Flavocoxid: A Botanical Extract Acts as a Balanced Inhibitor of Multiple Inflammatory Pathways
David M. Brady, ND, DC, CCN, DACBN
There is great concern in the medical community over the excessive use of both non-steroidal anti-inflammatory drugs (NSAID) such as COX-2 inhibitors, and steroidal anti-inflammatory medications. There is also concern over the use of narcotic pain relievers, due to potentially serious side effects and dependency. In fact, patients generally use substantial doses of these prescription drugs on a chronic or ongoing episodic basis, thereby resulting in increased risk of long-term side effects, particularly among the elderly. There are emerging highly standardized and evidence-based natural agents that effectively modulate the same enzyme pathways as anti-inflammatory medications, but with much lower side-effect profiles. One such extract backed by strong supporting human-outcome studies, flavocoxid, will be discussed in this article with emphasis on its safety profile and balanced action across a multitude of inflammatory pathways.
Integrative medicine clinicians from various professional backgrounds and fields, including NDs, are encountering an ever-growing population of patients/clients suffering from acute and chronic pain conditions, many of these being inflammatory in nature. Examples include sports injuries, degenerative and inflammatory arthritis, autoimmune-related disorders, and many more. Many of these patients experience significant gastrointestinal, renal, coagulation, and other side effects, and may not even be aware of them until they cause a serious medical disorder.1,2 Many of these same individuals would likely be interested in evidence-based, effective natural agents that reduce, and in many cases eliminate, the drug-associated side effects. Integrative providers need to understand the benefits and risks of standard interventions, as well as those of the available evidence-based complementary approaches.
Some important facts about commonly used natural anti-inflammatory compounds3-84:
Natural anti-inflammatory compounds do not act as selective cyclooxygenase (COX) inhibitors. They constitute an array of compounds that have various combination effects of inhibiting both COX-2 and COX-1, in addition to the lipoxygenase (LOX) and phospholipase A2 enzymes. It is important that they also inhibit COX-1 to some degree because this provides a mild blood thinning effect, counteracting the blood clotting effect of COX-2 inhibition. In this sense, they act somewhat similar to non-selective NSAIDs (such as naproxen, diclofenac, and ibuprofen), although these medications do exert some dominance on the COX-1 isoenzyme. However, they also have many additional benefits, such as antioxidant activity, and do not promote gastrointestinal (GI) bleeding.
Natural anti-inflammatory agents may be a better choice for blood thinning than aspirin, which acts predominantly as a selective COX-1 inhibitor. Aspirin binds to platelets in an irreversible manner, resulting in serious risk of bleeding in cases of overdose and strong GI side effects. This is not the case with natural anti-inflammatory agents.
Natural anti-inflammatory compounds prevent the expression of “inducible” COX-2 which results from oxidative stress, due to the potent antioxidant effect of many of these compounds.
Proteolytic enzymes help reduce acute and chronic inflammation in ways unrelated to COX and LOX inhibition, such as the molecular debridement of the chemotaxis-promoting protein fragments and inflammatory mediators liberated from injured cells. These enzymes also have additional anti-thrombotic and anti-inflammatory effects.
Please refer to the table for a more complete understanding of the differences between the compounds referenced above.3
Flavocoxid is a specially manufactured and extensively studied natural food-based product composed of enriched plant extracts from two botanicals: Scutellaria baicalensis and Acacia catechu. Flavocoxid contains the same “active” constituents and micronutrients that can be found in many fruits, nuts, vegetables, and teas.85 Flavonoids, which are low-molecular weight compounds and part of the larger class of compounds known as polyphenols, are ubiquitous in plants.86 More than 9000 different flavonoids have been characterized, many of which are consumed regularly in the human diet. Their basic structure consists of a 3-ring nucleus with a large number of side chain possibilities.86 Flavocoxid contains 2 primary active ingredients, baicalin and catechin. Baicalin is part of a larger class of flavonoids knows as free-B-ring flavonoids, whereas catechin is part of a class known as flavans. The plant sources for the free-B-ring, baicalin, and the flavan, catechin, have nutritional value and have been used in medicinal preparations and in foods for many years, especially in Asian countries.
