Adv Ther (2010) 27(11):12. DOI 10.1007/s12325-010-0064-z
ORIGINAL RESEARCH
Efficacy and Safety of Flavocoxid, a Novel Therapeutic, Compared with Naproxen: a Randomized Multicenter Controlled Trial in Subjects with Osteoarthritis of the Knee Robert M. Levy · Alexander Khokhlov · Sergey Kopenkin · Boris Bart · Tatiana Ermolova · Raiasa Kantemirova ·
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Vadim Mazurov · Marjorie Bell · Paul Caldron · Lakshmi Pillai · Bruce P. Burnett
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Alexander Khokhlov Yaraslavl State Medical Academy, Yaraslavl, Russia
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Robert M. Levy () · Lakshmi Pillai · Bruce P. Burnett Primus Pharmaceuticals, Inc., 4725 N. Scottsdale Road, Suite 200, Scottsdale, AZ 85251, USA. Email:
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Introduction: Flavocoxid is a novel flavonoidbased “dual inhibitor” of the 5-lipoxygenase (5-LOX) enzyme and the cyclooxygenase (COX) enzymes. This study was designed to compare
the effectiveness and safety of flavocoxid to naproxen in subjects with moderate to severe osteoarthritis (OA) of the knee. Methods: In this randomized, multicenter, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. The trial was structured to show noninferiority of flavocoxid to naproxen. Primary outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and subscales and a timed walk. Results: More than 90% of the subjects in both groups noted significant reduction in the signs and symptoms of knee OA. There were no statistically significant differences in efficacy between the flavocoxid and naproxen groups when the entire intent-to-treat population was analyzed. The flavocoxid group had significantly fewer upper gastrointestinal (UGI) and renal (edema) adverse events (AEs) as well as a strong trend toward fewer respiratory AEs. Conclusion: Flavocoxid, a first-in-class flavonoid-based therapeutic that inhibits COX-1 and COX-2 as well as 5-LOX, was as effective as naproxen in managing the signs and symptoms of OA of the knee. Flavocoxid demonstrated better UGI, renal (edema), and respiratory safety profiles than naproxen.
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ABSTRACT
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Received: July 9, 2010 / Published online: © Springer Healthcare 2010
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Boris Bart Russian State Medical University Federal Agency of Health Care and Social Development, Moscow, Russia
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Sergey Kopenkin Russian State Medical University, Moscow, Russia
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Tatiana Ermolova St. Petersburg Medical Academy of Postgraduate Studies, St. Petersburg, Russia Raiasa Kantemirova Federal State Institute St. Petersburg Scientific and Practical Center of Medical and Social Expertise, St. Petersburg, Russia Vadim Mazurov St. Petersburg Medical Academy of Postgraduate Studies, St. Petersburg, Russia Marjorie Bell ClinDataServices, Bloomington, IN, USA Paul Caldron Arizona Arthritis and Rheumatology Research, Scottsdale, AZ, USA
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Keywords: 5-lipoxygenase; clinical trial; cyclooxygenase; flavocoxid, flavonoids; naproxen; osteoarthritis
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Osteoarthritis (OA) is the most common form of joint disease in adults worldwide, affecting 25 to 40 million people in the United States,1-3 with similar data reported for other countries.4 Epidemiological studies show that countries with high antioxidant diets such as those in Asian and Mediterranean regions have a substantially lower incidence of knee OA,5 suggesting a potential role for nutrition in the etiology of the disease. OA results in impaired quality of life issues including pain, mobility, functional and social disability, as well as depression,6,7 and imposes a significant societal burden.8,9 Although multiple treatment modalities have been used to manage the signs and symptoms of OA, including physical therapy, analgesics, intra-articular injections of corticosteroids or hyaluronate preparations, and surgical interventions, nonsteroidal anti-inflammatory drugs (NSAIDs), including both cyclooxygenase (COX)-1 and COX-2 inhibitors, remain the mainstay of most chemical therapeutic regimens. While effective at relieving pain and inflammation, the use of these drugs is often limited by toxic effects on the gastrointestinal (GI) tract, kidneys, platelets, cardiovascular system, and liver. Most of these adverse effects are mediated by metabolites generated via the primary enzyme pathways involved in arachidonic acid (AA) metabolism, COX-1, COX-2, and 5-lipoxygenase (5-LOX), all of which serve important physiologic functions both within and beyond articular structures.10,11 It is thought that systemic imbalance in the levels of AA metabolites, due to selective blocking of one metabolic pathway over another, may account for much of the toxicity
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INTRODUCTION
