Treatment of osteoarthritis: Non-steroidal anti-inflammatory drugs (NSAIDs)

The first widely known NSAID was salicylic acid, first synthesized in 1874; soon it was found to be effective in rheumatic fever. In 1875, sodium salicylate was used for the treatment of rheumatic fever for the first time. In the mid-eighties of the XIX century. Sodium salicylate is widely used as a drug for the treatment of fever of various origins (malaria, typhus), rheumatic fever, rheumatoid arthritis and gout. A young chemist, Felix Hoffman, who worked at the Bayer Company in Germany, added an acetyl group to salicylic acid to improve its organoleptic properties. Thus, more than 100 years ago, the company "Bayer" first released the drug Aspirin for the pharmaceutical market and to this day, acetylsalicylic acid remains one of the most sold drugs in the world (more than 45 thousand tons per year).

The indomethacin that appeared in the pharmaceutical market in 1963 was the product of many years of searching for new anti-inflammatory agents. Soon after indomethacin, such drugs as ibuprofen, naproxen, and others were created.

After more than a century after the synthesis of acetylsalicylic acid and 40 years from the introduction of indomethacin to the pharmaceutical market, the NSAID group remains a subject of interest and numerous controversies, mainly with respect to mechanisms of action and side effects.

The first publication, which noted the negative effect of acetylsalicylic acid on the mucosa of the digestive tract, appeared in 1938. When gastroscopy in patients taking acetylsalicylic acid, erosions and chronic peptic ulcers were found .. A few later other side effects of this drug were described. Successful use of acetylsalicylic acid in patients with arthritis facilitated the search for funds that are not inferior to it in efficiency, but are safer, mainly in relation to the digestive tract. Such drugs as phenylbutazone, indomethacin, and phenamates have been developed. However, all of them, possessing an analogous acetylsalicylic acid, antipyretic, analgesic and anti-inflammatory action, caused side effects characteristic of it. When different chemical groups of drugs have the same therapeutic properties and they have the same range of side effects, it becomes apparent that their activity is related to the same biochemical process.

For several decades, pharmacologists and biochemists have been looking for a mechanism for the action of NSAIDs. The solution to the problem arose in the course of studies of prostaglandins - a group of biologically active substances released from all tissues except for erythrocytes and cyclooxygenase (COX) formed under the action of the enzyme to arachidonic acid mobilized from cell membranes. JR Vane and co-authors from The Royal College of Surgeons pointed out that the release of prostaglandins from sensitized lung guinea pig cells was prevented by acetylsalicylic acid. Using the supernatant of the homogenate of damaged lung guinea pig cells as a source of COX, JR Vane et al (1971) found a dose-dependent inhibition of prostaglandin formation by salicylic and acetylsalicylic acids and indomethacin.

In further studies using various NSAIDs it was found that they not only inhibit COX, but their activity against COX correlated with anti-inflammatory activity. The oppression of COX and, thus, the suppression of the formation of prostaglandins began to be considered as a unified mechanism for the action of NSAIDs.

Thus, the analgesic and anti-inflammatory effect of NSAIDs is due to inhibition of the activity of COX, a key enzyme in the metabolism of arachidonic acid. The first stage of the inflammatory cascade is the release of polyunsaturated fatty acids (including arachidonic acid), connected by ether linkage with glycerol of phospholipids of cell membranes, under the influence of phospholipases A ₂ or C. Free arachidonic acid is a substrate for the complex PGN synthetase, which includes the active centers of COX and peroxidase. COX converts arachidonic acid into nrG ₂, which in turn is converted to PGN ₂ by peroxidase. Thus, NSAIDs inhibit the conversion of arachidonic acid to PGS ₂. In addition, arachidonic acid is a substrate for 5- and 12-lipoxygenases catalyzing its transformation into biologically active leukotrienes and hydroxy-eicosatetraic acids. PG have pro-inflammatory properties, they increase the permeability of the vessel wall and the release of bradykinins.

The accumulation of PG correlates with the intensity of inflammation and hyperalgesia. It is known that any peripheral pain is associated with an increase in the sensitivity of specialized neurons - nociceptors, creating a signal that is recognized as pain. A powerful inductor of pain sensitivity is PG. In themselves, they are not moderators of pain, they are only able to increase the sensitivity of no-absorbers to different stimuli. GHGs seem to switch the normal ("silent") nociceptors to a state in which they are easily excited by any factor.

Of special interest is the discovery of two isoforms, COX-COX-1 and COX-2, which play a different role in the regulation of PG synthesis. The possibility of the existence of two forms of COX became the first to speak after the publication of JL Masferrer and co-authors (1990) of the results of a study of the effect of bacterial polysaccharide on the synthesis of PG by human monocytes in vitro. The authors showed that dexamethasone blocked an increase in the synthesis of PG under the action of a polysaccharide, but did not affect its basal level. In addition, dexamethasone depressant production of PG was accompanied by the synthesis of a new COX. Two isoforms of COX were discovered by molecular biologists who studied the neoplastic transformation of chick embryonic cells. They found that the structure of the inducible form of COX differs from the constitutive form and is encoded by other genes.

Functional activity of COX-1 and COX-2

Function	COX-1	COX-2
Homeostatic / Physiological	Cytoprotection Activation of platelets Kidney function Differentiation of macrophages	Reproduction Kidney function Remodeling of bone tissue Function of the pancreas Vascular tone Reparation of tissues
Pathological	Inflammation	Inflammation Pain Fever Violation of proliferation

COX-1 is a constitutive enzyme that is constantly present in the cells of various organs and regulates the synthesis of PG, which ensure normal functional activity of the cells. The level of activity of COX-1 remains relatively constant, while the expression of COX-2 is increased to 80 times with inflammation. Nevertheless, there is evidence that COX-1 may also play a role in inflammation, and COX-2 plays a more complex role in regulating physiological and pathological processes in the human body. In recent years, the role of COX-2 in the development of not only inflammation, but also other pathophysiological processes, primarily malignant transformation of cells, has been studied.

