What is tsog 1 2. New generation non-steroidal anti-inflammatory drugs (NSAIDs): review

Nonsteroidal anti-inflammatory drugs (NSAIDs, NSAIDs) have found use in many areas of medicine. They are the basis for the treatment of rheumatological diseases. In this article we will take a closer look at the advantages and disadvantages of modern representatives of this group of drugs. Particular attention will be paid to the so-called selective COX-2 inhibitors.

Selective COX 2 inhibitors

The action of older generation NSAIDs is based on blocking COX 1 and COX 2 (an enzyme involved in inflammation). Interfering with the protective enzyme COX-1 causes many side effects. It is for this reason that chemists have set themselves the problem of developing new drugs.

In modern medicine, selective COX 2 inhibitors are preferred, which are more effective and have fewer side effects.

Modern NSAIDs

There are no absolutely safe NSAIDs. Depending on the dosage and duration of use, they can be nephro- and hepatotoxic. Coxibs can negatively affect the cardiovascular system, therefore the following drugs are used only as prescribed by a doctor.

Movalis (Movasin, Melox, Melbek, )

The main substance is meloxicam. It is enough to take 1 tablet regardless of the time of day. The advantage of the drug is the possibility of relatively long-term use without the risk of developing negative changes. Available in the form of tablets, ointments, injections, suppositories.

Celecoxib (aka Celebrex)

Capsule form. The main effect is analgesic and anti-inflammatory. It has virtually no irritating effect on the gastric mucosa.

Valdecoxib

A group of coxibs, like celecoxib. Analgesic, anti-inflammatory, antipyretic activity. Indications: osteoarthritis, rheumatoid arthritis, primary dysmenorrhea.

Tsog 2 is a drug that is well tolerated by the body. Indispensable in the treatment of arthrosis, since it inhibits the destruction of collagen fibers and cartilage tissue. Recently, there has been evidence of negative effects on the liver with long-term oral use.

Nise (nimesulide)

Moderately selective towards COX 2. Class of sulfonamides. When taken orally, it is well absorbed from the gastrointestinal tract. With long-term use it does not accumulate. The gel form has a local analgesic and anti-inflammatory effect. Reduces joint pain, neutralizes morning stiffness and swelling. Duration of treatment is 10 days.

Etoricoxib (Arcoxia)

Powerful analgesic, high degree of anti-inflammatory effect. Small doses do not irritate the gastrointestinal mucosa. A side effect is increased blood pressure. It is for this reason that treatment begins with small doses and under medical supervision.

Xefocam

Belongs to the group of oxicams, but is a non-selective NSAID. High analgesic ability, has no effect on the central nervous system and is not addictive. The disadvantage is the high cost.

For quotation: Nasonov E.L. The use of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors at the beginning of the 21st century // Breast Cancer. 2003. No. 7. P. 375

Institute of Rheumatology RAMS, Moscow

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

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

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

Our previous publications and materials from other authors discuss in detail the current standards of NSAID therapy. However, experience in the clinical use of NSAIDs, and especially COX-2 inhibitors, is expanding and improving very quickly. The purpose of the publication is to draw the attention of doctors to some new trends and recommendations regarding the rational use of NSAIDs in medicine.

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

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

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

Basic research -

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

If there are risk factors - examination for the presence of H. pylori infection, gastroscopy.

Clinical examination -

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

Laboratory examination -

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

Note: when treating with diclofenac, aspartate aminotransferase and alanine aminotransferase should be determined after 8 weeks. after starting treatment. When taking angiotensin-converting enzyme (ACE) inhibitors concomitantly, serum creatinine should be determined every 3 weeks.

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

Damage to the gastrointestinal tract

For patients with risk factors for gastroenterological side effects (primarily with a history of ulcers), it is advisable to immediately prescribe COX-2 inhibitors. The expansion of indications for their use is currently limited mainly by “pharmacoeconomic” considerations associated with the higher cost of these drugs compared to “standard” NSAIDs. According to modern recommendations, inhibitors COX-2 should be prescribed if the following indications exist: :

For patients with risk factors for gastroenterological side effects (primarily with a history of ulcers), it is advisable to immediately prescribe COX-2 inhibitors. The expansion of indications for their use is currently limited mainly by “pharmacoeconomic” considerations associated with the higher cost of these drugs compared to “standard” NSAIDs. According to modern recommendations, inhibitors:

• if it is necessary to take “standard” NSAIDs for a long time at the maximum recommended doses;
• patient age over 65 years;
• presence of ulcerative complications in the anamnesis;
• taking medications that increase the risk of complications (glucocorticoids, anticoagulants);
• the presence of severe concomitant diseases.

It is obvious that over time, the indications for prescribing COX-2 inhibitors will only expand.

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

Pathology of the cardiovascular system and kidneys

All NSAIDs ("standard" and COX-2 inhibitors) can potentially have a negative effect on kidney function and the circulatory system. In general, these complications occur in approximately 1-5% of patients (that is, with the same frequency as gastroenterological side effects) and often require hospital treatment. Their risk is especially high in elderly and senile people (often with “hidden” cardiac or renal failure) (Table 2) or suffering from relevant concomitant diseases. NSAIDs (including low doses of acetylsalicylic acid) reduce the effectiveness of ACE inhibitors, diuretics, beta-blockers, increase blood pressure and negatively affect the overall survival of patients with heart failure. COX-2 inhibitors have adverse effects on renal function similar to those of “standard” NSAIDs. But some of them (celecoxib) still cause destabilization of blood pressure in patients with stable arterial hypertension to a lesser extent than “standard” NSAIDs (ibuprofen, diclofenac, naproxen) and another COX-2 inhibitor, rofecoxib. There was no effect of celecoxib on ambulatory blood pressure in patients with arterial hypertension receiving ACE inhibitors (lisinopril). However, whether the results of these studies can be extrapolated to the entire population of patients with arterial hypertension remains unclear. Therefore, the use of any NSAIDs (including COX-2 inhibitors) in patients with concomitant cardiovascular diseases and renal pathology should be carried out with extreme caution.