of anti-inflammatory agents.12,13 For example, the proinflammatory leukoattractant, leukotriene B4 (LTB4), a product of AA metabolism from the 5-LOX pathway, is found in high concentrations in the mucosal walls of NSAID-induced gastric ulcers.14,15 Similarly, underopposed inhibition of COX-2 relative to COX-1 may result in excessive production of vasoconstrictive thromboxanes relative to vasodilatory prostacylins, resulting in hypertension, suboptimal coronary artery flow, reduced glomerular filtration rate, edema, and renal insufficiency.16-18 Another metabolic pathway, consisting of nonenzymatic oxidation of AA, results in the production of prostaglandin F2 a-like compounds (F[2]-isoprostanes) that play a role in renovascular constriction19,20 and are also known to be elevated in the joints of OA patients.21 Serious consequences may arise from selective inhibition of either the COX-1 or COX-2 pathways compounded with a “shunt” of AA metabolism through the 5-LOX pathway. Clinical studies have revealed that, in the shortterm, COX-2 selective inhibition may be gastric sparing, but can lead to increased cardiovascular side effects.22,23 In addition, Fiorucci et al. have shown that the combination of celecoxib and low-dose aspirin statistically increases mucosal damage scores in healthy volunteers, as analyzed by endoscopy.24 “Dual pathway inhibition” of COX and LOX may greatly reduce the downstream production of inflammatory mediators12 while preserving appropriate physiological balance between them and may result in an improved safety profile in normal clinical practice. Products that block both COX and LOX pathways have entered clinical development in the past several years but no “dual inhibitor” drugs for OA are currently on the market for use in humans.25-28 Flavocoxid is a prescription product for the clinical dietary management of the metabolic processes involved in the pathogenesis of OA. Under United States Federal Statutes and Food
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on Supervision for Healthcare and Social Development, Moscow, Russia according to good clinical practice and International Conference on Harmonization guidelines. All subjects were fully informed about the purposes and procedures of the study and signed an informed consent document according to the principles of the Declaration of Helsinki. This was a 12-week, randomized, multicenter, double-blind, active-comparator controlled study. Subjects were chosen from rheumatologists’ clinical practices and were required to have Kellgren-Lawrence (K-L) grade 2-3 OA of a knee, determined by radiographic measurements, in need of anti-inflammatory therapy as determined by a defined symptomatic “flare” after NSAID discontinuance. Radiographs were scored by two reviewers not related to the investigative sites and not familiar with the subjects. The randomization schedule was computer generated and the code was the responsibility of a person not involved in the conduct of the study in any other way. Subjects were required to have been taking an anti-inflammatory agent (NSAID or selective COX-2 inhibitor) in full therapeutic doses for at least 1 month prior to the screening visit. Subjects discontinued their anti-inflammatory medication at the screening visit to begin a wash out period and must have had a minimum score of 50 mm on a 100 mm visual analog scale (VAS) for pain at the baseline visit and a flare of at least 15 mm on that scale from the screening visit to the baseline visit to continue in the study. Subjects were provided acetaminophen up to 3 g daily for rescue analgesia but were instructed to avoid use for 24 hours prior to clinic visits. Doses of flavocoxid and naproxen were chosen as those representing the maximum conventional daily prescription usage for each product. Subjects were included if they were between 35-85 years of age, had K-L grade 2-3 OA in at
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and Drug Administration (US FDA) regulations, flavocoxid is classified as a medical food, a therapeutic category distinct from drugs and supplements. Flavocoxid is a proprietary formulation of two flavonoid molecules, baicalin and catechin, extracted from the botanical sources, Scutellaria baicalensis and Acacia catechu, respectively, concentrated and standardized to >90% purity.29,30 In preclinical biochemical assays, the product has been shown to possess significant balanced inhibitory activity against the COX-1 and COX-2 enzymes, with additional 5-LOX inhibition.30 It has been shown that flavocoxid’s activity is directed toward the peroxidase rather than the cyclooxygenase moiety of the cyclooxygenase enzymes.31 Flavocoxid was also shown to reduce nuclear factor kappa B activation and downstream genomic production of inducible inflammatory proteins such as COX‑2, 5-LOX, inducible nitric oxide synthase (iNOS), and various cytokines,29 an activity that appears to be due to a potent oxygen radical absorbing capacity.32 Prior pilot safety and efficacy studies have suggested that flavocoxid has a beneficial effect in the management of OA while preserving a favorable safety profile.33-35 In view of the known limitations of conventional anti-inflammatory agents, a novel therapy that possesses anti-inflammatory activity comparable with presently used agents, together with an enhanced safety profile, would be desirable. To this end, the present study was designed to compare the effectiveness and safety of full therapeutic doses of flavocoxid with those of naproxen in subjects with moderate to severe OA of the knee using conventional clinical efficacy and safety endpoint parameters.