In spite of the fact that both isoforms of COX have the same molecular weight (71 kD), only 60% of their amino acids are homologous. They also have different locations in the cell: COX-1 is mainly in the cytoplasm or endoplasmic reticulum, whereas COX-2 is located perinuclear and in the endoplasmic reticulum.

COX-2 causes the synthesis of PG, which causes inflammation, mitogenesis, cell proliferation, and destruction. The powerful inducers of COX-2 activity are IL-1, TNF, epidermal and thrombocyte growth factors, and others, ie, those biologically active factors that play a part in the development of inflammation.

Recently, data on the significant role of COX-2 in the development of hyperalgesia appeared. According to generalized data, COG-2 mRNA is able to be induced in the spinal cord after the development of peripheral inflammation. According to the Institute of Rheumatology RAMS, with peripheral inflammation in the cerebrospinal fluid, the level of PG highly sensitive to COX-2 depression increases. Recent studies have demonstrated that COX-2 is a natural (constitutive) enzyme expressing itself in the spinal cord. Thus, COX-2 induces all areas of pain transmission-local, spinal and central.

Thus, the results of recent studies "erase" the clear distinction between COX-1 and COX-2 as constitutive and inducible, as well as physiological and pathological enzymes. Obviously, both isoforms in some tissues can induce inflammation, while in others it can maintain the normal function of cells.

According to the latest data, there may be another isoform - COX-3. Investigating the effects of COX inhibitors in laboratory rats with experimental pleurisy for 48 hours after stimulus injection, the authors found that selective COX-2 inhibitors, as well as non-selective COX inhibitors (eg, indomethacin), exhibit anti-inflammatory activity at the onset of the inflammatory response, which coincides with expression COX-2 protein. However, after 6 hours, selective inhibitors of COX-2 ceased to act, while non-selective inhibitors continued to act. At this time, COX-2 protein expression was not observed. The most surprising was the fact that after 48 hours, when the inflammatory process was almost completely resolved, the expression of COX-2 appeared again. This COX-2 protein did not induce the synthesis of pro-inflammatory PGE _{2 in} either the ex vivo experiment with exogenous arachidonic acid or in vivo. On the contrary, at this time, the production of in vivo anti-inflammatory GHG (PGO ₂ and PGR ₂ ), as well as a representative of the family of cyclopentenones (Shokhod D ¹²¹⁴ PP ₂ ) was observed .

The inhibition of a new COX isoenzyme by selective and nonselective COX-2 inhibitors between 24 hours and 48 hours after the administration of the stimulus led to the fact that the inflammation was not resolved (as in untreated animals), but persisted. According to DA Willoughby and co-authors (2000), the described phenomenon is the third isoform of COX-COX-3, which unlike the first two causes the formation of anti-inflammatory prostanoids.

It has been shown that NSAIDs inhibit the activity of both isoforms of COX, but their anti-inflammatory activity is associated with COX-2 depression.

After studying the three-dimensional structure of COX-1 and COX-2, it appears that the isoforms differ from each other mainly by the structure of the binding zone with the substrate-arachidonic acid. The active zone of COX-2 is larger than that of COX-1, and it has a secondary internal pocket, which plays an important role, since by providing the pharmacological agent with a "tail" complementary to this pocket, it is possible to obtain a drug whose dimensions are too large for the core COX-1, but the shape corresponds to the COX-2 core.

Most known NSAIDs suppress primarily the activity of COX-1, which explains the occurrence of such complications as gastropathy, impaired renal function, platelet aggregation, encephalopathy, hepatotoxicity,

NSAID-induced side effects can occur wherever PG is produced, most often in the digestive system, kidneys, liver, blood system. In the elderly, some changes (a decrease in the production of hydrochloric acid in the stomach, the mobility of the wall of the stomach and intestine and blood flow in it, the mass of the cells of the mucous membrane, a decrease in renal plasma flow, glomerular filtration, the function of the tubules, a decrease in the total volume of water in the body, blood plasma, reduction of cardiac output) contribute to an increased risk of developing side effects of NSAIDs. Simultaneous intake of drugs from several groups (especially glucocorticoids), the presence of concomitant pathology ( cardiovascular disease, kidney, liver, bronchial asthma) also increase the risk of toxicity development of NSAIDs.

The results of the studies indicate the appearance of symptoms on the part of the digestive tract in 30% of people taking NSAIDs. Among elderly patients taking NSAIDs, the incidence of hospitalization due to the development of peptic ulcers was 4 times higher than that of people of the same age group who did not take NSAIDs. According to Arthritis, Rheumatism, and the Aging Medical Information System (ARAMIS), y 733 1000 patients with osteoarthritis taking NSAIDs for 1 year, serious complications from the digestive tract were noted. In the USA, among patients with rheumatoid arthritis and osteoarthrosis, there are 16.5 thousand deaths due to NSAID intake, which is comparable to AIDS mortality and significantly exceeds the death rate from Hodgkin's lymphoma, cervical cancer, myeloma or bronchial asthma. A meta-analysis of 16 controlled studies revealed that the relative risk of serious side effects (those leading to hospitalization or death) from the digestive tract in people taking NSAIDs was 3 times higher than that of non-NSAIDs. According to the results of this meta-analysis, the risk factors for the occurrence of severe side effects were age over 60 years, diseases of the digestive system (gastritis, peptic ulcer) in an anamnesis, concomitant reception of SCS; The highest risk of adverse reactions from the digestive system was noted in the first three months of treatment.