The development path for flavocoxid began in January of 1996 when a scientifically-based Korean ingredients supplier using pharmaceutical-like screening and development practices began to isolate multiple anti-inflammatory compounds from Aloe vera and Picrorhiza kurroa. This work was then followed by the development of high-throughput (HTP) extraction and fractionation methods of plant extracts in 1998. At the same time, screening of over 1200 plant extracts and tens of thousands of HTP fractions using the COX-1, COX-2, and 5-LOX enzymes began in earnest.87 Twenty-two initial plant extracts were identified having COX-1, COX-2, and 5-LOX activity. In secondary screening in cells, the company found that 14 of the initial 22 extracts were cytotoxic in monocytes. Further animal toxicity analysis showed that only 2 did not produce any significant changes in the physiology of animals, in terms of both acute and sub-chronic toxicity. These plant extracts from Scutellaria baicalensis and Acacia catechu were further characterized via HTP fractionation. It was further discovered that baicalin from Scutellaria baicalensis, and catechin from Acacia catechu, were the primary active ingredients in both plant fractionations having COX-1, COX-2, and 5-LOX activity.87
Extensive laboratory and animal toxicology testing followed in 2002-2003, characterizing the safety of the combination of these naturally derived compounds.88 This research showed that the molecules composing flavocoxid at certain ratios inhibited COX-1 and COX-2 enzymes to an equal degree while also inhibiting the 5-LOX enzyme (Figure 1). Results from these enzyme assays also correlated with observations made in cell assays. Animal models of inflammation also showed that flavocoxid could alleviate arachidonic acid-induced arthritis, considered part of the pathophysiology of osteoarthritis. In addition, later proteomic and genomic studies demonstrated that flavocoxid down-regulated specific cytokines involved in the initial inflammatory cascade after cell damage due to trauma, as well as COX-2 and 5-LOX production. These results suggest that flavocoxid has both protein and genomic inhibition effects for the management of inflammation. Drug interaction studies, as well as mutagenesis studies, have also been performed to assure safety of the extract.89
In 2002 through early 2003, human safety and efficacy testing ensued at Georgetown University, comparing placebo (n=39) versus flavocoxid (n=29) at 250 mg per day.88 No changes in blood electrolytes, serology, liver enzymes, renal markers, or general health were observed in this study. Any adverse events from flavocoxid were found to be comparable to placebo. Concurrently, initial efficacy testing was conducted at McGill University in Canada, comparing placebo (n=15), flavocoxid (n=15) at 125 mg BID, flavocoxid (n=15) at 250 mg BID, and celecoxib (n=15) at 100 mg BID. Significant reductions in pain and stiffness, as well as improvements in mobility, were observed for flavocoxid at both doses compared with celecoxib.90 These initial safety and efficacy studies were completed almost a year before marketing of flavocoxid as a medical food began in Puerto Rico in March of 2004.
In the GOAL study, a total of 1067 individuals at 41 rheumatology practices were enrolled and prescribed flavocoxid, 500 mg BID, for 60 days. The Physician Global Assessment of Disease (PGAD) visual analog scale (VAS) was used as a global measure to assess signs and symptoms of osteoarthritis (OA), including joint discomfort, functional stiffness, functional mobility and quality of life. In, addition, GI tolerability was assessed by individual questions scored on a 5-part Likert scale. Of the 1005 patients who completed all follow-up visits, physicians recorded an average improvement in VAS scores from 60.1 +18.8 at baseline to 42.5 +21.9 at 8 weeks (p<0.001) in 65.8% of patients, with the highest degree of improvement seen in those subjects with moderate-to-severe OA at baseline. An additional important finding was that, of those patients who had previously paused or interrupted their use of NSAID due to upper GI-related issues, ~90% tolerated flavocoxid and completed the study. The use of flavocoxid also resulted in a >30% reduction or cessation of the use of gastroprotective medications such as proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2s) in subjects.91
Post-Marketing Reported Adverse Events
Since the release of flavocoxid in 2004, there have been 4 reported cases of acute liver toxicity and elevated liver enzymes, which were attributed to individual reactions to flavocoxid. All subjects were women, ranging in age from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months of starting flavocoxid and demonstrated elevated liver function tests (LFTs) and serum bilirubin. All serum markers returned to normal within 3 to 12 weeks after flavocoxid was discontinued, and all patients recovered without experiencing acute liver failure of chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient.92
There have also been 7 confirmed reports of hypersensitivity pneumonitis.93 These events occurred sporadically and without warning or apparent predisposing factors. All required cessation of flavocoxid, as well as treatment with supplemental oxygen and parenteral corticosteroids. This is in contrast to the reduction in respiratory adverse events of an infectious nature seen in clinical trials of flavocoxid against placebo94 and against naproxen.95 These types of lung events are extremely rare but you should be aware of them in the unlikely event that you encounter one.