METHODS This study was conducted with oversight by The Ethics Committee at the Federal Service
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of reliability across clinical trials32,36-38 and multilanguage validation, these were studied in detail. The results are reported in primary form as recorded by subjects. As such, higher numbers represent better scores. Additionally, VAS scales for Subject Global Response to Therapy (SGRT) and Investigator Global Response to Therapy (IGRT) were used to assess overall changes in symptoms and function. Safety was assessed by physical examinations, adverse event (AE) reporting, routine laboratory tests, and fecal occult blood monitoring. Statistical Analysis
Sample size for the trial was determined on the assumption that flavocoxid would be as effective as naproxen in managing the signs and symptoms of OA in subjects with moderate to severe OA of the knee. For the WOMAC index score, a sample size of 86 subjects per group achieved 90% power to detect noninferiority using a one-sided, two-sample t test with alpha=0.025. The standard deviation was estimated to be 20% for each study arm. The efficacy analysis was conducted on an “intent-to-treat” population, which was comprised of all subjects who were randomized into the study and took at least one dose of study product. Differences in responses between groups were assessed by analysis of variance. The initial models contained terms for treatment group, clinical site, and treatment group by clinical site interaction. Models were reduced in a stepwise manner until only significant (P≤0.05) terms or treatment group remained. Assumptions of normality of residuals and homogeneity of variance were investigated for each response variable using the Shapiro-Wilk test.39 If it was determined that the distribution could not be approximated by a normal curve, then values were ranked in ascending order with
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least one knee, were in general good health, had not taken any anti-inflammatory medication for at least 1 week prior to the randomization visit and were not pregnant or breast feeding. Subjects were excluded from participation in the study for the following reasons, among others: K-L grade 1 or 4 OA in the target knee; K-L grade 4 OA in any knee or hip; any form of arthropathy other than OA; any musculoskeletal or neurological condition that might alter gait or confound evaluation of the target knee; use of any gastroprotective medication, whether by prescription, or over the counter within 2 weeks of the screening visit; intra-articular corticosteroids within 3 months or hyaluronate preparations within 6 months of the screening visit; use of mechanical ambulation aids; history of bleeding disorders or use of anticoagulant medications; history of chronic UGI disease or UGI bleeding within 3 years of screening; positive fecal occult blood at screening; significant renal, cardiovascular or neoplastic disease or any other disease that, in the opinion of the investigator, might put the subject at undue risk during the study; history of allergy to aspirin, NSAIDs, or flavonoids; consumption of more than 2 units of alcohol daily. Dietary supplements and low dose aspirin for cardioprotection were permitted as long as their use remained constant for the length of the study. Efficacy parameters were measured at baseline, 6 weeks, and 12 weeks. One primary efficacy endpoint was a timed walk of just over 9 m (30 feet). For this test, subjects, without an initial warm up, walked 9.14 m, turned, and walked back the same distance as quickly as possible. The return walk was timed and recorded as the walking time. The second primary endpoint was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) index, while the WOMAC subscales were used as secondary endpoints. Because of their long history
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220 subjects (106 flavocoxid and 114 naproxen) who completed all scheduled visits. Baseline Demographic Characteristics
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No attempt was made to match the study groups with respect to any demographic variable. However, due to the relative homogeneity of the population, the groups were very similar with regard to average and range of age, race (all were Caucasian), weight, height and body mass index (BMI) (Table 1). Significant proportions of the study groups were women (87.7% and
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tied values being given a mean rank prior to running statistical models. A Fisher’s exact test was used to determine the percentage of patients who improved versus those who did not improve for each arm. Safety was assessed for all subjects who received at least one dose of study product by the evaluation of treatment-emergent AEs and changes in vital signs, bodyweight, and laboratory parameters. The occurrence of AEs was tabulated and Fisher’s exact test (twotailed) was utilized for between treatment group comparisons. Changes from baseline in vital sign measurements and laboratory parameters were analyzed using analysis of variance (ANOVA) as described for the efficacy analyses.