All NSAIDs ("standard" and COX-2 inhibitors) can potentially have a negative effect on kidney function and the circulatory system. In general, these complications occur in approximately 1-5% of patients (that is, with the same frequency as gastroenterological side effects) and often require hospital treatment. Their risk is especially high in elderly and senile people (often with “hidden” cardiac or renal failure) (Table 2) or suffering from relevant concomitant diseases. NSAIDs (including low doses of acetylsalicylic acid) reduce the effectiveness of ACE inhibitors, diuretics, beta-blockers, increase blood pressure and negatively affect the overall survival of patients with heart failure. COX-2 inhibitors have adverse effects on renal function similar to those of “standard” NSAIDs. But some of them (celecoxib) still cause destabilization of blood pressure in patients with stable arterial hypertension to a lesser extent than “standard” NSAIDs (ibuprofen, diclofenac, naproxen) and another COX-2 inhibitor, rofecoxib. There was no effect of celecoxib on ambulatory blood pressure in patients with arterial hypertension receiving ACE inhibitors (lisinopril). However, whether the results of these studies can be extrapolated to the entire population of patients with arterial hypertension remains unclear. Therefore, the use of any NSAIDs (including COX-2 inhibitors) in patients with concomitant cardiovascular diseases and renal pathology should be carried out with extreme caution.

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

Another equally important aspect of this problem from a practical point of view is related to combined use of NSAIDs and acetylsalicylic acid . Obviously, the need for such therapy can be very high, given the elderly age of patients who are the main “consumers” of NSAIDs, and the high risk of cardiovascular accidents in patients with inflammatory rheumatic diseases. Since taking low doses of acetylsalicylic acid itself can cause the development of severe complications from the gastrointestinal tract, a natural question arises what are the real advantages of COX-2 inhibitors over “standard” NSAIDs in patients forced to take low doses of acetylsalicylic acid. Indeed, according to the study CLASS a significant decrease in the incidence of severe gastroenterological side effects during treatment with celecoxib (compared to “non-selective” NSAIDs) was detected only in patients who did not receive low doses of acetylsalicylic acid. However, a recent meta-analysis of celecoxib trials suggests a clear trend towards a reduction in both symptomatic side effects and severe gastrointestinal complications with treatment with COX-2 inhibitors compared with “standard” NSAIDs. The incidence of severe gastroenterological complications in patients receiving low doses of acetylsalicylic acid was 51% less when taking celecoxib than NSAIDs.

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

Lung pathology

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

Fracture repair

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

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

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Osteoarthritis is a multifactorial chronic progressive disease, which is characterized by an imbalance between anabolic and catabolic processes, primarily in hyaline cartilage. In addition to hyaline cartilage in osteoarthritis, the pathological process involves the synovial membrane with the development of varying degrees of recurrent synovitis, as well as subchondral bone, articular capsule, intra-articular ligaments and periarticular muscles.

Osteoarthritis occurs at any age, but most often after 45-50 years. At the age of over 70 years, radiological signs of osteoarthritis are found in 90% of women and 80% of men, and in 20% of them osteoarthritis is clinically manifest. Pain and limited joint mobility caused by this disease sharply worsen the quality of life of patients and represent a serious socio-economic problem, being one of the main causes of disability.

The goal of drug therapy for osteoarthritis is to reduce and even completely stop pain in the joints and restore their functions, as well as prevent further progression of this disease by correcting impaired metabolism in hyaline cartilage. The drug therapy regimen for osteoarthritis includes two main classes of drugs:

• immediate action symptomatic drugs;
• drugs that structurally modify cartilage.

Second class drugs slow down the rate of progression of the disease, that is, they have a chondroprotective effect. Such medications primarily include structural analogues of cartilage tissue, namely the drug Dona (viartril, arthril, praxis, bioflex), the active ingredient of which is glucosamine sulfate, as well as the drug structum, which is chondroitin sulfate. These drugs modulate the essential functions of chondrocytes in osteoarthritis-damaged cartilage, stimulating the synthesis of sulfated and non-sulfated proteoglycans comparable to physiological proteoglycans, including their ability to form strong complexes with hyaluronic acid.

In addition to structum and don, second-class medications also include rumalon, which is an extract from cartilage tissue and bone marrow of calves; diacerin - interleukin-1 inhibitor; non-hydrolysable compounds from soy and avocado; hyaluronic acid preparations.

Many of the slow-acting drugs have not only chondroprotective, but also direct anti-inflammatory effects.

But still, non-steroidal anti-inflammatory drugs (NSAIDs) have the most striking anti-inflammatory effect, without which complex therapy for osteoarthritis is unthinkable. Their prescription is justified by the fact that, although osteoarthritis is a degenerative disease, manifestations of secondary synovitis or an inflammatory process in the periarticular soft tissues aggravate its progression. That is why the concept of “osteoarthritis” is accepted abroad. Drugs in this group are able to quickly reduce the intensity of pain in the affected joints, up to its complete relief, suppress exudative phenomena and restore range of motion, that is, actively influence the main subjective and objective symptoms of osteoarthritis. Many patients with this disease take NSAIDs almost constantly, since these are the only drugs that have a pronounced therapeutic effect and allow patients to maintain the ability to care for themselves.

Currently, several groups of NSAIDs are well known, pharmacokinetics have been studied in detail, indications for use, dosage regimens, and the range of possible adverse reactions have been clearly defined.

The main representatives of NSAIDs are derivatives of arylcarboxylic acids (aspirin, sodium salicylate, flufenamic and mefenamic acids), arylalkanoic acids (diclofenac, ibuprofen, flurbiprofen, naproxen, tolmetin, indomethacin, sulindac), enoliconic acid (phenylbutazone, piroxicam, meloxicam). The main mechanism of action of NSAIDs is the suppression of prostaglandin biosynthesis.

