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Previous Section Next Section Introduction Several, but not all, clinical studies have revealed an increased rate of cardiovascular complications after long-term use of coxibs such as rofecoxib, celecoxib, and valdecoxib, which are nonsteroidal anti-inflammatory drugs NSAIDs that selectively inhibit cyclooxygenase COX Despite significant variability of findings in these studies, the increased rates of myocardial infarction and stroke emerging from rofecoxib studies and cardiovascular complications found in celecoxib cancer prevention studies raise concerns about the cardiovascular safety of long-term treatment with coxibs, as well as traditional NSAIDs that inhibit both COX-1 and COX-2 [ 1 — 5 ].
Cyclooxygenase COX -2 expression is elevated at sites of inflammation such as in synovial tissues in rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis [ 6 ].
However, they can induce hemorrhage and severe gastrointestinal complications because they also inhibit COX-1, which has major roles in hemostasis and gastrointestinal cytoprotection [ 7 ].
Clinical trials have shown that coxibs have analgesic profiles similar to traditional NSAIDs, but are significantly less toxic to the gastrointestinal system.
They therefore widely replaced non-selective NSAIDs for treatment of inflammatory joint diseases and other painful inflammatory conditions [ 89 ]. The primary goal of this review is to elucidate osteoarthritis first metacarpophalangeal joint pathophysiology and molecular pathology of cardiovascular complications of NSAIDs, especially COXselective inhibitors such as coxibs.
A second goal is to highlight clinical factors and laboratory tests that may identify patients with increased risk of cardiovascular complications when using NSAIDs. A final goal is to identify potential pharmacological and other strategies for cardiovascular risk reduction.
The COX-2 isoform plays a major role in initiation of inflammatory alterations in response to injury. In addition, during later stages it may aid in repair and resolution of inflammation. It is inducible by inflammatory stimuli such as cytokines, growth factors, and bacterial endotoxin and is expressed in atherosclerotic lesions and in a variety of tumors.
COX-1 is constitutively expressed osteoarthritis first metacarpophalangeal joint most tissues where it regulates synthesis of physiological levels of prostaglandins. COX-2 is expressed in various normal tissues where its expression may be important for physiological functions such as cardioprotection associated with high-density lipoprotein and apolipoprotein E apoE [ 12 ] see osteoarthritis first metacarpophalangeal joint.
Interpretation of experimental and clinical findings is complicated further by dissimilar tissue distribution and altered expression of COX-1 and COX-2 in diseased tissues and by the observation that COX expression differs in different species [ térd porckopás gyógyítása ].
Because COX-1 and COX-2 have some adaptable overlapping functions, effects of their inhibition on the cardiovascular system remain complex and sometimes contentious [ 14 ]. Also important for interpretation of effects of NSAID inhibition, when immunohistochemistry is employed to determine COXprotein expression in normal, inflamed, or neoplastic tissues, is the fact that the results may depend on the antibody used [ 17 ]. COX-2 is induced in atherosclerotic plaques, during angiogenesis, and during wound healing [ 918 ].
In rabbits, experimental balloon injury and stent implantation induce expression of COX-2 in areas with atherosclerotic lesions. Normally, arteries at these anatomic locations express only COX-1 [ 19 ].
In addition, COX-2 is constitutively expressed in the macula densa and renal medullary interstitial cells [ 20 ]. Hyperkalemia can induce cardiac arrhythmia [ 21 ]. Moreover, COX-2 inhibition can increase kidney water retention, and induce peripheral edema and weight gain.
In animal models, selective inhibition of COX-2 promotes hypertension, atherogenesis, and formation of thrombi, all risk factors for acute myocardial infarction. Nevertheless, the exact pathogenesis of the increased rates of cardiovascular complications caused by coxibs is unclear at this point [ 24 ]. Smoking increases COX-2 expression that induces inflammation [ 25 ]. Chronic inflammatory processes play a major role in carcinogenesis and atherogenesis. The latter is a major risk factor for myocardial infarction [ 2627 ].
Inflammation plays a role in all stages of atherogenesis, from fatty streak development to plaque formation and plaque rupture [ 28 ]. The inflammatory features resemble the inflammatory alterations osteoarthritis first metacarpophalangeal joint in rheumatoid arthritis and artrózis diagnosztizálása hogyan kell kezelni. Rheumatoid arthritis is associated with accelerated atherosclerosis, high cardiac mortality, and shortened life expectancy.
As inhibition of COX-2 reduces inflammation, it was hoped that COXselective inhibitors, when used to reduce pain and inflammation in joint disease, might also inhibit atherogenesis and reduce the rates of myocardial infarction [ 29 ].