All therapeutic products that have significant physiological effects may have some level of potential toxicity and adverse effects, even a medical food with GRAS status like flavocoxid. Considering the hundreds of thousands of prescriptions filled for flavocoxid vs the number of reported significant side effects, flavocoxid maintains an impressive safety record when compared to other anti-inflammatory agents. However, it is recommended to monitor liver function tests on your flavocoxid patients according to the schedule you usually use in your practice, just as you would consider doing with other anti-inflammatory agents or medications. Post-marketing surveillance data on flavocoxid is collected on an ongoing basis to evaluate adverse events of patients while on flavocoxid. Currently, over 100 000 patients have been monitored by self-reporting or by physician-reported incidences, with an adverse event rate of ~0.1%. In a 2009 clinical trial,94 sponsored by an NIH grant (Phase I SBIR Grant #: 1 R41 AR051232-01) and conducted at the University of Alabama-Birmingham, no significant differences were found, in terms of adverse effects, between osteoarthritis patients treated with flavocoxid (250 mg BID; n=30) or placebo (n=29).
Genomic/Protein Mechanism of Action (MOA) Data
Flavocoxid reduced the protein expression of COX-2 and 5-LOX, though not COX-1, presumably through an antioxidant mechanism of action (MOA) in a macrophage cell model.96 This MOA was correlated to decreased NFκB activation and increased IκBα expression, the cytoplasmic control factor of NFκB. The expression of NFκB is controlled in part by oxidative activation. Tumor necrosis factor-α (TNFα) gene and protein expression, as well as iNOS protein expression, were also decreased through the same mechanism. Consequently, levels of PGE2, LTB4 and nitric oxide (NO) metabolites were decreased due to the corresponding protein down-regulation. Flavocoxid acted as an antioxidant, decreasing malondialdehyde (a direct oxidative product of arachidonic acid) concentrations in cell culture. This MOA data was confirmed in a Duchene muscular dystrophy (DMD) animal model by Messina et al.97
The importance of this antioxidant mechanism cannot be underestimated, especially for the management of chronic discomfort that occurs in osteoarthritis. All the molecules produced from the COX-2, 5-LOX and iNOS pathways (eg, prostaglandins, leukotrienes, and nitric oxide) bind to and activate the pain receptors, causing nociceptive pain signals to be transmitted back to the brain. In addition, cytokines also bind these receptors, as do a myriad reactive oxygen species (ROS). Flavocoxid, indicated for the clinical dietary management of osteoarthritis under physician supervision, works in all of these pathways and as a direct antioxidant on most of the ROS.
Head-to-Head Comparative Clinical Trials: Flavocoxid vs Naproxen
Clinical trials of flavocoxid have continued with a well-controlled, head-to-head comparative study of 103 patients with OA of the knee, treated with either flavocoxid (500 mg BID) or naproxen (500 mg BID) for 4 weeks.98 Flavocoxid and naproxen showed comparable effectiveness at alleviating OA signs and symptoms, and both appeared generally safe, though the subjects taking naproxen experienced more edema and musculoskeletal discomfort as side effects. In addition, further substantiation that flavocoxid does not interact with aspirin, or affect bleeding times or platelet aggregation was conducted and published by Pillai et al (99). A larger, well-controlled, head-to-head comparative study (n=220) of flavocoxid (500 mg BID) vs naproxen (500 mg BID) for 12 weeks was then published by Levy et al, showing comparative improvements in OA, as reflected by Western Ontario and McMasters Universities Osteoarthritis Index [WOMAC] scores (Figure 2).95 The flavocoxid group also showed comparatively fewer adverse effects. Further substantiation that flavocoxid does not interact with aspirin or affect bleeding times or platelet aggregation was provided and published by Pillai et al.99 Newer work on flavocoxid has included the study of its effect on collagen-induced arthritis in animal models100 and its effects in an animal model of induced pancreatitis.101
Flavocoxid is currently available in two commercially marketed medical food products designed to be used under the supervision of a qualified licensed health care provider: 1) a medical food that is available in 250-mg and 500-mg versions through conventional prescription, and 2) a professionally dispensed (via licensed health care provider practice dispensary or authorized patient-direct order from the manufacturer) medical food product that also contains novel functional collagen peptides for joint health.