As is known, prostaglandins are characterized by a wide range of biological actions. They are mediators of inflammatory reactions and contribute to the development of edema and exudation, sensitize receptors to pain mediators (histamines and bradykinin), and also lower the threshold of pain sensitivity, increase the sensitivity of the hypothalamic centers to the action of pyrogens. Prostaglandins also regulate a large number of physiological processes, including intestinal motility, platelet aggregation, vascular tone, kidney function, gastric juice secretion, and trophism of the gastric mucosa. This makes it clear why NSAIDs have not only therapeutic anti-inflammatory, analgesic and antipyretic effects, but also numerous undesirable side effects.

The most common side effects are from the gastrointestinal tract (GIT), which manifest themselves in the form of gastric or intestinal dyspepsia, the formation of erosions and ulcers in the stomach and duodenum. Interestingly, in the United States, the number of deaths from gastrointestinal complications associated with traditional NSAIDs exceeds deaths from cervical cancer, bronchial asthma or melanoma.

The impetus for the development of new classes of NSAIDs with a smaller spectrum of side effects and good tolerability was the discovery in 1991 of two isoforms of cyclooxygenase (COX) - COX-1 and COX-2. Even earlier, J. Vane discovered that the anti-inflammatory effect of NSAIDs is associated with the suppression of COX, a key enzyme in the biosynthesis of prostaglandins. In 1995, the concept was put forward that COX-1 is a constitutive protective enzyme that has a cytoprotective effect and is naturally present in many tissues of the body, while COX-2 has pro-inflammatory activity and accumulates in high concentrations only in areas of inflammation. At the same time, it became clear that the side effects of NSAIDs are associated with inhibition of COX-1, and their anti-inflammatory effect is associated with inhibition of COX-2. Thus, the effectiveness and safety of NSAIDs are associated with selective suppression of COX-2 (b).

The modern pathogenetic classification of NSAIDs is based on their effect on individual COX isofermes. Thus, most NSAIDs used until recently (indole derivatives, diclofenac sodium, ibuprofen, piroxicam, etc.) are non-selective COX inhibitors. Meloxicam and nimesulide are COX-2 selective drugs. They have a certain anti-inflammatory effect at doses that inhibit COX-2 and yet cause significant inhibition of COX-1. A new class of specific COX-2 inhibitors includes celecoxib (Celebrex) and rofecoxib. As can be seen from the definition, specific COX-2 inhibitors act only on COX-2 and do not affect COX-1.

Celebrex was only accepted for clinical use in December 1998. This drug is the first specific COX-2 inhibitor specifically designed to reduce the number of adverse reactions (compared to other NSAIDs). The pharmacokinetic properties of Celebrex have been studied in healthy people. When taken orally, its maximum plasma concentration appears after 3 hours. 90% of the drug dose is metabolized in the liver and excreted in bile. The protein-binding capacity of this NSAID reaches 97%, and the half-life is 10-12 hours. The duration of action of Celebrex is 11 hours. The drug is poorly soluble in water and therefore is used only internally. Antacids reduce the bioavailability of the drug, and food intake increases it by 10-20%. Pharmacokinetics does not depend on age, which is especially important given the elderly age of patients with osteoarthritis. When treating osteoarthritis, the daily dose of Celebrex usually does not exceed 200-400 mg, but more often it is prescribed 200 mg once a day or 100 mg twice a day. It is best to take the drug with food, although the recommendations of the company that produces Celebrex indicate that its administration does not depend on food intake.

Placebo-controlled and comparative studies (with other NSAIDs) have shown the high therapeutic effectiveness of Celebrex in patients with osteoarthritis of the knee and hip joints. It turned out that this drug at a dose of 200 or 400 mg per day is comparable in its anti-inflammatory and analgesic activity to 1000 mg of naproxen, 150 mg of diclofenac or 2400 mg of ibuprofen. It had a positive effect on such indicators of the pathological process as the severity of joint pain, the severity and duration of morning stiffness, general disease activity assessed by the doctor and the patient, as well as the WOMAC index and the function of the affected joints. At the same time, the drug reliably changed their values. In the vast majority of patients with secondary synovitis, resolution of exudative phenomena in the knee joints was observed.

In contrast to standard NSAIDs, which inhibit the synthesis of proteoglycans in arthritic cartilage and thereby further contribute to the progressive degeneration of cartilage, Celebrex has a chondroneutral effect, and possibly even prevents the lysis of chondrocytes and takes part in the repair of cartilage after damage. It follows from this that, if necessary, it can be used for a long time (for several weeks or even months) without any negative effect on the tissue of the affected joint.

Celebrex, which has the same therapeutic efficacy as other NSAIDs, is characterized by higher tolerability and safety of use. When taking the drug, it is possible to develop such side effects as abdominal pain, diarrhea, nausea, headache, dizziness, rhinitis, sinusitis. However, the incidence of these reactions is not statistically significant compared with placebo.

In cases where this drug was used for one week in high and ultra-high doses, no gastrointestinal toxicity was detected, according to endoscopic monitoring. The incidence of gastric and duodenal ulcers with 200 mg Celebrex, 1000 mg naproxen, and 2400 mg ibuprofen administered continuously for three months was 7.5%, 36.4%, and 23.3%, respectively.

The use of specific COX-2 inhibitors in patients with osteoarthritis is also justified by the fact that they are compatible with other medicinal agents. This allows for adequate and timely treatment of concomitant diseases, which naturally occur in older people.