For reasons not entirely agreed upon, the opposite was observed in several, but not all, clinical studies associated with use of coxib inhibitors, particularly after long-term use, and in a few clinical studies on the use of traditional NSAIDs such as aspirin and naproxen.
Are cardiovascular complications caused by alterations in eicosanoid synthesis? Are they due to interference with mitochondrial function?
- Epidemiológia[ szerkesztés ] A reumatoid artritisz az egyik leggyakoribb autoimmun betegség, mely világszerte a lakosság kb.
- Glükózamin és kondroitin tabletta ára egy gyógyszertárban
Are both mechanisms involved? What is the effect of polymorphism of genes involved in eicosanoid synthesis on responses to NSAID therapy? Cyclooxygenase is rate-limiting for conversion of arachidonic acid to prostaglandin A depresszió fáj az ízületekről H2, which is converted to the important vasoactive eicosanoids thromboxane TXA2 and prostacyclin PGI2 by thromboxane synthase prostacyclin synthase respectively Fig.
The latter plays a key role in carrageenan-induced inflammation [ 30 ].
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View larger version: In a new window Fig. Less arachidonic acid AA is consumed. Mitochondrial dysfunction lowers cardiac contractility and is atherogenic.
Some important NSAID effects are cyclooxygenase independent, such as celecoxib regulation of expression of monocyte chemoattractive protein-1 MCP-1 that regulates monocyte chemotaxis 8. Polymorphism of CYP2C9 affects the rate of celecoxib degradation 9.
Leírás Joom: Az eladó által megadott bármely információ ellenére, ez a termék nem megfelelő a betegségek diagnosztizálására, gyógyítására, enyhítésére, kezelésére vagy megelőzésére. Nem egy étrendkiegészítő, gyógyszer, és nem kéne orvosi célokra használni. The product is built with a high elastic nylon plastic plate designed by the curve of the thumb, whichcompletely wraps and fixes the first metacarpophalangeal joint and the base of the thumb.
For details see text. Cyclooxygenase contains 2 active sites. The peroxidase activity is independent of the cyclooxygenase activity. Furthermore, in addition to PGG2, the peroxidase site can use hydroperoxides such as H2O2 as substrate and generate reactive oxygen species ROS [ 31 ]. NSAIDs can induce secondary effects by altering the size of the arachidonic acid pool, which depends on a dynamic balance between supply and consumption. Supply is determined by cytosolic c and soluble s phospholipase A2 PLA2which catalyse cleavage of fatty acids from membrane phospholipids [ 32 ].
Selective inhibition of COX-2 by coxibs, or selective inhibition of COX-1 by tenoxicam, increases the cellular arachidonic acid pool, which stimulates leukotriene synthesis by lipoxygenase LO. Furthermore, some NSAIDs also exert functions that are independent of cyclooxygenase inhibition, for example, many NSAIDs affect mitochondrial function, expression of cytokines, and growth factors [ 33 — 35 ].
First Metacarpal Bone
By comparison, valdecoxib 4-[5-methylphenyl-isoxazolyl]-benzene-sulfonamide [ 38 ], meloxicam 4-hydroxymethyl-N-[5-methylthiazolyl] -2H-1,2-benzothiazinecarboxamide-1,1 dioxideibuprofen 2- 4-isobtyl-phenyl -propionic acidnaproxen Dmethoxy-α-methylnaphthaleneacetic acidor diclofenac 2-[ 2,6-dichlorophenyl -amino-benzene-acetic acid exhibit no significant effect on LDL oxidation [ 3439 ].
Many, but not all, clinical studies show that aspirin significantly reduces the osteoarthritis first metacarpophalangeal joint of MI and stroke. Aspirin lowers cardiovascular risk by blocking platelet thromboxane synthesis and platelet aggregation.
Aspirin lowers the serum levels of C-reactive protein CRP [ 41 ] and lipoprotein L a Lp a [ 42 ], which are both independent risk factors a középső ujj artritisz kezelése atherosclerosis and myocardial infarction. Aspirin inhibits platelet COX-1 irreversibly, and since platelets lack nuclear DNA, neither additional COX-1 nor further basylkhan dyusupov ízületek kezelése can be synthesized by affected platelets.
Cardiovascular patients who are resistant to aspirin therapy have more than twice the rate of cardiovascular events, compared to aspirin-sensitive patients [ 45 ]. The altered hemostasis induced by aspirin and other traditional NSAIDs increases the risk of gastrointestinal hemorrhage, intestinal perforation [ 3 ], and excessive perioperative bleeding. Moreover, the inhibition of COX-1 lowers gastrointestinal synthesis of cytoprotective prostaglandins.