Adverse Effects of NSAIDs

Side effects from the digestive tract include functional disorders, esophagitis, esophageal stricture, gastritis, mucosal erosion, ulcers, perforation, gastrointestinal bleeding, lethal outcome. In addition to the well-known effects of NSAIDs on the mucous membrane of the stomach and duodenum, there is increasing evidence of the development of side effects against the mucosa of both the small and large intestine. NSAID-induced enteropathies were described, which were accompanied by the formation of strictures of the small and large intestines, ulcers, perforation, atrophy of the villi of the mucous membrane. SE Gabriel et al. (1991) described impaired intestinal wall permeability in patients taking NSAIDs.

According to endoscopic studies, NSAIDs can cause erosion and hemorrhage in the submucosal layer in any part of the digestive tract, but most often in the stomach in the prepiloric department and antrum. In most cases, erosive and ulcerative complications of therapy with NSAIDs are asymptomatic.

Recently, in a number of studies, it has been established that only the inhibition of COX-1 can not explain the mechanism of the formation of NSAID-induced ulcers. Important is the direct damaging effect of NSAIDs on the cells of the gastric mucosa with mitochondrial damage and the disturbance of oxidative phosphorylation, which in turn disrupts the energy processes in the cell. It is possible that the formation of ulcers requires the presence of two factors - oppression of COX-1 and the disturbance of oxidative phosphorylation. Therefore, probably, flurbiprofen and nabumetone - drugs that do not violate oxidative phosphorylation, are better tolerated in comparison with other nonselective NSAIDs.

With the continued use of NSAIDs, the development of side effects depends on the dosing and duration of therapy. Admission of NSAIDs for 3 months causes side effects on the part of the digestive tract in 1-2% of patients, during the year - in 2-5%.

Currently, the possible role of Helicobacter pylori in the development of NSAID-induced side effects from the digestive system is discussed . It is known that 95% of patients with peptic ulcer of the duodenum are infected with Helicobacter pylori, while in the majority of cases, NSAID-induced side effects develop in the gastric mucosa where the infection rate is 60-80%. In addition, the mechanism of damage to the mucosa of the digestive tract Helicobacter pylori is not associated with the synthesis of PG. Nevertheless, there is evidence that NSAIDs play a role in the recurrence of ulcers, so patients with a history of peptic ulcer are at a risk of developing side effects in the therapy of NSAIDs. It is currently unknown whether the eradication of Helicobacter / ry / ori reduces the risk of side effects from the digestive system in patients receiving NSAIDs.

NSAIDs can cause kidney side effects, including acute renal failure / prenatal azotemia, renal vasoconstriction, allergic interstitial nephritis, nephrotic syndrome, hyperkalemic / hypoeninemic hypoaldosteronism, sodium and water retention, resistance to diuretic treatment, hyponatremia. However, epidemiological studies indicate a low risk of developing kidney dysfunction under the influence of NSAIDs.

Risk factors for the development of side effects from the kidneys in patients taking NSAIDs.

• Presence of kidney pathology
• Diabetes
• Arterial hypertension
• Congestive heart failure
• Cirrhosis of the liver
• Reduction of the volume of circulating blood (diuretics, sweating)

Nephrotoxicity of NSAIDs is realized by two mechanisms - oppression of synthesis of PG and idiosyncrasy to NSAIDs. In conditions of normal perfusion, the kidneys do not produce GHG, so there are no side effects when using NSAIDs. Reduction of renal perfusion (with CRF and CHF, dehydration, liver disease, in old age) is accompanied by the production of PGE ₂ and PP ₂. These PGs induce local vasodilation to maintain normal glomerular blood flow, and also stimulate diuresis, natriuresis and release of renin. If such a patient takes NSAIDs, he has decreased renal blood flow and glomerular filtration, increased secretion of antidiuretic hormone, sodium chloride and water retention, suppressed the release of renin. There is a state of giporeninemic hypoalldosteronism, possibly the development of acute renal failure. Inhibition of NSAIDs COX can also lead to hyperkalemia, especially in patients with concomitant diseases, primarily diabetes mellitus, as well as to leveling the effects of diuretic and antihypertensive therapy.

Allergic interstitial nephritis is a manifestation of idiosyncrasy to NSAIDs, accompanied by fever, skin rashes and eosinophilia, occurs 1-2 weeks after the initiation of NSAID therapy and undergoes reverse development when they are withdrawn. Other manifestations of idiosyncrasy to NSAIDs include lipoid nephrosis and papillary necrosis.

Despite the fact that hepatotoxicity is a rare manifestation of NSAID intolerance, the incidence of this side effect varies with the use of different drugs of this group. Thus, liver damage when taking acetylsalicylic acid depends on the dose of the drug and on the disease - with systemic lupus erythematosus and juvenile rheumatoid arthritis, hepatotoxicity develops more often than with other diseases. Hepatopathy caused by the use of acetylsalicylic acid, often occurs asymptomatically, rarely leads to the development of chronic hepatic insufficiency and very rarely - to a lethal outcome.

[1], [2], [3], [4]

Types of NSAID-induced liver damage

Hepatocellular	Cholestatic	Mixed
Acetylsalicylic acid Diclofenac Ibuprofen	Benoxaprofen Nabumeton	Sulindak Piroxicam Naproxen

In addition, there were data on liver damage with nimesulide.

Most patients taking this class of drugs are among the elderly who need constant prevention of acute cardiovascular events. Based on an analysis of 181,441 case histories, WA Ray and co-authors (2002) concluded that despite the combined blocking of COX-1 and COX-2, non-selective NSAIDs do not have cardioprotective effects (unlike low-dose acetylsalicylic acid) they can be prescribed together with acetylsalicylic acid. For example, ibuprofen blocks the inhibitory effect of low doses of acetylsalicylic acid on thromboxane release and platelet aggregation, and more slowly acting diclofenac has delayed similar effects and therefore is better combined with acetylsalicylic acid. At the same time, it was found that coxibs and paracetamol do not compete with acetylsalicylic acid in low doses with respect to the disaggregation function. However, acetylsalicylic acid can worsen the tolerability of NSAIDs, as demonstrated in the CLASS study. Thus, when choosing NSAIDs for patients receiving acetylsalicylic acid in low doses, it is necessary to take into account the nature of their interaction.