Literature

1. Nasonov E. L. Specific inhibitors of cyclooxygenase-2 and inflammation: prospects for using the drug Celebrex // Russian Rheumatology. 1999. No. 4. pp. 1-8.
2. Tsvetkova E. S. Modern pharmacotherapy of osteoarthritis // Consilium medicum. 1999. 1. C 205-206.
3. Kaplan-Machlis B., Klostermeyer B., S. The cyclooxygenase-2 inhibitors: safety and effectiveness // Ann. Pharmacotherapy. 1999. 33: 979-988.
4. Product information. Celebrex (celecoxib capsules). New York: Gd Searl and Co., 1998.
5. Strand F. Efficacy of COX-2 specific inhibition in musculoskeletal pain and inflammation: clinical update. COX-2 specific inhibition. Satellite symposium at 2000 National Scene Mitting ACR. Philadelphia, 2000, 8.
6. Vane J. R., Botting R. M. The future of NSAID therapy: selective COX-2 inhibitors // Clinical Practice. 2000. 54: 7-9.

note

• Osteoarthritis is a multifactorial chronic progressive disease.
• The goal of drug therapy for osteoarthritis is to reduce or eliminate joint pain and restore joint function.
• The basis of therapy for osteoarthritis is drugs that structurally modify cartilage and NSAIDs
• The effectiveness and safety of NSAIDs is associated with selective inhibition of COX-2.
• Celebrex is the first specific COX-2 inhibitor.

TO HELP THE PRACTITIONER

© KARATEEV A.E., 2014 UDC 615.276.036.06

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

Karateev A.E.

FSBI Research Institute of Rheumatology named after. V.A. Nasonova" RAMS, Moscow

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an indispensable tool for controlling acute and chronic pain. They are widely used for diseases of the musculoskeletal system, as well as for pain relief after injuries and surgical interventions. Unfortunately, NSAIDs can cause a number of class-specific side effects, primarily affecting the gastrointestinal tract (GIT) and cardiovascular system (CVS). The most well-known complication is NSAID gastropathy, which manifests itself by the development of gastric and/or duodenal ulcers, bleeding, perforation and gastrointestinal tract obstruction. Prevention of NSAID gastropathy is based 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 have virtually no effect on the physiological enzyme COX-1, suppressing only its inducible variety COX-2 . This reduces the negative impact of NSAIDs on the protective potential of the gastrointestinal mucosa and reduces the likelihood of its damage.

In Russia, the coxib family is represented by two drugs - celecoxib and etoricoxib, which have undergone serious testing to prove their superiority compared to 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 them, celecoxib (800 mg/day), as well as comparators - diclofenac (150 mg/day) and ibuprofen (2400 mg/day), were prescribed for 6 months to approximately 8000 patients with rheumatoid arthritis (RA) and osteoarthritis. (OA). According to indications, low-dose aspirin - LDA (325 mg/day or less) could be prescribed, which was ultimately received by about 20% of participants. Total se-

Serious gastrointestinal complications occurred in 0.76% of patients receiving celecoxib and in 1.45% of patients in the active control group. This difference turned out to be statistically insignificant, but it was significant in individuals who did not receive NDA: 0.44% versus 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 when using celecoxib is confirmed by a meta-analysis of 31 RCTs (a total of 39,605 patients): dangerous gastrointestinal complications while taking this drug occurred more than 2 times less often than in the control (0.4% and 0.9 % respectively) .

The benefits of celecoxib were shown by 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 of the 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 symptom 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 an increased risk of cardiovascular accidents.

A comprehensive approach to assessing 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. The total incidence of gastrointestinal bleeding, perforation, gastric and duodenal ulcers, and 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, took 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 turned out to be significantly higher than when using celecoxib: stomach/duodenal ulcers occurred in 20 and 5 patients, IDA - in 77 and 15, and treatment discontinuation due to complications was required in 8% and 6% of patients, respectively (p< 0,001) .

Further 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 video capsule endoscopy techniques. 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 condition of the upper gastrointestinal tract between groups, but with regard to damage to the small intestine the situation was different. In the celecoxib group, the number of patients with damage to the small intestinal mucosa was significantly lower than in the naproxen group (16 and 55%, p< 0,001), хотя и больше, чем в группе плацебо (7%) .

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

Celecoxib H. pylori -

Rice. 1. Incidence of serious gastrointestinal complications, including a decrease in hemoglobin levels of more than 20 g/L, during 6 months of celecoxib and traditional NSAIDs, depending on H. pylori infection: GI-REASONS RCT (n = 8067).

personal n-NSAIDs. Features of this work included taking into account H. pylori infection (this microorganism was detected in approximately 33.6% of participants), permission to use proton pump inhibitors (PPIs) and H2 receptor blockers (22.4% and 23.8% of patients received them) and exclusion of taking NDA. The main safety outcome was the incidence of gastrointestinal complications, including episodes of hemoglobin level decrease 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 CONDOR, clearly supports the superior safety of celecoxib compared with traditional NSAIDs, including in situations simulating real-world clinical practice.

Etoricoxib, like celecoxib, was developed to improve the safety of NSAID therapy. It has now become the end point for 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 clearly confirmed the high level of safety of etoricoxib. Thus, a meta-analysis of RCTs completed by 2003, which 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%, when using comparators (diclofenac, naproxen, ibuprofen) - 2.48% (p< 0,001) .

Serious evidence of the greater safety of etoricoxib was provided by 2 large-scale 12-week RCTs (n = 742 and n = 680), which assessed the incidence of endoscopic ulcers of the upper gastrointestinal tract in patients with RA and OA taking 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 disrupted by the publication of the results of MEDAL, the largest RCT of an NSAID to date. The explicit goal of this study was to prove that etoricoxib is no more dangerous for cardiovascular disease than traditional NSAIDs. MEDAL participants included 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 LDAs. In ito-

The main result was achieved: the number of cardiovascular accidents (including deaths) when using etoricoxib and diclofenac turned out to be almost the same.

However, the data on the incidence of serious gastrointestinal complications came as an unpleasant surprise to the MIDAL organizers. Although their total frequency when using etoricoxib was significantly lower than when using 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 MEDAL results completely erase the data of previous studies, but they do make us think that we do not know all aspects of the development of gastrointestinal complications associated with the use of NSAIDs, and that with their long-term use, pathogenetic factors may begin to act. not significant for their relatively short-term use.