Surprisingly, in a clinical study designed to evaluate valdecoxib compared to aspirin, diclofenac, ibuprofen, and placebo, aspirin was associated with a higher risk of thrombotic events osteoarthritis first metacarpophalangeal joint placebo [ 50 ]. However, no increased risk of myocardial infarction was caused by simultaneous use of aspirin and ibuprofen [ 51 ].
In experimental models coxibs cause significantly fewer gastrointestinal complications than traditional NSAIDs [ 52 ]. Rofecoxib, celecoxib, and valdecoxib [ 553 ] oral medication, injectable counterpart: parecoxib differ considerably in their COXselectivity. The exact degree of inhibition of COX-2 versus inhibition of COX-1 varies in different publications, and the following values are representative examples: rofecoxibetodolacmeloxicamand celecoxib 9-fold [ 54 ].
Other investigators found that in a whole blood assay rofecoxib exhibited a fold preference for COX-2 compared with COX-1; the corresponding values for celecoxib, diclofenac, meloxicam, and indomethacin 1-[p-chlorobenzoyl]methoxymethylindoleacetic acid [ 3455 ] were 6. Importantly, in vitro selectivity values are method-dependent, and may not accurately predict selectivity in clinical applications.
Note that some reported selectivity values for meloxicam and indomethacin differ somewhat from those indicated in this gradation list. Rofecoxib is a compound with high analgesic and antiphlogistic efficacy osteoarthritis first metacarpophalangeal joint carrageenan- induced inflammation in rodents.
It has demonstrated analgesic potency similar to ibuprofen. However, unlike ibuprofen rofecoxib does not inhibit thromboxane synthesis [ 3757 ]. A study by the rofecoxib manufacturer of a group of patients treated with different NSAIDs a csípő fáj a kocogás után osteoarthritis found no difference in cardiovascular thrombotic events between users of rofecoxib, celecoxib, or non-selective NSAIDs such as ibuprofen, nabumetone 4-[6-methoxynaphthalenyl]butan-one [ 34 ], and diclofenac [ 58 ].
A Canadian study supported this interpretation; it reported no increased risk of myocardial infarction in rofecoxib users [ 59 ]. Additionally, an extensive review of data from multiple rofecoxib studies affirmed that there was no solid evidence for increased cardiovascular risk in patients using rofecoxib [ 60 ]. This point of view was corroborated by other experts [ 61 ]. In a gastrointestinal outcomes research study of rofecoxib, which included patients with rheumatoid arthritis treated either with rofecoxib or naproxen a non-selective cyclooxygenase inhibitorpatients in the rofecoxib treatment group had significantly fewer gastrointestinal complications than those in the naproxen-treated group [ 56 ].
However, the study showed an increased incidence of myocardial infarction and other thrombotic complications in the group of patients treated with rofecoxib. The rates of myocardial infarction were 0. Several clinical studies have shown osteoarthritis first metacarpophalangeal joint naproxen [ 62 ] may be cardioprotective [44,60,63, 64].
These findings led to a suggestion that the interpretation of an increased rate of myocardial infarction in rofecoxib users was biased because of the cardioprotective effects of naproxen. However, other studies corroborated that rofecoxib therapy in patients with rheumatoid arthritis is associated with increased risk of myocardial infarction [ 6566 ].
Also, in a group of patients over 65 years of age, use of rofecoxib was associated with increased risk of myocardial infarction compared to use of celecoxib or other NSAIDs. The reports of such diverse clinical findings have led to controversy, dispute, and uncertainty. Ethical stances emerged about perceived undue delay in issuing warnings about cardiovascular complications [ 68 ]. Public controversy over rofecoxib findings and the final decision to withdraw the drug from the market drew attention to other COXselective inhibitors, eg, celecoxib [ 7374 ] and valdecoxib [ 5 ].
The rates of cardiovascular events were similar for celecoxib and traditional NSAIDs, and surprisingly, were unaffected by concomitant aspirin use [ 75 ]. Since celecoxib gerinc és deréktáji kezelés a sulfonamide osteoarthritis first metacarpophalangeal joint, structurally different from rofecoxib and less COXselective, it was argued that celecoxib probably provides some inhibition of platelet COX-1 and thus diminishes thrombogenesis and cardiovascular complications by reducing thromboxane synthesis.
Osteoarthritis first metacarpophalangeal joint view of such reasoning, celecoxib was considered safer than rofecoxib. This opinion was supported by the results of several clinical studies [ 7677 ]. A search of a large, trial database covering use of celecoxib showed no evidence of undue thrombotic risk. Celecoxib dosages ranged from mg to mg twice daily [ 79 ].
However, in the Adenoma Prevention with Celecoxib APC trial, which included patients, an increased rate of myocardial infarction was detected among patient using celecoxib. Patients who had been consuming celecoxib or mg twice daily had 2.
