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Annals of Clinical & Laboratory Science 35:137-143 (2005)
© 2005 Association of Clinical Scientists

In Vivo Effect of Celecoxib and Tenoxicam on Oxidant/Anti-oxidant Status of Patients with Knee Osteoarthritis

Salih Ozgocmen1, Ozge Ardicoglu1, Hasan Erdogan2, Ersin Fadillioglu3 and Huseyin Gudul1
1 Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Firat University Faculty of Medicine, Elazig; 2 Department of Physiology, Gaziosmanpasa University Faculty of Medicine, Tokat; 3 Department of Physiology, Inonu University Faculty of Medicine, Malatya, Turkey

Address correspondence to Salih Ozgocmen, M.D., Firat Universitesi, Tip Fakultesi Fiziksel Tip ve Rehabilitasyon Anabilim Dali, TR-23119, Elazig, Turkey; tel 90 424 233 3555; fax 90 424 248 0509; e-mail sozgocmen{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The aim of this study was to compare the in vivo effects on free radical metabolism of 2 non-steroidal anti-inflammatory drugs (NSAIDs): tenoxicam, an oxicam preferentially cyclooxygenase-1 (COX-1) inhibitor, and celecoxib, a sulfonamide selective COX-2 inhibitor. The serum levels of oxidative stress-related enzymes (ie, xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)), of a lipid peroxidation marker (malondialdehyde (MDA)), and of nitric oxide (NO) in patients with knee osteoarthritis were studied at baseline and after a 4-wk course of treatment with celecoxib (n = 11) and tenoxicam (n = 12). Celecoxib-treated patients had significant decrease in nitrite levels (p = 0.043), whereas SOD, XO, GSH-Px enzyme activities, and MDA levels did not change significantly compared to baseline. Tenoxicam-treated patients had significant decrease in nitrite levels (p = 0.036) and XO activity (p = 0.01), but their SOD, GSH-Px enzyme activities, and MDA levels were unchanged from baseline. There was significant correlation between the patients’ (n = 23) Western Ontario and McMaster Universities (WOMAC) LK3.0 Osteoarthritis Index, WOMAC-pain scores, and MDA levels (r = 0.50, p = 0.014) and the patients’ WOMAC-stiffness scores and XO enzyme activity (r = 0.46, p = 0.027) at baseline. Significant improvement was found in pain-VAS, patients’ global assessment, and WOMAC pain, stiffness, and physical function scores in celecoxib and tenoxicam-treated groups. In summary, our study revealed that tenoxicam may have antioxidant effects, and that celecoxib and tenoxicam may reduce nitrite levels, indicating an alteration of NO pathways.

(received 23 November 2004; accepted 31 January 2005)

Keywords: osteoarthritis, celecoxib, tenoxicam, oxidative stress, free radicals, nitric oxide


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Formation of reactive oxygen species (ROS) has been suggested to play important roles in various inflammatory diseases including rheumatoid arthritis (RA) and ankylosing spondylitis (AS) [1–3]. ROS are deleterious agents involved in cartilage degradation and chondrocyte survival [4–6]. ROS such as superoxide anion (O2–•), hydroxyl radical (•OH), hydrogen peroxide (H2O2), and hypochlorous acid (HOCl) are highly reactive chemical species that are important in inflammatory and antibacterial responses where they participate in pathological processes including the arachidonic acid cascade and phagocytosis [7]. Under normal homeostatic conditions, the production of endogenous ROS (generated by NADPH oxidase, xanthine oxidase (XO), or cytochrome P450, etc) are balanced by the actions of cellular antioxidant defense systems, including enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)), and non-enzymatic species (glutathione, ascorbate, tocopherol, retinol) to avoid oxidative stress.

Non-steroid anti-inflammatory drugs are widely used in the management of osteoarthritis (OA); their primary effects are on prostaglandin (PG) synthesis through inhibition of the cyclooxygenase (COX) enzymes. Two isoforms of COX have been well-recognized (COX-1 and COX-2). COX-1 is a constitutively expressed enzyme in many tissues, and COX-2 is an inducible enzyme predominantly expressed at the sites of inflammation. The activation of COX-1 promotes the release of eicosanoids that are involved in physiologic processes including the production of thromboxane A2, prostacyclin, and PGE2. Inhibition of COX-1 with non-selective NSAIDs can result in side effects such as platelet dysfunction and gastrointestinal (GI) damage [8]. Selective COX-2 inhibitors preferentially reduce inflammation with fewer GI side effects, compared to traditional NSAIDs [9–11].