The concept of a “medical food” is a relatively recent one, and this product category is growing rapidly. Products now regarded as medical foods were first regulated as drugs by the FDA until 1972, when the agency issued an Advance Notice of Proposed Rulemaking (ANPR), which it has since withdrawn. In 1988, Congress established the legal category of medical foods in the Orphan Drug Amendment, which states that “medical foods” are designed to be orally consumed, administered under the supervision of a physician, specially formulated and processed (ie, cannot be derived at the given concentration or formulation through a change in diet alone), and intended for the specific dietary management of a disease or condition that has distinctive nutritional requirements.102 That definition was subsequently incorporated into the Nutrition Labeling and Education Act of 1990 (NLEA), wherein Congress exempted medical foods from the nutrition labeling, health claim, and nutrient disclosure requirements applied to most other foods. This has created a territory somewhere between supplement and drug where products can be marketed with the supported medical claims as long as they contain only ingredients with GRAS (Generally Recognized as Safe) status by the FDA (as supported by robust dossiers of consensus scientific support, including published direct human outcome data and toxicology data), and are labeled for the dietary management of a specific disease or condition that has distinctive nutritional requirements. These products are expressly required to follow “good scientific principles,” which broadly includes being supported by well controlled clinical and scientific studies (using the formulation in the finished product) recognized by experts in the field, such as peer review in recognized medical and scientific journals. This raises the bar for natural products well beyond what is currently required to produce and market a product in the nutritional supplement regulatory category, where the manufacturer is extremely restricted in making any disease or health-related claims for the product, even when support for the individual ingredients may exist in the literature.
While there are many traditionally used natural agents with anti-inflammatory properties in naturopathic and integrative medicine, there are not many that are backed by rigorous scientific studies proving safety and efficacy and which meet the standards of classification as a medical food. Flavocoxid is one of these well-studied natural compounds, and provides the integrative clinician with a reliable, proven, low-side-effect profile. Flavocoxid is a natural fit for the dietary management of metabolic inflammatory processes in conditions such as osteoarthritis.
David M. Brady, ND has 22 years of experience as an integrative clinical practitioner and over 18 years in health sciences academia as faculty and an administrator. He currently serves as the Vice Provost for the Division of Health Sciences, Director of the Human Nutrition Institute, and Associate Professor of Clinical Sciences at the University of Bridgeport in Connecticut. Dr Brady is the Chief Medical Officer for Designs for Health, Inc., is an expert consultant to the nutritional supplement and clinical laboratory industries, and is an internationally sought-after presenter on nutritional, naturopathic and integrative medicine. He has appeared on the plenary speaking panel of some of the largest and most prestigious conferences in the field, such as, IFM, ACAM, A4M, IHS, AANP, NWANP, and ACA-CON. Dr Brady has published numerous scientific papers and textbooks related to chronic pain, autoimmunity and functional gastroenterology and is a featured contributing author in the medical textbooks: Advancing Medicine with Food and Nutrients, 2nd Ed. (Kohlstadt I. Boca Raton, FL: CRC Press; 2012), Integrative Gastroenterology (Mullin G. New York, NY: Oxford Press, Weil Integrative Medicine Library; 2011) and Laboratory Evaluations for Integrative and Functional Medicine, 2nd Ed. (Bralley JA, Lord RS.. Duluth, GA: Metametrix Institute; 2008).
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