Efficacy
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A total of 264 subjects were screened and 223 were randomized to the study. Of these, two dropped out for personal reasons unrelated to the study (one each from the flavocoxid and naproxen groups) and one because of severe epigastric pain (naproxen group). This left
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The primary efficacy parameters evaluated were the WOMAC index and a 9.14 m (30‑foot) timed walk. Secondary endpoints were the WOMAC subscales of pain, stiffness, and physical function. In addition, visual analog
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Table 1. Baseline demographic characteristics. Characteristic
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RESULTS
78.9% in the flavocoxid and naproxen groups, respectively). Most subjects were somewhat overweight to obese with equivalent average BMIs (flavocoxid=30.8; naproxen=30.2).
Naproxen (500 mg twice daily) n=114
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Gender Female, n (%) 93 (87.7%) 90 (78.9%) Male, n (%) 13 (12.3%) 24 (21.1%) Total, n (%) 106 (100.0%) 114 (100.0%) Age, years Mean (SEM) 60.6 (0.94) 61.1 (0.82) Minimum, maximum 39.0, 79.0 42.0, 82.0 No. Caucasian 106 (100.0%) 114 (100.0%) Mean (SEM) weight, kg 84.5 (1.25) 84.6 (1.37) Mean (SEM) height, cm 165.9 (0.74) 167.3 (0.81) Mean (SEM) BMI, kg/m2 30.8 (0.47) 30.2 (0.41)
P value
BMI=body mass index; SEM=standard error of the mean.
0.08 0.73 1.00 0.97 0.19 0.31
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of flavocoxid and 94% of naproxen subjects (Figure 2). At the 12-week evaluation, the percentage improvement from the 6-week value in the flavocoxid arm increased slightly while the naproxen arm decreased slightly, although the difference did not reach statistical significance. Although no statistical significance was reached, a trend in favor of flavocoxid became apparent with time in the WOMAC index (P=0.74 at 6 weeks; P=0.19 at 12 weeks), WOMAC physical function (P=0.96 at 6 weeks; P=0.13 at 12 weeks), and timed walk (P=0.21 at 6 weeks; P=0.08 at 12 weeks) scores (Table 2).
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scales for SGRT and IGRT were used to gain insight into the overall response to treatment but were not part of the endpoint analyses. A summary of these parameters is shown in Table 2. Both the flavocoxid and naproxen groups improved in all parameters at 6 weeks with further improvement at 12 weeks. Figures 1A and 1B show the improvements in WOMAC index and pain scores. No statistically significant differences between the flavocoxid and naproxen groups are apparent. Improvement in WOMAC index scores over a 6-week period was seen in 91%
Baseline, mean (SEM)
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WOMAC index* Flavocoxid 40.55 (1.35) 59.68 (1.67) 66.47 (1.80) 0.74 Naproxen 41.46 (1.17) 61.32 (1.70) 65.86 (1.86) WOMAC: pain* Flavocoxid 43.21 (1.36) 63.07 (1.80) 70.09 (1.36) 0.62 Naproxen 43.55 (1.33) 64.56 (1.78) 68.38 (1.96) WOMAC: stiffness* Flavocoxid 38.44 (1.94) 56.96 (2.10) 63.80 (2.20) 0.79 Naproxen 39.91 (1.78) 60.31 (2.09) 66.34 (2.230 WOMAC: physical function* Flavocoxid 40.01 (1.40) 59.00 (1.66) 65.72 (1.80) 0.96 Naproxen 41.02 (1.19) 60.49 (1.72) 65.07 (1.84) SGRT† Flavocoxid NA 5.94 (0.20) 6.39 (0.20) 0.06 Naproxen NA 5.89 (0.17) 6.26 (0.16) IGRT‡ Flavocoxid NA 5.95 (0.19) 6.39 (0.20) 0.67 Naproxen NA 5.85 (0.17) 6.31 (0.15) Timed walk (seconds) Flavocoxid 16.07 (0.56) 13.51 (0.56) 12.61 (0.59) 0.21 Naproxen 15.39 (0.46) 13.20 (0.48) 12.43 (0.47)
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Table 2. Summary of efficacy parameters outcomes for flavocoxid and naproxen at 6 and 12 weeks.
