-necrotic lesions of the gastrointestinal tract, (gastrointestinal tract), which may be a serious threat to patients' health. The risk of complications of drug therapy NSAIDs in individuals of the elderly and senile age, which are the main "consumers" of NSAIDs. Therefore, in recent years, special attention has been attracted to the development of new generation drugs that preserve all positive (high-inflammatory, analgesic and antipyretic activity) of the quality of modern NSAIDs, but less toxic.

Forms of cyclooxygenase

The main mechanism of the NSAID action associated with in the inhibition of cyclooxygenase activity (COW) - enzyme regulating the formation of prostaglandins (GH), was deciphered about 30 years ago. Great progress in this area was achieved in the early 1990s due to the discovery of two isoforms of the COF: structural enzyme (COF-1) which regulates PG products involved in providing normal (physiological) cell functional activity, and enzyme induced (COF-2) participating in the synthesis of PG in the inflammation zone. These data allowed us to suggest that those listed above the therapeutic effects of NSAID are associated with their ability to inhibit COX-2, While the most common side effects (lesion of the gastrointestinal tract, kidneys, disturbance of platelet aggregation) - with the suppression of the activity of COF-1 . Indeed, in the process of studying the pharmacological properties of modern NSAIDs, it was shown that all drugs inhibit both isoforms of the COX, although in a specically degree. When comparing the results of experimental (in the inhibition of COF in vitro) and clinical and epidemiological (relating to the prevalence of NSAID gastrophropathies) studies found that the NSAIDs, the more strongly overwhelming activity of COF-1 (aspirin, indomethacin, pyroquin), more often cause the tract of the tract Preparations exhibiting equivalent inhibitory activity with respect to both isoforms (diclofenac, ibuprofen, etc.) and especially often compared with NSAIDs, more selective for COX-2 (meloxico, etc.). These results, in combination with deciphering the three-dimensional spatial structure of COF-1 and COG-2 and the kinetics of the interaction of the NSAID with the active centers of these enzymes, served as the basis for the development of new drugs, selectively overwhelming the activity of COG-2. It was found that the Active Center COG-2, unlike COG-1, has an additional side hydrophilic "cavity", the formation of which is explained by the substitute for a large isoleucine molecule at position 523 in COX-1 on a small valine molecule in COF-2. At the same time, the chemical structure of some drugs synthesized in recent years, more selective in relation to COF-2, differs from the structure of traditional NSAIDs by the presence of a rigid side chain, capable of penetrating into the side "cavity" of COF-2 and thereby more strongly suppress activity It is this isoenzya.

Selective COF-2 inhibitors

The first specific inhibitor of COG-2, implemented in clinical practice, is undoubtedly the drug celecoxib, which in the chemical structure is 4-gasoline sulfonamide). Celecoxib is currently registered and allowed to clinical use for the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) in the United States and some other countries, including in Russia.

It should be emphasized that the results of experimental studies of the celecoxib actually served as the first reliable confirmation of the hypothesis that inhibition of COF-2, in the absence of suppression of COF-1, allows you to control the development of prostaglandin-dependent inflammation and pain . In Vitro experiments, it was found that the introduction of celexib rats with adjuvant arthritis by 80-85% reduces the severity of inflammatory edema and hyperalgesia. This is equivalent to the effect of a complete therapeutic dose of the non-selective COX-1 inhibitor and COX-2 indomethacin and is slightly inferior to dexamethane, which blocks COX-2 at the level of expression of the IRNA of this isoenzya. In vitro experiments, it was shown that, depending on the test method, the drug is about 10-3,000 times selective to COX-2 than COF-1 and significantly exceeds the traditional NSAIDs.

It is fundamentally important data that in vivo 50%-inhibition of COX-1-dependent PG synthesis in the stomach is achieved at the concentration of the preparation of more than 200 mg / kg, while for the full suppression of COF-2 dependent PG synthesis in the inflammation zone 0.2 mg / kg is enough (Table 1). This unique property of the drug is associated with the peculiarities of its chemical structure (Fig. 1). It is believed that the side polar sulfonamide group penetrates the active center of COX-2, localized inside a specific hydrophilic side "cavity", and inhibitively dependently dependently inhibit its activity. On the contrary, the other part of the molecule is located in the hydrophobic central channel COX-1, but very little interacts with its active site, without causing a significant suppression of the activity of this isoenzyme.