NSAIDs causing side effects on the part of the liver

Rarely	Ibuprofen
	Indomethacin
	Naproxen
	Oxaprozin
	Piroxicam
Rarely	Diclofenac
	Phenylbutazone
	Sulindak

In recent years, the problem of the interaction of NSAIDs and antihypertensive drugs, as well as the use of NSAIDs in hypertension, has become topical. It is known that in connection with the suppression of COX-1, which is necessary to maintain many physiological functions, including renal circulation, NSAIDs can neutralize the effect of many antihypertensive agents, especially ACE inhibitors and beta-adrenoreceptor blockers. In addition, the effect of specific inhibitors of COX-2 on the cardiovascular system has not been adequately studied. In a randomized comparative study of the use of celecoxib (200 mg / day) and rofecoxib (25 mg / day) in more than 800 patients with osteoarthritis who received antihypertensive therapy for essential hypertension, A. Welton et al (2001) found that systolic blood pressure increased in 17% of patients taking rofecoxib, and 11% of those taking celecoxib, and diastolic BP - in 2.3 and 1.5%, respectively. After 6 weeks of treatment in patients receiving rofecoxib, systolic blood pressure increased by an average of 2.5 mm Hg. Art. Compared with the initial, and in the group of patients taking celecoxib, even decreased by 0.5 mm Hg. Art. The authors concluded about the compatibility of coxibs and hypotensive drugs, but the tolerability of celecoxib was better - less edematous syndrome and destabilization of BP. Almost half of the patients in both groups of antihypertensive drugs received diuretics, ACE inhibitors, calcium antagonists, beta-adrenoreceptor blockers in the form of monotherapy, the remaining patients in each group (48.5 and 44.9%, respectively, celecoxib and rofecoxib) received combination therapy and more than a third (37.9 and 37.1%) in each group - acetylsalicylic acid in low doses. Thus, the results of this study indicate the compatibility of specific inhibitors of COX-2 celecoxib and rofecoxib with various antihypertensive drugs or their combinations, as well as a combination with acetylsalicylic acid in the presence of a risk of thrombosis.

In addition to mediated PG, NSAIDs also have other effects that are not associated with PG and COX. Among them - a direct impact on various processes in cells and cell membranes. Thus, NSAIDs inhibit the activation and chemotaxis of neutrophilic granulocytes, reduce the production of free oxygen radicals in them. As lipophilic substances, NSAIDs are embedded in the lipid bilayer of cell membranes and, thereby preventing interaction between proteins, inhibit signal transmission. Some NSAIDs in vitro inhibit the ingress of phagocytes into the inflammation zone.

Along with inhibition of GH synthesis, there are data on other mechanisms of analgesic activity of NSAIDs. These include: central opioid-like antinociceptive action: blockade of NMDA-receptors (an increase in the synthesis of kynurenic acid), a change in the conformation of the a-subunits of the G protein, suppression of afferent pain signals (neurokinins, glutamic acid), an increase in 5-hydroxytryptamine content. Data on the dissociation between anti-inflammatory (COX-dependent) and analgesic (antinociceptive) effects of NSAIDs indirectly testify to the existence of PG-independent mechanisms.

Classification of NSAIDs

A number of NSAIDs affect the synthesis of proteoglycans by chondrocytes in vitro. JT Dinger and M. Parker (1997) proposed the classification of NSAIDs based on their effect in vitro on the synthesis of matrix components of cartilage in osteoarthritis:

inhibitory:

• indomethacin,
• naproxen,
• ibuprofen,
• nimesulide,

neutral:

• piroxicam,
• nabumethon,

stimulating:

• shadyap,
• aceclofenac.

However, the extrapolation of the results of such studies to the human body is questionable. GJ Carrol and co-authors (1992) performed monthly aspiration of articular fluid from the knee joints in 20 patients with osteoarthrosis who took piroxicam and found a slight decrease in the concentration of keratan sulfate. Despite the fact that the results obtained may indicate a decrease in the catabolism of proteoglycans, as the authors emphasize, other interpretations are possible.

Salicylates inhibit the activity of phospholipase C in macrophages. Some NSAIDs in vitro inhibit the production of rheumatoid factor, prevent the adhesion of neutrophilic granulocytes to endotheliocytes and reduce the expression of L-selectins, thereby inhibiting the migration of granulocytes to the inflammation zone.

Another important non-GHG-related biological effect of NSAIDs is the effect on the metabolism of nitric oxide. Thus, NSAIDs inhibit NF-kV-dependent transcription, which leads to blockage of inducible NO-synthase. The latter, induced by pro-inflammatory cytokines, produces a large amount of NO, which leads to increased signs of inflammation-hyperemia, increased vascular permeability, etc. Acetylsalicylic acid in therapeutic doses depresses the expression of inducible NO synthase and subsequent production of NO.

Thus, depending on the nature of the blocking of COX, NSAIDs are divided into selective and nonselective COX inhibitors. Selective inhibitors of COX-2 have a smaller spectrum of side effects and better tolerability. Relative selectivity NSAIDs for each isomer is defined as the ratio of COX-2 / COX-1 and 1C is calculated from the indicator ₅₀ of the drug for both isoforms that expresses the drug concentration which inhibits PG synthesis by 50%. The selectivity coefficient below 1 indicates relative selectivity to COX-2, while the coefficient above 1 is relative selectivity to COX-1.