Thus, there is good evidence to suggest a significant reduction in the risk of serious gastrointestinal complications and better tolerability of coxibs (celecoxib and etoricoxib) compared with n-NSAIDs. The evidence for the benefit of celecoxib appears clearer; the drug has proven to be safer in relation to complications not only in the upper, but also in the underlying sections of the gastrointestinal tract.

The low risk of gastrointestinal complications when using celecoxib is confirmed by data from population studies. At the end of 2012, a meta-analysis of 28 epidemiological studies (performed from 1980 to 2011) was published, which assessed the development of gastrointestinal complications with the use of various NSAIDs. Celecoxib demonstrated a minimal relative risk (RR) for gastrointestinal complications of 1.45; the danger 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 authors of this study identified the same low risk of gastrointestinal complications as for celecoxib for one of the representatives of traditional NSAIDs, aceclofenac (1.43).

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

The data of F. Chen et al. are indicative. . This study included 441 patients with rheumatic diseases who had a history of serious bleeding from upper gastrointestinal ulcers secondary to NSAID use. After successful healing of ulcers and eradication of H. pylori, all patients received celecoxib (400 mg/day) either without additional prophylaxis or in combination with esomeprazole (20 mg) for 12 months. During the observation period, rebleeding occurred in 8.9% of patients receiving celecoxib alone and in none of the patients receiving celecoxib with esomeprazole.

The main disadvantage of celecoxib and etoricoxib is that they belong to highly selective COX-2 inhibitors - that type of NSAID, 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-based studies and meta-analyses 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 cardiovascular disease. This fact is confirmed by a series of population-based studies that were reviewed in a well-known systematic review (including a meta-analysis) by P. McGettigan and D. Henry. The authors assessed data from 30 case-control studies, including 184,946 patients with cardiovascular complications, and 21 cohort studies (with a total of more than 2.7 million patients) performed up to 2011. The total risk of cardiovascular complications (RR) with the use of celecoxib was 1.17 (1.08-1.27); this was slightly more than with naproxen - 1.09 (1.02-1.16) and equal to that with ibuprofen - 1.18 (1.11-1.25). When using other NSAIDs, this figure was 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 may increase the risk of cardiovascular accidents. Thus, in 2011, S. Trelle et al. published the results of a meta-analysis of 31 RCTs (a total of 116,429 patients), which studied the safety of celecoxib, etorocoxib, lumirocoxib and rofecoxib; Various n-NSAIDs and placebo served as controls. The evaluation criterion was the risk of developing myocardial infarction, stroke and death due to cardiovascular complications. According to the data obtained, the risk of developing myocardial infarction against the background

celecoxib was higher than etoricoxib (OR 1.35 and 0.75), as well as comparators diclofenac (0.82) and naproxen (0.82), but lower than ibuprofen (1.61). . Most importantly, celecoxib was associated with an increased risk of death (2.07), especially compared with naproxen (0.98). True, it was slightly lower than when using ibuprofen (2.39) and significantly lower than when using diclofenac (3.98) and etoricoxib (4.07).

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

Another evidence of the possible negative effect of celecoxib on the cardiovascular system was a large-scale population study by G. Gislason et al. . The authors studied the relationship between taking NSAIDs and the risk of death in patients who had myocardial infarction. The study group consisted of 58,432 patients who underwent a successful course of treatment after the first myocardial infarction in the period from 1995 to 2002. Subsequently, 9,773 patients suffered a second myocardial infarction, and 16,573 patients died. As the analysis showed, taking 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 obvious that celecoxib is today the recognized gold standard for gastrointestinal tolerability. Nevertheless, the use of celecoxib cannot, of course, be considered a solution to the problem of 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 the synthetic analogue of PGE2, misoprostol, which eliminated the adverse effects of COX-1 blockade, and therefore prevented the development of gastrointestinal complications associated with taking 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 mi-

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

Subsequently, based on this gastroprotector, “protected” NSAIDs were created, such as arthro-tek, containing 50 mg of diclofenac sodium and 200 mcg of misoprostol.

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

PPIs have quickly gained popularity as effective and convenient gastroprotectors. A series of large-scale RCTs have 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 the gastroprotective medications prescribed to them. This may be due to a certain inconvenience for patients (“take two tablets instead of one”), an increase in the cost of treatment, as well as a lack of motivation in the case when taking NSAIDs is not accompanied by any unpleasant symptoms (“why take a gastroprotector?” , if my stomach doesn’t hurt?”). In addition, older patients may simply forget and skip taking preventive 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 a serious risk of gastrointestinal complications, but almost a third (32%) of patients were found to use 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 combination drugs containing NSAIDs and an antiulcer agent. The revival of the idea of ​​a “protected NSAID” occurred 20 years after the creation of arthro-tek, and the main reason for this was the decline in interest in selective COX-2 inhibitors after the “coxib crisis”.

Today, many experts consider the main factor limiting the use of NSAIDs not the pathology of the gastrointestinal tract, but the danger of cardiovascular accidents. After all, an effective method for preventing cardiovascular complications associated with NSAIDs, unfortunately, has not yet been developed. the only effective method for preventing thromboembolic complications is the prescription of antithrombotic drugs, such as NDA, which sharply increases the likelihood of gastrointestinal complications.

Although a 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-based and clinical studies, 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 advisable to use to create combination products. PPIs are the most acceptable as a gastroprotector: they are effective, easy to use and well tolerated. True, PPIs can have their own side effects, such as a certain increase in the frequency of intestinal infections, community-acquired pneumonia, changes in the metabolism of clopidagrel and methotrexate. In addition, in recent years, the issue of the possible negative impact of long-term use of PPIs on the progression of postmenopausal osteoporosis and an increased risk of osteoporetic fractures has been discussed. At the same time, their high effectiveness in preventing dangerous gastrointestinal complications fully compensates for the relatively low risk of possible side effects caused by the PPIs themselves.