Pharmacological characteristic

Zeanetoxib has very low solubility in water, which makes it difficult to create dosage form For parenteral administration. The metabolism of the drug occurs in the liver (\u003e 70%), followed by biliary excretion and depends on the activity of cytochrome P 450 2c9. At the same time, inert metabolites are formed, which do not show inhibitory activity in relation to COX-1 or COF-2.

When orally acceptance bioavailability of the drug It is 75%. Eating increases (by 7-20%), and antacids reduces (25%) bioavailability, but this does not affect the clinical efficacy of the drug. Belkovo-binding ability of the drugvery high and reaches 97%. When taking the drug at a dose of 200 mg 2 times a day, its maximum blood plasma concentration is 1500 ng / ml, which is significantly higher than the expected therapeutic level (300 ng / ml). With considering semi-health period (10-12 h), this allows the drug in a dose of 200 mg once a day, at least with OA. The linear profile of pharmacokinetics celecoxib is preserved even when taking a dose, 3 times higher than therapeutic (1200 mg / day). It is noteworthy that in individuals of elderly and in patients with moderate liver failure of significant clinically significant changes in pharmacokinetics, celecoxib is not marked.

When studying medicinal interactionsit was shown that the reception of such drugs, as methotrexate, warfarin, phenytoin, tolbulamd, does not have a significant effect on the celecoxib pharmacokinetics. At the same time, it is necessary to keep in mind that salts of lithium, paroxetine and especially fluukonazole increase the half-life of the drug in plasma. Despite the absence medicinal interaction With indirect anticoagulants (warfarin), in patients taking both drugs, it is necessary to monitor blood coagulation and the titration of the anticoagulant dose.

Clinical efficacy

According to clinical tests of phase II, an effective dose of the drug in patients with OA is 100-400 mg / day, and RA - 200-800 mg / day.

Analgesic effect of celecoxib has been demonstrated on a classic model. tooth and postoperative pain . It has been established that in patients subjected to dental operations, according to analgesic activity, the drug at a dose of 100 or 400 mg exceeds placebo and is not inferior to aspirin.

Long-term (6-12 months) double blind placebo-controlled and comparative (with other NSAIDs) clinical tests of efficacy and safety celecoxib were carried out by more than 11,000 patients with preferably damage to the knee and hip joints and RA, and 35% of patients were in Aged older than 65 years.

It has been established that the celecoxib (400 mg) is similar in efficiency with such widely used drugs as naproxen (500 mg 2 times a day) and diclofenac (75 mg 2 times a day), and reliably exceeds placebo on the effect on such parameters as quality Life and physical activity of patients.

Safety

In the process of clinical trials, special attention was paid to the safety of treatment, which was estimated at a very large clinical material (more than 4,700 patients), including using serial endoscopic studies of the upper gastrointestinal departments. The results obtained in the study of healthy volunteers showed that severity endoscopic changes of the gastric mucosa Against the background of treatment, the celecoxib at a dose of 100-200 mg / day for 7 days is the same as when receiving placebo, and significantly less than when taking a naproxen (500 mg 2 times a day). In the process of a long (3-6 months) of a dynamic endoscopic study of patients with OA and RA, it was found that the frequency of the formation of an ulcer in the stomach and duodenalistician In patients who took celecoxib, no placebo differs from placebo and significantly lower than when taking a naproxen and diclofenac (Table 2).

Data that, in contrast to other NSAIDs (ibuprofen, diclofenac, naproxen and aspirin), are given, when appointing celexib, volunteers (even in a dose of 6 times superior therapeutic) no violations of platelet aggregation (COF-1 dependent phenomenon) and suppressing the synthesis of thrombooxane in 2. These materials are well consistent with the results of the analysis of clinical trials on a significant reduction in the frequency of bleeding, in patients treated celecoxy compared to other NSAIDs (Table 3).

When comparing the results of clinical tests of celecoxib with literature data relating to the frequency of gastroenterological side effects arising against the background of treatment with standard NSAIDs, it turned out that the use of celecoxib allows approximately 8 times to reduce the frequency of the gastrointestinal lesion (Table 4). To assess the prevalence of ulcer-necrotic damage to the tract, along with endoscopic examination, a thorough monitoring of hemoglobin content was carried out, a decrease in the level of which very well correlates with the severity of hidden gastrointestinal bleeding. With a dynamic study of the hemoglobin level in 771 patients receiving placebo, 812 and 809 patients treated celecoxib, respectively, at a dose of 100 mg and 200 mg 2 times a day and 781 patients receiving naproxen (500 mg 2 times a day), it was found that the decline The hemoglobin content is reliably more pronounced against the background of the method of naproxen than celecoxib (P<0,025), в то время как достоверных различий в группах пациентов, получавших целекоксиб и плацебо не отмечено.