Some NSAIDs enhance ROS generation whereas others attenuate ROS formation [12–20]. Our purpose was to compare the in vivo effects on ROS metabolism of celecoxib, a sulfonamide selective COX-2 inhibitor, and tenoxicam, an oxicam that preferentially inhibits COX-1. The activities of oxidative stress-related enzymes (ie, XO, SOD, GSH-Px), malondialdehyde (MDA) level, and nitric oxide (NO) level in serum of OA patients were studied at baseline and after a 4-wk course of treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients.  Twenty-three patients with knee OA were administered either celecoxib or tenoxicam for 4 wk; 11 patients were treated with celecoxib (200 mg po daily), and the rest with tenoxicam (20 mg po daily). Celecoxib-treated patients (2 men, 9 women) had a mean age of 54.2 ± 9.6 yr (range 33–65) and a disease duration of 5.3 ± 5.6 yr (range 1–20). Tenoxicam-treated patients (2 men, 10 women) had a mean age of 52.6 ± 6.0 yr (range 44–65) and a disease duration of 4.8 ± 3.5 yr (range 1–10).

Inclusion criteria.  The patients were 18–65 yr old, Functional Class I–III, with primary OA of the knee who met the ACR diagnostic criteria [21], defined by knee pain and recent radiographic evidence of osteophytes. In addition, they had at least one of the following: age >50 yr, morning stiffness <30 min in duration, and/or crepitus, and a baseline visual analog scale (VAS) pain intensity score of >30 mm in the index joint.

Exclusion criteria.  Patients with the following conditions were excluded from the study: current drug usage (including supplementary vitamins) for uncontrolled concomitant disease or chronic condition(s) that might interfere with the assessment of clinical findings of OA and serum oxidative stress markers; other prior disease or joint replacement at the index joint; a history of GI ulcers and bleeding, inflammatory arthritis, gout, pseudogout, or Paget’s disease that might interfere with the assessments; history of excessive alcohol consumption, smoking, and regular aerobic exercise program; diagnosis of chronic pain syndrome (eg, fibromyalgia, chronic fatigue syndrome); intramuscular, intravenous, or soft tissue corticosteroids within 1 mo prior to the study; use of intra-articular corticosteroids in the index knee joint within 2 mo prior to the study; intra-articular viscosupplementation in the index knee joint during the past 6 mo, or intra-articular viscosupplementation in a non-index knee in the past 3 mo; history of clinically significant intolerance to celecoxib and tenoxicam or known hypersensitivity to sulfonamides. All of the patients voluntarily participated in the study and gave written informed consent. No supplementary therapies, special diets, or aerobic exercise programs were allowed during the study period. Compliance was assessed by tablet counting; subjects with <70% compliance were excluded from the study.

Outcome measures.  Pain was assessed using a visual analog scale (VAS; 0–100 mm). Patient’s global assessment (PGA) and Western Ontario and McMaster Universities (WOMAC) LK3.0 Osteoarthritis Index was performed at baseline and at the end of the treatment [22]. The WOMAC LK3.0 Osteoarthritis Index is a validated, multidimensional questionnaire of defined reliability, content, construct validity, and responsiveness. It consists of 24 questions (5 on pain, 17 on physical function, and 2 on stiffness), each scored on a 5-point Likert scale (0 to 4, 0 representing none). The PGA was scored from 0 to 4 (0 representing very good).

Biochemical assays.  Blood samples were obtained at baseline and at the end of the clinical study period for analysis of oxidative stress-related analytes. The blood was centrifuged and the supernatant serum was stored frozen until use for analysis of GSH-Px, XO, MDA, NO and SOD.

MDA levels were determined by reaction with thiobarbituric acid (TBA) [23]. In the TBA test reaction, MDA or MDA-like substances and TBA react to produce a pink pigment with an absorption maximum at 532 nm. The reaction was performed at pH 2–3 and 90°C for 15 min. The sample was then mixed with 2 volumes of cold 10% (w/v) trichloroacetic acid to precipitate proteins. The precipitate was pelleted by centrifugation and an aliquot of the supernatant was reacted with an equal volume of 0.67% (w/v) TBA in a boiling water bath for 10 min. After cooling, the absorbance was read at 532 nm. The results were expressed as µmol/L.