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*(0=worst, 100=best); †(0=no change, 10=excellent); ‡(0=none, 10=outstanding). IGRT=Investigator Global Response to Therapy; NA=not applicable; SEM=standard error of the mean; SGRT=Subject Global Response to Therapy; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index.
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Safety
Figure 1. Change in selected outcome parameters with time at 6 and 12 weeks. (A) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) index (6 weeks: P=0.64; 12 weeks: P=0.19). (B) WOMAC: pain (6 weeks: P=0.62; 12 weeks: P=0.35). Mean WOMAC index
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Figure 2. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores; percentage change from baseline. This figure shows the percentage of subjects from the total intent-to-treat population reporting an improvement in WOMAC index scores.
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A total of 71 AEs were recorded in each group (67% flavocoxid; 62% naproxen). Of these, 45 (42.5%) in the flavocoxid group and 51 (44.7%) in the naproxen group were considered by investigators to be related to study product. No serious AEs were noted in either study group. Two positive fecal occult bloods were found in each study arm without associated GI symptoms or change in hematologic parameters. A wide range of minor AEs was reported, most in less than 1% of the study populations. There were a few notable differences in AE profile between flavocoxid and naproxen including more episodes of edema (P=0.016), dyspepsia (P=0.041), and total ear-nose-throat (ENT)/respiratory complaints (P=0.150) in the naproxen group, and flatulence (P=0.042) in the flavocoxid group (Table 3). No statistically significant differences in laboratory abnormalities were found although there was a mean increase of 0.015 mg/dL in serum creatinine in the naproxen arm and a mean decrease of 0.018 mg/dL in the flavocoxid arm (P=0.18), suggesting a possible trend toward less renal toxicity with flavocoxid. In all, 24 subjects had elevations of hepatic transaminase enzymes greater than 1.2 the upper limit of normal (ULN) at screening (13 flavocoxid;
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Table 3. Summary of statistically significant and trending adverse events. Adverse events Edema (no. of episodes) Dyspepsia Flatulence Body as a whole Constipation Respiratory
Flavocoxid Naproxen (n=106) (n=114) P value 2 11 4 4 0 9
13 24 1 9 4 17
0.016 0.041 0.042 0.070 0.120 0.150
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postulate that the red cell mass must be first saturated with flavocoxid before fully active free serum concentrations can be reached. Further experimentation is needed to determine if this explains the seemingly slower onset of action of flavocoxid observed in some patients. There was a higher incidence of UGI complaints in the naproxen group, with a significant increase in dyspepsia. Edema was significantly more common in the naproxen group. Although no subject developed frank azotemia, there was a mean increase in creatinine and blood urea nitrogen (BUN) levels in the naproxen arm and a mean decrease in the flavocoxid arm, neither of which achieved statistical significance. Flavocoxid may offer an advantage in terms of UGI and renal (edema) side effects due to its in inhibition of leukotriene production.30,44,45 There were 17 upper respiratory AEs in the naproxen group versus nine in the flavocoxid group (P=0.15). This is similar, although less dramatic, to a finding reported in an earlier study in which flavocoxid was compared with placebo.33 The reasons for this observation are not entirely clear although the flavonoids in flavocoxid are known to have antibacterial and
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Currently prescribed NSAIDs and selective COX-2 inhibiting agents are often effective for controlling the pain and inflammation associated with OA, but may be associated with poor patient tolerance and/or significant physiological side effects. Agents that regulate all three major metabolic pathways of AA metabolism (COX-1, COX-2 and 5-LOX), the so-called “dual inhibitors,” are thought to have better safety profiles because of their more balanced inhibition of the enzymatic pathways leading to the generation of inflammatory metabolites.26,27,40,41 In this study comparing the clinical efficacy of flavocoxid to naproxen, both study arms showed improvement at 6 weeks with further improvement at 12 weeks. When the entire intent to treat population was examined, no statistically significant differences in efficacy were seen between the two arms of the study