The idea of ​​the combined use of a “cardiosafe” n-NSAID and a PPI, 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 (FCNE, Vimovo™).

In order to confirm the reduction in the incidence of gastrointestinal complications with the use of the new drug, 2 large-scale 6-month RCTs were performed (n = 854). These studies compared FKNE and conventional enteric naproxen. According to the results obtained, the incidence of gastric and duodenal ulcers that occurred while taking FKNE was 4.6% in the first study, and 8.1% in the second. In patients receiving 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 withdrawals due to adverse gastrointestinal effects in patients taking FKNE 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 with respect to the risk of developing side gastrointestinal effects.

The 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 FKNE (1 tablet 2 times a day), celecoxib (200 mg/day) or placebo. The new drug was not inferior in effectiveness to the comparison drug. As for tolerability, it was better (not significant) when using the combination drug. Thus, the number of withdrawals due to gastrointestinal complications while taking FKNE, 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 study. 5% .

Simultaneously with FKNE, 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, taking into account the fact that ketoprofen is an effective analgesic, and a successful dosage form with a slow release of the active substance allows it to be taken once a day; however, serious clinical studies that would show the safety of the new drug have not yet been conducted no, so it’s still difficult to judge its merits.

The only alternative to PPIs as a gastroprotector may be the H2 receptor blocker famotidine. Evidence of its effectiveness came from a 6-month RCT in 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, turned out to be significant only for famotidine at a dose of 80 mg (^< 0,05) .

There appear to be no large RCTs that have directly compared famotidine and PPIs for the prevention of NSAID gastropathy. Nevertheless, their effectiveness can be compared based on the results of a 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 enoxyparine or thrombolysis was administered. To prevent gastrointestinal complications for the entire duration of antiplatelet therapy (from 4 to 52 weeks), patients were prescribed famotidine (40 mg/day) or esomeprazole (20 mg/day). As a result, the stomach

in combination naproxen in combination 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) .

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

Thus, famotidine is clearly inferior to PPIs in terms of preventive effect against complications associated with taking LDAs. With regard to NSAID gastropathy, the situation is not entirely clear, but famotidine is unlikely to have any benefits in this case. At the same time, a number of experts consider an important advantage of famotidine to be the absence of complications inherent to PPIs, and most importantly, the negative impact on the metabolism of clopidagrel, the most important 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., the maximum daily dose of ibuprofen is supposed to be used - 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, ulcer history 6.2%, NDA use 15%. According to the data obtained, the number of stomach 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 incidence of ulcers is obvious, they occurred more often when using the combination of ibuprofen and famotidine than when using FKNE (Fig. 2). Although such a comparison is not entirely valid, it nevertheless clearly suggests itself, since these works had a similar structure, number and characteristics of patients.

An important disadvantage of Duexis may be the inclusion of ibuprofen in its composition. There is strong evidence

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

In general, although the concept of combination drugs is very interesting, it has certain disadvantages. Thus, these drugs are inconvenient for use in short courses or on demand. For example, enteric naproxen in FKNE begins to act only 3 hours after administration, which means that this drug is suitable for the control of chronic pain, but not for its emergency relief.

Another problem is that PPIs and famotidine provide protection only in the upper gastrointestinal tract, without affecting the development of NSAID enteropathy. And this pathology, as shown above, can have very serious clinical significance.

The prevalence of this pathology is demonstrated by the results of the work of M. Doherty et al. . The authors assessed the effectiveness of ibuprofen and paracetamol (in monotherapy or in combination) in 892 patients with OA. The study participants consisted of 4 groups: in the 1st group, paracetamol (1 g) was prescribed, in the 2nd group - ibuprofen (400 mg), in the 3rd group - paracetamol (0.5 g) and ibuprofen (200 mg), in 4 -th - paracetamol (1 g) and ibuprofen (400 mg); The patients took all medications 3 times a day. Against the background of such treatment, after 3 months, a decrease in hemoglobin level 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 the above-cited study by J. Goldstein et al. The majority of volunteers who received naproxen with omeprazole for 2 weeks experienced erosive changes in the mucous membrane of the small intestine.

At the same time, only real clinical experience allows one to assess the significance of a particular medical problem. In this regard, it is interesting to note that J. Goldstein et al. , who 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 FKNE and conventional naproxen. However, there is no mention of the development of anemia among participants in these studies. Similarly, there were no significant problems with small bowel pathology in patients treated with FCNE when compared with celecoxib. Thus, in total, in two RCTs (n = 1229) against the background of 3 months of taking a combination of naproxen and esomeprazole, the hemoglobin level decreased by more than

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

Index

Coxibs (celecoxib, etoricoxib)

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

Advantages

Flaws

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

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

Low incidence of upper gastrointestinal complications

Low incidence of gastric ulcers when combined with aspirin

Better tolerability compared to traditional NSAIDs

n-NSAIDs included in combination drugs are considered the least dangerous in terms of the development of cardiovascular accidents (especially naproxen)

Not suitable for acute pain relief (Vimovo™)

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

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

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

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

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

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

Karateev Andrey Evgenievich - Dr. med. sciences, head lab. [email protected]

LITERATURE (REFERENCES)

1. Karateev A.E., Yakhno N.N., Lazebnik L.B. etc. Use of non-steroidal anti-inflammatory drugs. Clinical recommendations. M.: IMA-PRESS; 2009.

2. Silverstein F., Faich G., Goldstein J. et al. Gastrointestinal toxicity with celecoxib versus nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxid long-term arthritis safety study. J.A.M.A. 2000; 84: 1247-55.

3. Singh G., Fort J., Goldstein J. et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-1 study. Am. J. Med. 2006; 119: 255-66.