Classification of NSAIDs depending on their ability to selectively block the activity of COX-1 or COX-2

Selective inhibitors of COX-1	Inhibitors of COX-1 and COX-2	Selective inhibitors of COX-2	Highly selective COX-2 inhibitors
Acetyl-salicylic acid in low doses	Most NSAIDs	Meloksikam Nabumeton Eto-dolac Nimesulide	Celecoxib Rofecoxib Phosolide

To determine the COX-selectivity of NSAIDs, various experimental models are used. It should be noted that direct comparison of the results of selectivity studies of NSAIDs obtained in different laboratories is impossible, since 1C ₅₀ and the COG-2 / COG-1 ratio vary greatly even when using the same technique. Such variability may depend on the type of cells used as a model, the type of enzyme preparation, the incubation time with NSAIDs, the method of inducing COX-2, the protein content in the nutrient medium, etc. For example, nabumetone exhibits COX-2-selective properties in the model , using a mouse enzyme in microsomal membranes, but its COX-2 selectivity is not sufficient to demonstrate it on human enzyme models in cell or microsomal membranes or human blood cells ex vivo (Patrignani P. Etal., 1994).

Thus, to more correctly assess the selectivity of NSAIDs, it is necessary that the results are confirmed on several models. The most revealing were studies using human blood cells. Although the absolute value may vary, the order of the COX-2 / COX-1 ratio is generally the same when the compounds are examined in several ways.

Non-selective COX inhibitors have not lost their relevance due to their high anti-inflammatory activity, pronounced analgesic effect, but their use is associated with a greater probability of developing side effects.

There are several tens of NSAIDs, similar in chemical, pharmacological properties and mechanism of action.

To date, there is no clear evidence of the superiority of one NSAID over another in effectiveness. Even if, according to the multicenter study, the advantages of the drug in this group are revealed, this is often not confirmed in routine clinical practice. However, it is realistic to assess and compare the tolerability of NSAIDs. Safety is the main feature by which the drugs of this group differ.

In a multicenter study, The LINK Study, it was demonstrated that prolonged use of indomethacin results in a 2-fold increase in joint cartilage loss compared with placebo. Hepatotoxicity is more often observed with diclofenac treatment. Aseptic meningitis is a rare but severe side reaction to taking ibuprofen and sulindac. Cystitis is a complication that is observed with tiaprofenic acid; Alveolitis can be induced by naproxen, indomethacin causes drowsiness. Changes in the blood formula, as well as various skin rashes can occasionally occur when all NSAIDs are taken. According to N. Bateman (1994), among unselective NSAIDs, ibuprofen and diclofenac are most safe, and the most toxic are piroxicam and azaprope. However, D. Henry and co-authors (1996) determined that the tolerability of ibuprofen in high doses did not differ from that of naproxen and indomethacin. At the same time, the efficacy and safety of derivatives of propionic acid served as the basis for the production of OTC forms of these drugs (ibuprofen, ketoprofen and naproxen), which are widely used to relieve pain of various etiologies.

[5], [6], [7], [8], [9], [10], [11], [12]

Classification of NSAIDs by chemical structure

I. Derivatives of acids
Arylcarboxylic acids
A. Salicylic acid derivatives (salicylates)	B. The derivatives of anthranilic acid (fenamates)
Acetylsalicylic acid	Flufenamic acid
Diflunisal	Mephenamic acid
Trisalicylate	MEKLOFENAMIC ACID
Benorylate	Niflumic acid
Sodium salicylate	Toxic acid
Arylalkanoic acids
A. Derivatives of arylacetic acid	B. Derivatives of heteroarylacetic acid
Diclofenac	Tolmetin
Fenclofenac	Zomepirac
Alclofenac	Klooperak
Fentianzac	Ketorolac
B. Indole / indoleacetic acid derivatives	D. Derivatives of arylpropionic acid
Indomethacin	Ibuprofen
Sulindak	Flurbiprofen
Eto-dolac	Ketoprofen
Acetecacin	Naproxen
	Fenoprofen
	Fenbufen
	Siprofen
	Indoprofen
	Acid tiaprofenic
	Pirprofen
Enolik acids
A. Pyrazolone derivatives of pyrazolidinediones)	B. Oksikamy
Phenylbutazone	Piroxicam
Oxyphenbutazone	Sudoxicam
Azaprospan	Meloksikam
Feprasone	Feprasone
II. Non-acid derivatives
Flourproquasone	Proquasone
Flumisole	Tiaramid
Tinoridine	Bufexamak
Colchicine	Epyrisol
Nabumeton	Nimesulide
III. Combined preparations
Diclofenac + misoprostol
Phenylbutazone + dexamethasone, etc.

Since serious side effects on the part of the digestive system are caused by NSAIDs, dose-dependent medication is prescribed, a COX-nonselective NSAID should be administered to a patient with osteoarthritis to relieve pain in a low, i.e., "analgesic" dose that can be raised to "anti-inflammatory ", If the first one turned out to be ineffective. Patients at risk of COX-nonselective NSAIDs, even in low doses, should be prescribed in combination with gastroprotectors.

In a 6-month, placebo-controlled clinical trial of MUCOSA (Misoprostol Ulcer Complications Outcomes Safety Assessment), the addition of a synthetic analogue of Mesoprostol (800 μg / day) to NSAIDs led to a 40% reduction in the incidence of serious side effects on the digestive system compared to placebo. In spite of the large number of patients examined (about 9,000,000), the decrease with the use of misoprostol of the risk of side effects hardly reached statistical significance (p = 0.049). Moreover, the use of misoprostol was associated with other dose-related side effects, in particular with diarrhea. Misoprostol in a dose of 400 mcg / day was better tolerated than at a dose of 800 mcg / day, but according to fibrogastroscopy it was less likely to cause a gastroprotective effect.