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although some trends were noted, particularly in the WOMAC index and physical functioning subscale and other secondary parameters. In most, but not all instances, these trends favored flavocoxid and tended to become more marked at the 12-week time point. These findings are consistent with what is known of the pharmacodynamics of flavonoids. Molecules such as catechin are passively and slowly absorbed into red blood cells and may also gain entry by binding to the glucose transport receptor (GLUT1).42 Many other flavonoids, including baicalin are adsorbed and bound onto the surface of red cells where they act as potent antioxidants in erythrocyte membranes.42,43 We
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11 naproxen). At 12 weeks, approximately half of these had normalized (seven flavocoxid; five naproxen). Conversely, there were 16 subjects whose transaminases were normal at screening and elevated at 12 weeks (11 flavocoxid; five naproxen [P=0.087]). There were 12 elevations of total bilirubin between screening and 12 weeks (five flavocoxid; seven naproxen [P=0.18]). There were only two subjects with elevated alkaline phosphatase (AP) at screening, one in each group. Almost all of the abnormalities for hepatic transaminases and bilirubin in both groups were within 1.5-3 times ULN for the reference laboratory and none exceeded five times the ULN. Because of the fluctuating numbers of minor transaminase abnormalities, it is unclear if these data are related to study products or due to environmental or cultural phenomena.
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development, small pilot trials had demonstrated efficacy against placebo (unpublished data) and this was not the object of this study. In retrospect, it would have been interesting to have a 2-week time point to better illustrate the difference in time to maximal efficacy between naproxen and flavocoxid. An additional limitation of this study was the relatively high number of subjects with minimally elevated hepatic transaminase levels at baseline that confounded evaluation of liver toxicity.
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CONCLUSION In this study, flavocoxid was as effective as naproxen in managing the signs and symptoms of OA of the knee and showed trending toward greater improvement compared to naproxen with longer time on therapy. Flavocoxid also had a significantly more favorable UGI and renal toxicity profile than naproxen suggesting that its dual inhibition mechanism of action may lead to greater safety. To our knowledge, the study reported here is the first published, formal, fulllength, large clinical trial designed to investigate the anti-inflammatory and safety features of flavonoids in the management of OA. As such, this study demonstrates another clinically useful property of this large class of bioactive botanical molecules and suggests that flavocoxid might be a reasonable choice for first-line therapy in the management of OA.
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Prescribing information for most NSAIDs suggests that the incidence of transaminase abnormalities greater than 1.2 times ULN may be as high as 15%.48 The reason for the somewhat high incidence and fluctuating levels of mild hepatic abnormalities at both screening and final visits in both arms of this study is unclear although alcohol consumption may have been underreported by the subjects. Moderate consumption of alcohol coupled with elevated BMI, for example, has been associated with hepatotoxicity.50 In this study, flavocoxid was as effective as naproxen in managing the signs and symptoms of OA of the knee and showed noteworthy trending toward greater improvement by 12 weeks compared to naproxen. Flavocoxid had a more favorable UGI and renal toxicity profile than naproxen suggesting that its dual inhibition mechanism of action may lead to greater safety. A potential limitation of this study is the lack of a placebo group that would have demonstrated efficacy against a null comparator. However, practicing physicians are not concerned if a new product is better than placebo when they have other therapeutic options, but wish to know how the product compares in efficacy and safety with one with which they are familiar. Earlier in
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antiviral activity. 46,47 Leukotriene inhibition by flavocoxid may also play a role in reducing respiratory mucosal inflammation and response to allergens. Further clinical trials focusing on respiratory function are needed to elucidate these possibilities. Some elevated hepatic transaminases were recorded in both arms with no statistically significant difference between the two. Almost all NSAIDs have been associated with hepatic abnormalities although symptomatic hepatic injury is rare, occurring once in about 10,000 patient years of NSAID use, with sulindac and diclofenac being the most frequent offenders.48,49
ACKNOWLEDGMENTS The authors gratefully acknowledge the services provided by AmeRuss, an international contract research organization, for their competent and professional organization and administration of this trial. The study was funded by Primus Pharmaceuticals, Inc., Scottsdale, AZ, USA.
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