4. Moore R., Derry S., Makinson G., McQuay H. Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis on information from company clinical reports. Arthr. Res. Ther. 2005; 7: 644-65.

5. Simon L., Weaver A., ​​Graham D. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized control trial. J.A.M.A. 1999; 282; 1921-8.

6. Emery P., Zeidler H., Kvien T. et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomized doubleblind comparison. Lancet. 1999; 354:2106-11.

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 allows us to identify target groups of patients in whom their use would be most appropriate. They should not be viewed as competitors; rather, coxibs and Vimovo™ will complement each other, expanding treatment options for chronic pain.

7. Sands G., Shell B., Zhang R. Adverse events in patients with blood loss: a pooled analysis of 51 clinical studies from the celecoxib clinical trial database. Open Rheumatol. J. 2012; 6:44-9.

8. Singh G., Agrawal N., Makinson G. et al. Safety without borders: upper and lower gastrointestinal safety of celecoxib in a pooled analysis of 52 prospective, randomized, double-blinded, parallel-group clinical trials. EULAR-2010 THU0437.

9. Chan F., Lanas A., Scheiman J. et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomized trial. Lancet. 2010; 376: 173-9.

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.

11. Cryer B., Li C., Simon L. et al. GI-REASONS: A Novel 6-Month, Prospective, Randomized, Open-Label, Blinded Endpoint (PROBE) Trial. Am. J. Gastroenterol. 2012; 108 (3): 392-400.

12. Schwartz J., Dallob A., Larson P. et al. Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus COX-1 in healthy subjects. J. Clin. Pharmacol. 2008, 48 (6): 745-54.

13. Ramey D., Watson D., Yu C. et al. The incidence of upper gastrointestinal adverse events in clinical trials of etoricoxib vs. non-select

gastroenterological problems in rheumatic diseases; e-mail:

tive NSAIDs: an updated combined analysis. Curr. Med. Res. Opin. 2005, 21(5): 715-22.

14. Hunt R., Harper S., Watson D. et al. The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy 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, randomized 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 treatment in patients with osteoarthritis. Scand. J. Rheumatol. 2001; 30: 19-24.

25. Saccar C. The pharmacology of esomeprazole and its role in gastric acid related diseases. Exp. Opin. Drug Metab. Toxicol. 2009; 5 (9): 1113-24.

26. Lanas A., Polo-Tomás M., Roncales P. et al. Prescription of and adherence to non-steroidal anti-inflammatory drugs and gastroprotective agents in at-risk gastrointestinal patients. Am. J. Gastroenterol. 2012; 107 (5): 707-14.

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.

28. Burmester G., Lanas A., Biasucci L. et al. The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opin-

ions of a multidisciplinary European expert panel. Ann. Rheum. Dis. 2011, 70 (5): 818-22.

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.

31. Drepper M., Spahr L., Frossard J. Clopidogrel and proton pump inhibitors - where do we stand in 2012? World J. Gastroenterol. 2012; 18 (18): 2161-71.

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.

37. Gigante A., Tagarro I. Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole. Clin. Drug Invest. 2012; 32 (4): 221-33.

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.

40. Humphries T. Famotidine: a notable lack of drug interactions. Scand. J. Gastroenterol. 1987; 22 (Suppl. 134): 55-60.

41. Bello A. Duexis® (ibuprofen 800 mg, famotidine 26.6 mg): a new approach to gastroprotection for patients with chronic pain and inflammation who require treatment with a nonsteroidal anti-inflammatory drug. Ther. Adv. Musculoskelet. Dis. 2012; 4 (5): 327-39.

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.

43. Patel T., Goldberg K. Use of aspirin and ibuprofen compared with aspirin alone and the risk of myocardial infarction. Arch. Intern. Med. 2004; 164:852-6.

44. Singh G., Graham D., Wang H. et al. Concominant aspirin use reduces the risk of acute myocardial infarction in users of cyclooxygenase-2 selective and some non-selective nonsteroidal anti-inflammatory drugs. Ann. Rheum. Dis. 2006; 65 (Suppl. II): 61 (0P0024).

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.

Cyclooxygenases (COX, COX-1, COX-2) are enzymes that are responsible for the formation of prostanoids, including prostaglandins, prostacyclins and thromboxane. Prostaglandins are mediators of inflammatory and anaphylactic reactions, and thromboxanes are mediators of vasoconstriction. Cyclooxygenases (COXs) catalyze the conversion of free fatty acids to prostanoids in two steps.

Two isoforms of cyclooxygenase COX-1 and COX-2

COX-1 is produced under normal conditions and is responsible for platelet aggregation, vascular tone, kidney function, and protection of the gastrointestinal tract.

TsOG-2 under normal conditions, it is absent in normal tissues of the body and is formed under the influence of certain cytokines that trigger an inflammatory response. It is COX-2 that is involved in the formation of inflammation and pain, for example, during or during the degeneration of cells into metastatic ones.

Typically, COX-2 is one of the targets for drug suppression of inflammation.

OPERATION SCHEME OF COX-1 AND COX-2

COX-2: what is it?

COX-2 is an enzyme used by our body to produce one of the inflammatory proteins called prostaglandin. Blocking or suppressing the production of COX-2 stops the production of prostaglandin, thereby reducing inflammation.

The COX-2 production pathway is also involved in the regulation of cell growth, triggering programmed cell death, and cytokine expression.(1)

COX-2 INHIBITORS AS ANTI-CANCER DRUGS

COX-2 inhibition

Inhibition of COX-2 production is the mechanism by which traditional medications, nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or aspirin, reduce the sensation of swelling and pain.