As an alternative to misoprostol, it is advisable to use H ₂ -receptor antagonists (eg, famotidine) or proton pump blockers (eg, omeprazole). Both groups of drugs demonstrated efficacy in the treatment and prevention of NSAID-induced ulcers in studies using fibrogastroscopy. However, at normal therapeutic doses, H ₂ antagonists were less effective than misoprostol, whereas omeprazole was not inferior in effectiveness to the treatment of NSAID-induced ulcers, was better tolerated, and was characterized by a lower relapse rate.

Meloxicam is a selective inhibitor of COX-2. The safety of meloxicam in vivo and its effectiveness in patients with osteoarthritis is noted in numerous publications.

The main objective of the multicenter, prospective, double-blind, randomized study of the MEloxicam Large-scale International Study Safety Assessment (MELISSA) was to study the tolerability of meloxicam (in Ukraine, the Mohvalis drug from Boehringer Ingelheim was registered and used) in large, relatively nonrandomized patient groups and supplement the data obtained in other studies in more limited settings (Hawkey C. Et al., 1998). As a comparator, diclofenac, a drug with a relatively low level of toxicity with respect to the digestive tract, was chosen. Based on the results of studies by M. Distel et al. (1996) and J. Hosie et al. (1996), a dose of meloxicam 7.5 mg / day was recommended for use in a short course with exacerbation of osteoarthritis symptoms. The study included 10,051 patients with osteoarthritis who were divided into three groups depending on the treatment received (meloxicam 7.5 mg / day, diclofenac dosage form with modified release of the active substance 100 mg / day or placebo for 28 days) . In the group of patients receiving meloxicam, significantly less side effects from the digestive system were registered than in patients treated with diclofenac (Figure 99). In the meloxicam group in 5, and in the diclofenac group, 7 patients had serious side effects (ulcerogenic effect, ulcer perforation, gastrointestinal bleeding) (p> 0.05). Endoscopically, 4 patients who received diclofenac were found to have ulceration complications, while no meloxicam group was found. In the meloxicam group, the total duration of hospitalization due to the development of side effects was 5 days, while in the diclofenac group, 121 days. Among those who refused treatment in this regard, 254 (5.48%) patients were taken meloxicam and 373 patients (7.96%) - diclofenac (p <0.001). Adverse events on the part of the digestive tract were the reason for patients' refusal to continue treatment in 3.02% of cases in the meloxicam group and in 6.14% of cases in the diclofenac group (p <0.001). However, a significantly greater number of patients receiving meloxicam withdrew from further treatment due to inadequate efficacy (80 of 4635 in the meloxicam group and 49 of 4688 in the diclofenac group, p <0.01). In the group of patients taking diclofenac, also noted a more pronounced positive dynamics for YOUR pain than in the meloxicam group. Thus, the results of the study suggest that the tolerability profile of meloxicam is significantly better than other NSAIDs, including diclofenac, which may be due to COX-2-selectivity, as well as other causes (eg, dose).

Meta-analysis of the results of 10 randomized comparative studies of the efficacy and / or tolerability of meloxicam in doses of 7.5 mg / day and 15 mg / day and reference NSAIDs (piroxicam 20 mg / day, diclofenac 100 mg / day, naproxen 750 mg / day) showed that the former caused significantly fewer side effects than reference NSAIDs (relative ratio - OS - 0.64, 95% CI 0.59-0.69) (Schoenfeld P., 1999). In particular, in patients taking meloxicam, less ulcerogenic effect, perforation of the ulcer and gastrointestinal bleeding (OC = 0.52.95% CI 0.28-0.96), they rarely refused further treatment in connection with the development side effects (OC = 0.59, 95% CI 0.52-0.67), as well as less complained of dyspepsia (OC = 0.73.95% CI 0.64-0.84).

Nimesulide is an NSAID that chemically differs from other members of this class in the absence of acidic properties. Nimesulide is a representative of a relatively new group of sulfonanilide derivatives (Bennett A., 1996). Interestingly, initially nimesulide was characterized as a weak COX inhibitor, which was found in various in vitro studies. It was assumed that for nimesulide, the "non-staglandin" mechanism is more important. According to JR Vane and RM Boning (1996), the selectivity of nimesulide, determined in vitro using a system of intact cells, is 0.1.

Pharmacokinetics of the drug is associated not only with its selectivity for COX-2, but also with the peculiarity of its chemical structure (unlike other NSAIDs, nimesulide has weak acid properties) and half-life (nimesulide 1.5-5 h, piroxicam - about 2 days).

Blocking the enzyme phosphodiesterase IV also causes other positive effects of nimesulide:

• oppression of the production of free oxygen radicals,
• blocking of metalloproteases (stromelysin (proteoglycanase) and collagenase)
• antihistamine effect.

The results of numerous studies indicate the high effectiveness and safety of nimesulide in patients with osteoarthritis. In a double-blind, placebo-controlled trial, P. Blardi and co-authors (1991) studied the efficacy of nimesulide in 40 patients with "osteoarthrosis of various localizations" and found the advantage of nimesulide in reducing joint pain and morning stiffness. In another study with a similar design, RL Dreiser and co-authors (1991) found a significant advantage of nimesulide compared to placebo in the treatment of 60 patients with osteoarthrosis of the knee joints for 2 weeks according to YOUR pain and API Leken, with the incidence of side effects in the group of patients , who received the drug, did not exceed that in the placebo group.

In Table. The results of controlled studies that compare the efficacy and safety of nimesulide with reference NSAIDs are summarized. The duration of treatment during these studies ranged from 3 weeks to 6 months, nimesulide and comparators were prescribed at therapeutic doses, with the exception of a study conducted by V. Fossaluzza et al. (1989), in which the daily dose of naproxen (500 mg) was clearly inadequate.