Given the fact that the frequency of gastroenterological adverse reactions against the background of the treatment of the NSAID significantly increases sick elderly and senile ageOf particular interest are the results related to the safety of the use of celexib in patients of older age groups. A total of 4073 patients under the age of 65, among which 2366 received celecoxib, and the remaining placebo or NSAIDs were examined. It was established that such a characteristic gastroenterological side effect, as abdominal pain, developed in patients treated with celecoxib, 2 times less often than those who took other NSAIDs (4 and 9.2%, respectively).

Frequency of disorders kidney and liver functions (an increase in the level of alkaline phosphatase, bilirubin, creatinine, hepatic enzymes) was less in patients treated celecoxab than diclofenac (p<0,05). Показано также, что the purpose of the celecoxib does not lead to the exacerbation of aspirin bronchial asthma and hidden heart failure.

Prospects for the use of COF-2 inhibitors

In recent years, the research of researchers has been attracted to the study of the role of COG-2-dependent synthesis of PG and the COF-2 itself in the development of a wide range of pathological conditions emerging beyond inflammation (oncopathology, the bone of the central nervous system and the cardiovascular system, disruption of bone metabolism, etc.) . According to epidemiological studies, in patients treated with NSAIDs, in 40-50% of cases noted reducing the frequency of colon cancer. Believe that antitumorianand antiproliferative action NSAID It may be indirect to the effect on the COX-2-dependent regulation of angiogenesis and apoptosis of tumor cells. In recent studies, it was shown that celecoxibus suppresses growth and induces apoptosis of in vitro and in vivo tumor cells.

Thus, along with an increase in the safety of the treatment of inflammatory rheumatic diseases, the introduction of high-selective COF-2 inhibitors (including celecoxib) opens up new perspectives in the prevention of malignant neoplasms.

Literature

1. Nonov E.L. Anti-inflammatory therapy of rheumatic diseases. Moscow. M-City., 1996, 345 s.

1. Nonov E.L. Anti-inflammatory therapy of rheumatic diseases. Moscow. M-City., 1996, 345 s.

2. Brooks p.m., R.O. Day. Nonsteroidal Anti-Inflammatory Drugs: Differences and Similarities. N. engl. J. Med. 1991; 324: 1716 - 25.

3. Wolfe M., Lichtenstein D.R., SINHG G. GASTROINTESTINAL TOXICITY OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. N. engl. J. Med. 1999; 24: 1888 - 99.

4. Penn E. Building a Better Aspirin. Science 1998; 280: 1191 - 2.

5. Masferrer J.L., Zweifel B.S., Seibert K., Needleman P. Selective Regulation of Cellular Cycloxygenase by DexameThasone and Endotoxin in Mice. J. Clin. Invest. 1990; 86: 1375 - 9.

6. Needleman P., Isacson P.C. The Discovery and Function of Cox-2. J. rheumatol. 1997; 24: 6 - 7.

7. Vane J. Towards a Better Aspirin. Nature 1994; 367: 215 - 216.

8. Pairet M., Van Ryn J., Mauz A., et al. Differential Inhibition of Cox-1 and Cox-2 by NSAID: A Summary of Results Obtained using Various Test System. In: Selective Cox-2 inhibitors. Pharmacology, Clinical Effects and Therapeutic Potential. J. Vane, J. Botting EDS. 1997. Kluwer Academic Publisher. 27 - 46.

9. Nasonov E.L., Tvetkova E.S., Tov N .. Selective cyclooxygenase-2 inhibitors: new prospects for the treatment of human diseases. Therapist. Archive 1998; 5: 8 - 14.

10. Hawkey C.J. Cox-2 inhibitors. Lancet 1999; 353: 307 - 14.

11. Penning T.D., Talley J.J., BERTENSHAW S.R., ET AL. SYNTHESIS AND BIOLOGICAL EVALUATION OF THE 1,5-DIARYLPYRAZOLE CLASS OF CYCLOOXYGENASE-2 INHIBITORS: Identification of SC-58636 (CELECOXIB). J. Med. Chem. 1997; 40: 1347 - 65.