Typically, NSAIDs inhibit both COX-2 and COX-1, an enzyme that helps protect the stomach lining. That's why Long-term use of NSAIDs causes a decrease in immunity and increases the risk of developing stomach ulcers.(2,3)

Relatively recently, drugs have been developed that can specifically inhibit COX-2, but long-term use of such drugs is still considered to be of uncertain side effects.(4)

In addition, drugs that inhibit COX-2 stimulate cardiovascular stress and increase the risk of heart attack, heart failure, or kidney failure.(5)

Nonsteroidal anti-inflammatory drugs (NSAIDs), as COX-2 inhibitors, reduce the blood's ability to clot, which poses a threat to people with bleeding disorders. An increased tendency to bleed due to NSAID use may also worsen stomach ulcers.(6 7)

NSAIDs include drugs such as ibuprofen, aspirin diclofenac

Selective COX-2 inhibitors include celecoxib, refocoxib,zileuton

Natural COX-2 inhibitors

COX-2 is only produced by the body as a result of an inflammatory response.(8) Rather than suppressing the inflammatory response, removing (reducing) the underlying inflammation - the original source - can reduce COX-2 production in most cases.

Scientists have suggested that some natural COX-2 inhibitors, which are alternatives to drugs, are a better choice than NSAIDs.(9,10)

SCHEME OF THE INFLUENCE OF COX-2 INHIBITORS ON THE PREVENTION OF THROMBOSIS

COX-2 and various diseases

Inflammation

Because COX-2 activates inflammatory pathways, it is associated with the development of various inflammations in the body.

Inhibition of COX-2 production is considered a potential therapeutic target for treating brain inflammation during stroke.(11)

Cancer

COX-2 expression is associated with an increased risk of developing stomach cancer.(12) Prolonged and elevated expression of COX-2 is associated with the development of , a form of aggressive skin cancer.(13) Since COX-2 plays an important role in regulating cell death, this may explain the association of this enzyme with cancer in general.(14) )

SCHEME OF THE EFFECT OF ARACHIDONIC ACID ON THE DEVELOPMENT OF MANY DISEASES

What increases COX-2

Factors that increase the production of COX-2 include the following substances:

• Arachidonic acid. This acid is a precursor for COX-2, so foods or dietary supplements containing arachidonic acid increase COX-2 activity.(15)
• Foods high in Omega-6 unsaturated fatty acid may help produce more arachidonic acid. Such products may reduce the effectiveness of COX-2 inhibitors, both medicinal and natural.(16)

METABOLISM PATHWAYS OF OMEGA-6 AND OMEGA-3 POLYUNSATURATED FATTY ACIDS AND THE DEVELOPMENT OF INFLAMMATORY AND ANTI-INFLAMMATORY PROCESSES

Factors that reduce COX-2

Scientists suggest that several natural alternative COX-2 inhibitors have a preference for long-term use over NSAIDs.(17)

Hormones

Hormone progesterone capable of suppressing the factor NF-kB, which is responsible for the activation of the COX-2 gene. Thus, the hormone progesterone can reduce uterine contractility.(18)

SCHEME OF INHIBITION OF COX-1 AND COX-2 BY SOME FLAVONOIDS FROM PLANTS

Food

Science includes food products that can reduce the production of COX-2:

1. . Foods high in polyphenols are good anti-inflammatory sources. Polyphenols can inhibit the production of COX-2.(19)
2. Grape. Grape polyphenols can also suppress the increase in COX-2 production (tested in mice).(20)
3. Mangosteen (gamma mangosteen) from Garcinia (21)
4. All berries are rich in anthocyanins (especially raspberries) (22)
5. Avocado (Persenone A) (23)
6. Banana (24)
7. Citrus (25)
8. High Content Foods (26)
9. Mushrooms. Considered to be good COX-2 inhibitors with general anti-inflammatory properties (27)
10. (curcumin) is able to stop the production of COX-2, preventing transcription (28)
11. Ginger is considered one of the most powerful COX-2 suppressors (29)
12. Nutmeg. The substance myristinis from nutmeg selectively inhibits COX-2 (30)
13. Aloe vera. The substance aloesin from aloe vera inhibits COX-2 (31)

Substances or biological additives

This list contains substances that, in food or in the form of biological additives, can reduce the production of COX-2:

1. Fish oil (32)
2. Pterostilbene (33)
3. Caffeic acid (34)
4. Butyrate (35)
5. Resveratrol (36,37,38)
6. Pyrroloquinoline quinone (vitamin B14) (39)
7. Retinoic acid (40)
8. Quercetin (41)
9. Pomegranate extract, pomegranate (42, 53)
10. Pycnogenol (43)
11. Rosmarinic acid. Considered a potent COX-2 inhibitor (44)
12. Glucosamine (45.46)
13. Chinese skullcap (47, 48)
14. Spirulina (49)
15. Astaxanthin (50)
16. Chrysin (52)
17. Cinnamon (54)
18. Boswellia (55)
19. White willow (close to the effect of aspirin) (56)
20. Black cumin (57)
21. Rooibos (58)
22. Nettle (59)
23. Bitter melon (60)
24. Cardomonin from Alpinia katsumadai (61)
25. Olive Leaf Extract (62)
26. Tulsi (63)
27. Fennel (64)
28. Lipoic Acid (65)
29. Salvia miltiorrhiza (Danshen) (66)
30. Astragalus (67)
31. Rehmannia adhesive (68)
32. Berberine (69)
33. Milk thistle (71)
34. Reishi (72)
35. Linen (73)
36. Zinc (74)
37. Honey (75)
38. Soybeans (76)
39. Theanine from tea (77)
40. Garlic (78)
41. Lycopene (79)
42. Epimedium (80)
43. Emodin (81)
44. Blueberries (82)
45. Ursulic acid (83)
46. Sodium benzoate (84)
47. Paprika (85)
48. Perilla (86)
49. Black cohosh (87)
50. Echinacea purpurea (88)
51. Wormwood extract (89)
52. Thunder God Vine (90)
53. Andrographis (91)
54. Ginseng (92)
55. EGCG (from tea, especially green) (93)
56. Chamomile (94)
57. Selenium (95)

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