Celecoxib is the first representative of a group of coxibs - specific inhibitors of COX-2. The drug meets all the criteria of COX-2-specific NSAIDs - inhibits COX-2 in vitro and in vivo, exhibits anti-inflammatory and analgesic activity in humans, the dose required to suppress GH synthesis in the stomach and platelet aggregation disorders in vivo is many times higher therapeutic. To inhibit the activity of COX-1, the concentration of celecoxib should be 375 times greater than that of COX-2 activity.

One of the first large comparative studies of the effectiveness of celecoxib (in Ukraine the preparation Celebreks was registered, which is jointly promoted by Pfizen and Pharmacia Corp.) was a study conducted by L. Simon and co-authors (1999), in which 1,149 patients with osteoarthritis divided into several groups: celecoxib 100, 200 and 400 mg twice a day (240,235 and 218 patients respectively), naproxen 500 mg twice a day (225 patients) and placebo (213 patients). The efficacy of both drugs was significantly higher than placebo. The incidence of ulcers in the gastrointestinal mucosa in the placebo group was 4%, it did not differ from that in patients receiving celecoxib (at a dose of 100 mg twice a day - 6%, at a dose of 200 mg twice a day - 4% , in a dose of 400 mg twice a day - 6%, p> 0.05 in all cases). The incidence of digestive tract injury in patients receiving naproxen was significantly higher - 26% (p <0.001 compared with placebo and all doses of celecoxib).

CLASS ( The Celecoxib Long-Term Arthritis Safety Study) is a multicenter (386-center) controlled double-blind randomized study of the tolerability of celecoxib in 8059 patients with osteoarthritis and rheumatoid arthritis. The study drug was administered at a dose of 400 mg 2 or 4 times a day, i.e. At a dose 2 or 4 times higher than the FDA allowed for patients with rheumatoid arthritis and osteoarthritis, while comparators were prescribed in therapeutic doses: ibuprofen in dose 800 mg 3 times a day and diclofenac at a dose of 75 mg 2 times a day. In addition, for the prevention of acute cardiovascular events, admission of acetylsalicylic acid in a dose of less than 325 mg / day. The results of the study indicate that the incidence of side effects from the upper gastrointestinal tract with celecoxib at a dose that is 2-4 times higher than the maximum therapeutic dose within 6 months is less than with the use of reference drugs (ibuprofen and diclofenac) in standard therapeutic doses. In patients taking NSAIDs, symptomatic ulcers of the upper gastrointestinal tract and their complications (perforation, stenosis, bleeding) were observed more often than in the treatment with celecoxib - in the celecoxib group the incidence of these side effects was 2.08%, in the group of comparison drugs - 3.54% (p = 0.02). A more detailed statistical analysis revealed the absence of significant differences in the incidence of gastric and duodenal ulcer complications between the study groups (0.76 and 1.45%, respectively, p = 0.09). According to the authors, this was due to the intake of a part of patients (> 20%) of acetylsalicylic acid - among this category of patients the incidence of complications of peptic ulcers in the groups of celecoxib and comparators was respectively 2.01 and 2.12% (p = 0.92) , the frequency of symptomatic ulcers and their complications - respectively 4.7 and 6% (p = 0.49). At the same time, a statistically significant difference in the incidence of complications of peptic ulcers between the groups of celebrex (0.44%) and NSAIDs (1.27%, p = 0.04) was found in patients who did not take acetylsalicylic acid, as well as the incidence of symptomatic ulcers and their complications (1.4 and 2.91%, respectively, p = 0.02). However, the incidence of side effects from the cardiovascular system in the celecoxib and NSAID groups was the same regardless of acetylsalicylic acid intake. Thus, according to the CLASS study, for celecoxib, in doses exceeding the therapeutic dose, a lower incidence of symptomatic ulcers of the upper gastrointestinal tract is associated with NSAIDs in standard doses. Concomitant therapy with acetylsalicylic acid in low doses led to a worsening of the tolerability of celecoxib in patients with osteoarthritis and rheumatoid arthritis.

Given that celecoxib does not inhibit platelet COX-1 and therefore, unlike nonselective NSAIDs, does not affect platelet aggregation, the issue of a possible increase in the frequency of cardiovascular disasters caused by hypercoagulability (infarction cardiovascular disease, stroke), previously described in patients taking another specific inhibitor of COX-2 - rofecoxib. However, in the analysis of a database that included more than 13,000 patients treated with celecoxib and the results of the CLASS study in patients with OA and RA, there was no increase in the incidence of these complications.

The aim of another double-blind, placebo-controlled, randomized trial was to compare the efficacy and tolerability of celecoxib 200 mg / day and diclofenac 150 mg / day in 600 patients with knee OA. The dynamics of the primary efficacy criteria (VASH and WOMAC) against the background of therapy with celecoxib and diclofenac for 6 weeks was more pronounced than in the placebo group. At the same time, there was no statistically significant difference in efficacy between those receiving celebrex and diclofenac. In 51% of patients, side effects were observed (in the placebo group - in 50%, in the celecoxib group - in 50% and in the diclofenac group - in 54% of cases).

The appearance of peripheral edema, flatulence and myalgia was more often noted in the celecoxib and diclofenac groups than in the placebo group: Other side effects were equally common in patients taking celecoxib and placebo. In patients taking diclofenac, side effects from the digestive system were recorded more frequently than in the celecoxib and placebo groups (25, 19 and 18%, respectively), among them dyspepsia, diarrhea, abdominal pain, nausea and constipation. In addition, a statistically significant increase in the level of hepatic transaminases, serum creatinine and a decrease in hemoglobin concentration in comparison with placebo was observed in the diclofenac group. In the celecoxib group, no such phenomena have been identified. It can be concluded that the efficacy of celecoxib 200 mg / day in reducing the symptoms of osteoarthritis of the knee is equivalent to that of diclofenac 150 mg / day, but celecoxib is superior in safety and tolerability.