Since NO is very labile, its direct measurement in the biological samples is difficult. In aqueous solution, NO reacts with molecular oxygen and accumulates in the plasma as nitrite (NO2–) and nitrate (NO3–) ions. These stable oxidation end products are readily measured in biological fluids and have been used in vitro and in vivo as indicators of NO production. The plasma total nitrite concentration was accepted as an index of NO production. For total nitrite detection, serum was treated with copperized cadmium granules to reduce NO3– to NO2–. Nitrite concentrations were quantified by a colorimetric assay based on the Griess reaction [24]. Briefly, a chromophore with a strong absorbance at 545 nm is formed by reaction of nitrite with a mixture of N-naphthylethylenediamine and sulphanilamide. A standard curve is established with a set of serial dilutions (10–8 to 10–3 mol/L) of sodium nitrite and results are expressed as µmol/L of serum.

The principle of the total SOD (EC 1.15.1.1 [EC] ) activity method is based on inhibition of nitroblue tetrazolium (NBT) reduction by O2–• generated by xanthine/xanthine oxidase [25]. Activity was assessed in the ethanol phase of plasma after 1.0 ml of ethanol/chloroform mixture (5:3, v:v) was added to the same volume of plasma and centrifuged. One unit of SOD was defined as the enzyme amount causing 50% inhibition of NBT reduction rate. Activity was expressed as U/mL.

Serum XO (EC 1.2.3.2 [EC] ) activity was measured spectrophotometrically by the formation of uric acid from xanthine through the increase in absorbance at 293 nm [26]. A calibration curve was constructed by using 10–50 mU/ml concentrations of standard XO solutions (Sigma X-1875). One unit of activity was defined as 1 µmol uric acid formed per min at 37°C, pH 7.5. Results were expressed as U/mL.

GSH-Px (EC 1.6.4.2 [EC] ) activity was measured by the method of Paglia and Valentine [27]. The enzymatic reaction was initiated by the addition of H2O2 to the reaction mixture containing reduced glutathione (GSH), reduced nicotinamide adenine dinucleotide phosphate (NADPH), and glutathione reductase. The change in the absorbance at 340 nm was monitored by a spectrophotometer. Activity was expressed as U/L.

Statistical analysis.  The Statistics Package for Social Sciences (SPSS Inc, Chicago, IL) was used for the analyses. Results were expressed as mean ± SD. Differences between the two groups at baseline were assessed by independent sample t test. Changes observed before and after celecoxib or tenoxicam were assessed by the paired sample t test. Spearman rank correlation and Pearson correlation coefficients were used to assess the relationships between parameters. A two-tailed p value of <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All patients in both groups completed the study. The baseline oxidative stress-related measurements in celecoxib and tenoxicam groups did not have significant difference when compared to each other (Table 1Go). Celecoxib-treated patients had a significant decrease only in nitrite levels (p = 0.043), whereas SOD, XO, GSH-Px enzyme activities, or MDA levels did not significantly change compared to baseline values (Table 1Go). Tenoxicam-treated patients had a significant decrease in nitrite levels (p = 0.036) and XO activity (p = 0.01) and unchanged SOD, GSH-Px enzyme activities, and MDA levels (p = 0.07, 0.61, and 0.34 respectively).


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  		Table 1. Oxidative stress-related parameters in serum of patients with knee ostoarthritis.
 
There were significant correlations between patients’ (n = 23) WOMAC-pain scores and MDA levels (r = 0.50, p = 0.014) and between patients’ WOMAC-stiffness scores and XO enzyme activity (r = 0.46, p = 0.027) at baseline. Other oxidative stress-related measurements did not have significant correlation with patients’ clinical measures (Table 2Go).


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  		Table 2. Outcome measures in patients with knee osteoarthritis.
 
Significant improvement in the celecoxib- and tenoxicam-treated groups was observed in the pain-VAS, PGA, and WOMAC pain, stiffness, and physical function scores (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study revealed that serum nitrite levels decreased with both celecoxib and tenoxicam treatments, but neither drug caused significant changes in serum MDA levels or serum SOD and GSH-Px activities. A limited number of in vivo or in vitro studies have been reported regarding the effects of NSAIDs on oxidant/antioxidant enzyme activities, nitric oxide levels, and lipid peroxidation [8,12–20]. Xanthine oxidase enzyme activity significantly changed only in the tenoxicam-treated patients. To the best of our knowledge, our study is the first to compare these 2 drugs with particular reference to their effects on oxidative stress metabolism using enzyme activities of XO, SOD, GSH-Px, and MDA and nitrite levels in OA patients.