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The APC trial was therefore discontinued in late December These findings raised additional concerns about the cardiovascular safety of long-term administration of coxibs. On the other hand, some clinical studies have indicated that use of traditional NSAIDs may also be associated with increased risks of cardiovascular complications. A clue to why naproxen may increase cardiovascular risk may be derived from a study of 9 healthy subjects, which showed that naproxen mg twice daily mimicked the effect on thromboxane synthesis of mg of aspirin daily, and importantly, that naproxen, but nem szimmetrikus ízületi fájdalom aspirin, significantly lowered prostacyclin synthesis [ 40 ].
Valdecoxib is a potent anti-inflammatory coxib, which is even more COX-2 selective than rofecoxib [ 83 ].
On the other hand, short-term 10 day treatment with valdecoxib after cardiac surgery led to increased rates of myocardial infarction, cardiac arrest, pulmonary embolism, and stroke [ 85 ]. Valdecoxib was removed from the market in early [ 54 ]. Interestingly, removal of the sulfonamide group of valdecoxib yields compounds that are COXselective inhibitors [ 86 ]. Other COXselective inhibitors. Clinical trials indicated that etoricoxib is well tolerated; at 60 mg or 90 mg dosages it is effective for lower back pain [ 97 ] and at mg dosage for post-operative dental pain [ 98 ].
Studies to evaluate the effects of these drugs on cardiovascular risk are pending. Previous Section Next Section Pathophysiology Therapeutic doses of coxibs can increase the risk of thrombosis by reducing endothelial cell synthesis of prostacyclin PGI2a vital vasodilator and platelet inhibitor.
This disrupts the normal balance between prostacyclin and COXderived thromboxane TXA2a vasoconstrictive eicosanoid that promotes platelet aggregation and thrombus formation. Furthermore, inhibition or gene knockout of thromboxane receptors TP and inhibition or gene laterális oldalszalag of prostacyclin receptors IP osteoarthritis first metacarpophalangeal joint inhibits and accelerates atherogenesis, respectively, showing the importance of proper balance of thromboxane and prostacyclin signaling.
- Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs
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- Kiugrott térd gyógyulási ideje
Aspirin lowers thromboxane synthesis by inhibiting platelet COX-1 irreversibly, but too much inhibition of COX-1 increases the risk of hemorrhage Fig. Platelets lack nuclear genes; consequently levels of enzymes in platelets are determined by expression of genes of the megakaryocytes that formed the platelets. Its expression determines the initial platelet thromboxane synthesis level, which controls platelet conversion of prostaglandin PG H2 to thromboxane, which promotes atherosclerosis by activating platelets and increasing leukocyte interaction with endothelial cells.
Contraction of vSMCs can lead to hypertension, another risk factor for atherogenesis.
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Gene induction, polymorphism and pharmacological inhibition of enzymes regulate platelet thromboxane synthesis. Similarly, inhibition of TP receptors with the receptor antagonist S slows atherosclerotic lesion formation in such mice. BM is an antagonist for the TP receptor and also inhibits thromboxane synthase.
Like traditional NSAIDs, coxibs can cause hypertension, which is a thrombogenesis risk factor and an independent risk factor for atherosclerosis.
Arterial constriction and renal sodium retention may contribute to the development of hypertension, which together with a coxib-induced prothrombotic state increases the risk of myocardial infarction and thrombotic stroke [ 499 ]. Osteoarthritis first metacarpophalangeal joint cells are a major source of prostacyclin. Inhibition of endothelial cell COX-2 but not platelet COX-1 by coxibs can therefore interfere with the proper balance, on the one hand, of platelet synthesis of prothrombotic thromboxane A2, which is unaffected by coxibs with the possible exception of celecoxiband, on the other hand, reduced osteoarthritis first metacarpophalangeal joint of antithrombotic prostacyclin.
Selective inhibition of COX-2 may alter the balance of prostacyclin and thromboxane synthesis. This is the most frequently proposed mechanism to explain the adverse prothrombotic effects of coxibs: they inhibit vascular synthesis of prostacyclin and thereby remove the platelet-inhibitory effect of prostacyclin osteoarthritis first metacarpophalangeal joint ].
Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs
This scenario is supported by clinical findings; administration of rofecoxib to patients reduced systemic prostacyclin osteoarthritis térdgyulladás to one-half or less of normal levels. This mechanism may, at least in part, explain the hypertension and increased rates of thromboembolic events observed in rofecoxib clinical studies [ 60 ].
The imbalance promotes a prothrombotic state, which implies a class effect that may apply to all coxibs . Others opine that existence of such a class effect cannot be supported by currently available clinical data.