Recent studies suggesting COX-2 participation in normal kidney development during embryogenesis and maintenance of electrolyte balance require a deeper study of the nephrologic and cardiovascular side effects of celecoxib. In addition, data have been obtained on the reduction of the hypotensive effect of angiotensin converting enzyme (ACE) inhibitors by another specific inhibitor of COX-2, with rofecoxib, and a dose-related increase in arterial pressure and the development of peripheral edema. Therefore, the data of A. Whelton and co-authors (2000), which analyzed the results of 50 clinical trials involving more than 13 000 patients, about 5000 of whom took celecoxib for at least 2 years, are of particular interest.

The most common side effects were peripheral edema (2.1%), arterial hypertension (0.8%), but their development did not depend on the dose and duration of treatment. In general, the frequency of peripheral edema in patients receiving celecoxib did not differ from that in placebo-treated patients and was lower than with nonselective NSAIDs. The development of edema did not lead to an increase in body weight or an increase in blood pressure, either in the group as a whole or in patients with risk factors for this complication, such as those receiving diuretic therapy. There were no negative drug interactions of celecoxib with beta-adrenergic blockers, calcium channel blockers, ACE inhibitors and diuretics. All these data convincingly show that celecoxib not only has a favorable safety profile for the digestive tract, but also is well tolerated by patients with a high risk of NSAID-induced kidney damage and cardiovascular pathology. Thus, the development of nephrologic and cardiovascular side effects is not a specific property of the class of COX-2 inhibitors and is probably associated with idiosyncrasy on rofecoxib or its metabolites.

Preliminary analysis showed the pharmacoeconomic benefits of celecoxib compared to nonselective NSAIDs in patients at risk of developing NSAID-induced severe complications from the digestive tract, taking into account the costs of their prevention (use of misoprostol or omeprazole). For example, in patients with RA without the risk of developing NSAID-gastropathy, the incidence of these complications is 0.4%. Assuming that celecoxib reduces the incidence of this complication by 50%, one complication will be prevented in only 1 out of every 500 patients. At the same time, in elderly patients with a 5% risk of NSAID-induced complications, celecoxib treatment can prevent their development in 1 out of 40 patients. This served as the basis for the inclusion of COX-2 inhibitors (and primarily celecoxib) in the OA therapy standard in the United States (ACR, 2000).

The aim of our study was to optimize the quality of treatment based on the inclusion in the drug treatment complex of OA-COX-2 inhibitor celecoxib and to study its effect on the quality of life of patients.

15 patients with OA aged 49-65 years were examined, the average duration of the disease was 5.0 + 2.3 years. An obligatory criterion for inclusion in the study was the presence of knee joints. In 10 patients with OA, II radiographic stage was diagnosed, in 5 patients - III. The washing period for NSAIDs was at least 7 days before the start of the study. Patients with OA received celecoxib at a dose of 200 mg / day for 3 months.

To determine the effectiveness of therapy in patients with osteoarthritis, the Leken index, pain on VAS, the success of treatment in the opinion of the patient and the doctor were evaluated. All patients with osteoarthritis before and after the course of therapy underwent an ultrasonographic study of the knee joints on the SONOLINE Omnia (Siemens) with a 7.5L70 linear transducer (frequency 7.5 MHz) in the ortho mode in the longitudinal and transverse planes. During ultrasound, a layer-by-layer evaluation of the joint capsule and its synovial membrane, as well as synovial fluid, hyaline cartilage, epiphyses of bones and periarticular tissues was performed.

The quality of life was assessed using the SF-36 questionnaire.

In patients with OA on the background of therapy with celecoxib, the severity of pain by VAS decreased by 54%, the Leken index by 51%. Patients evaluated the effectiveness of celecoxib treatment as very good and good (9 and 6 people respectively).

According to the analysis of SF-36 scales, the effect of the disease on the emotional state, physical functions and mental health of patients is not very significant. A large number of positive responses to treatment were noted.

The tolerability of treatment is assessed as good and very good by both the doctor and the patients. Nausea was observed in 1 patient, 2 - pain in the epigastric region and right upper quadrant, in 1 - visual acuity reduction (there were no objective changes in the examination of the ophthalmologist).

All the side effects disappeared on their own and did not require the cancellation or reduction of the dose of the drug.

In 85% of patients with osteoarthritis, the proposed scheme of therapy allowed to completely stop the pain, and the previously noted synovitis (according to the clinical examination, ultrasound) was not found in any of the patients.

Under the influence of complex therapy, the majority of quality of life indicators and especially daily activity and emotional state significantly improved in patients.

Another representative of the coxib group is rofecoxib. In a series of clinical studies, the efficacy of rofecoxib was established in patients with osteoarthritis (at a dose of 12.5 mg / day and 25 mg / day), rheumatoid arthritis (25 mg / day) and low back pain syndrome (25 mg / day). According to a double-blind, placebo-controlled randomized comparative study of the use of celecoxib at a dose of 200 mg / day (63 patients with knee osteoarthritis) and rofecoxib 25 mg / day (59 patients with osteoarthrosis of the knee), after 6 weeks of statistically significant differences in the positive dynamics of the main efficacy criteria against the background of taking celecoxib and rofecoxib was not detected (p> 0.55), while the changes in the indices were significantly higher than in the placebo group (p <0.05). The total number of side effects in the celecoxib and rofecoxib groups was the same, however, in the former, side effects from the digestive tract were much less frequent, indicating better tolerability of celecoxib compared to rofecoxib in the doses studied.

[13], [14], [15], [16], [17], [18], [19], [20], [21]