In a recent study, Cimen et al [16] examined the in vivo effects of celecoxib, ibuprofen, and meloxicam on free radical metabolism of erythrocytes in patients with OA. The authors concluded that these NSAIDs caused similar impairment in enzymatic and non-enzymatic antioxidant defense systems in erythrocytes despite their different mechanisms of action on COX. They found a significant decrease in erythrocyte SOD enzyme activity and antioxidant potentials in all groups treated with celecoxib, meloxicam, and ibuprofen [16]. In our study, both drugs increased the average serum SOD activities, but the difference was not statistically significant.

Besides, we showed that tenoxicam reduced XO activity and nitrite levels in vivo. The free radical scavenging activity of tenoxicam has been demonstrated in experimental models of different cell-free systems by using different techniques [12]. Tenoxicam has been shown to inhibit superoxide anion generation by neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP), calcium ionophore A23187 [GenBank] , and serum-treated zymosan [28]. Furthermore, tenoxicam has been shown to be a cofactor for the reduction of peroxidases [29]. The in vitro effect of tenoxicam enhancing erythrocyte CAT activity has been demonstrated by Orhan and Sahin [30]. Similarly, van Antwerpen and Neve [14] suggested that oxicams (ie, tenoxicam, piroxicam, meloxicam) were more reactive against ROS than nimesulide and ibuprofen. On the other hand, we must point out that these studies, including ours, represent short-term effects of these drugs.

Xanthine oxidase is known to play a crucial role in ischemia-reperfusion injury. During ischemia, ATP is degraded to hypoxanthine and xanthine dehydrogenase is converted to XO. During reperfusion, XO catalyses the reaction of hypoxanthine or xanthine and molecular oxygen to superoxide radicals. These radicals rapidly react with nitric oxide, peroxynitrite, and other reactive species [31]. ROS attack polyunsaturated fatty acids (PUFAs) in the membrane lipids to produce lipid peroxidation. The assessments of serum MDA or 4-hydroxynonenal are the most commonly applied methods for the measurement of lipid peroxidation. Related to partial oxygen pressure variations, mechanical stress, immunomodulatory or inflammatory processes, chondrocytes mainly produce nitric oxide and superoxide [4]. The generation of these radicals can lead to formation of peroxynitrite, which is a more potent and long-lived oxidant and contributes to tissue injury mediated by inflammatory cells. There are divergent effects of this interaction; first, superoxide limits some of the effects of NO vasodilatation by converting it to ONOO–; secondly, scavenging superoxide anion while converting to ONOO– suggests that NO may provide a free radical scavenging effect [32,33].

Increased synovial fluid nitrite levels in OA patients, reduced cartilage erosions with intra-articular injection of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of inducible NO synthase (iNOS), incriminate NO as a potent mediator for cartilage destruction [34,35]. On the other hand, experimental data suggest that NO-mediated cell death by apoptosis requires the generation of additional ROS [6]. A combination of COX-2 inhibitors and hyaluronic acid has been shown to reduce NO production by highly degenerated chondrocytes [36] and COX-2 has been suggested to have a proapoptotic function on synovial fibroblasts from human OA synovium [37]. Nevertheless, NSAIDs were shown to inhibit NO-induced apoptosis independent of their effects on COX activity [38]. These data are in agreement with previous experimental studies indicating that inhibition of PGE2 by COX-2 inhibitors, or addition of exogenous PGE2 to the media, do not affect spontaneous NO production significantly [33]. Our findings–similar nitrite lowering effect of tenoxicam, a traditional nonselective NSAID, and celecoxib, a COX-2 selective NSAID–are not surprising. Our data warrant further studies to assess the interaction between the protective effects of nitric oxide in the microvasculature (ie, myocardial ischemia-reperfusion injury, adult respiratory distress syndrome) and interaction of nitric oxide pathways with side effects or adverse events related to NSAIDs.

In summary, our study showed that tenoxicam may have antioxidant effects, and that celecoxib and tenoxicam may reduce nitrite levels, indicating an alteration in NO pathways. The relationship between patients’ pain and stiffness scores and oxidative stress-related measurements warrants further research to assess the potential role of free radicals and antioxidants in the pathogenesis and clinical features of OA. Knowledge of the underlying mechanisms might offer new therapeutic approaches for joint diseases and prevention of cartilage damage.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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