12. Anderson G.D., Hauser S.D., Bremer M.E., et al. Selective Inhibition of Cyclooxygenase-2 Reveses Inflammation and Expression of Cox-2 and IL-6 in Rat Adjuvant Arthritis. J.Clin.invest. 1996; 97: 2672 - 9.

13. SEIBERT K., Zhang Y., Leathy K., et al. PHARMACOLOGICAL AND BIOCHEMICAL DEMONSTRATION OF THE ROLE OF CYCLOOXYGENASE-2 IN INFLAMMATION AND PAIN. Proc. NATL. ACAD. SCI USA. 1994; 91: 12013 - 7.

14. Isakson P., Zweifel B., Masferrer J., et al. Specific Cox-2 Inhibitors: From Bench to Bedside. In: Vane J., Botting J, EDS. Selective Cox-2 IniBitors: Pharmacology, Clinical Effects and Therapeutic Potential. London: WILLAM HARVEY PRESS, 1997; 127 - 33.

15. Gierse J.K., Hauser S.D., Creely D.P., et al. Expresssion and Selective Inhibition of the Constitutive and Inducible Forms of Human Cyclooxigenase. Biochem. J., 1995; 305: 479 - 84.

16. Hubburd R.C., Mehkisch D.R., et al. SC-58635, A Highly Selective inhibitor of Cox-2, Is Aneffective Analgesis In Acute Post Surgical Pain Model. J. Invest. Med. 1996; 44: 293a.

17. Mehlisch D.R., Hubbard R.c., et al. Analgesis Efficasy and Plasma Levels of Highly Selective Inhibitor of Cox-2 (SC-58635) in Patients with Post-Surgical Dental Pain. CLIN. Oharmacol. Ther. 1997; 61: 195.

18. Celebrex Data Sheet. Searle, 1999.

19. Geis G.s. Update On Clinical Developments With Celecoxib, A New Specific Cox-2 Inhibitor: What can we expect. Scand. J. rheumatol. 1999; 28 (Suppl. 109): 31 - 7.

20. Geis G.S., Hubbard R., Callison D., Yu S., Zhao W. Safety and Efficasy of Celecocib, A Specific Cox-2 Inhibitor, in Patients with Rheumatoid Arthritis. Arthritis Rheum 1998; 41 (Suppl.): S364.

21. Geis G.S., Steed H., Morant S., Naudin R., Hubbard R. Efficacy and Safety of CeleCoxib, A Specific Cox-2 Inhibitor, in Patients with Rheumatoid Arthritis. Arthritis Rheum. 1998; 41 (Suppl.): S316.

22. Hubbard R.c., Koeper R., YU S.S., ET AL. Pilot Study of SC-58635, A COX-2, Selective inhibitor, in rheumatoid arthritis. Arthritis Rheum. 1997; 40 (Suppl. 9): S125.

23. Hubbard R.C., Geis G.S., Woods E., Yu S., Zhao W. Efficacy, Tolerability and Safety of Celecoxib, a Specific Cox-2 inhibitor in Osteoarthritis. Arthritis Rheum. 1998; 41: S196.

24. ZHAO S.Z., Hatoum H.T., Hubbard A.C., et al. Effect of CeleCoxib, A Novel Cox-2 Inhibitor, On Health-Related Quality Of Life of Patients with Osteoarthritis of the Knee. Arthritis Rheum. 1997; 40: S88.

25. Lanza F.L., Gallison D.A., Hubbard R.S., et al. A Pilot Study of the Gastroduodenal Effects of SC-58635, A COX-2-Selecrive Inhibitor. Arthritis Rheum. 1997; 40: (Suppl. 9): 372 ABST.

26. Dubois R.N., Abramson S.B., Crofform L., et al. Cyclooxygenase in Biology and Medicine. FASEB J. 1998; 12: 1063 - 73.

27. Kawamori T., Rao C.V., SEIBERT K., Reddy B.S. Chemopreventive Activity of Celecoxib, A Specific Cyclooxygenase-2 Inhibitor, Against Colon Carcinogenesis. Cancer Res. 1998; 58: 409 - 12.

28. MacDonald T.M., Morant S.V., Robinson G.c., et al. Association of Upper Gastrointestinal Taxicity of Non-Steroidal Anti-Inflammatory Drugs With Continues Exposure: Cohort Study. Brit. Med. J. 1997; 315: 1333 - 7.

29. Signh G. Recent Considerations in Nonsteroidal Anti-Inflammatory Drug Gastropathy. Am. J. Med. 1998: 108 (1b): 31s - 38s.

Codexib:

Kebrex

(SEARL)